ACS Publications. Most Trusted. Most Cited. Most Read
The Chemistry of Kratom [Mitragyna speciosa]: Updated Characterization Data and Methods to Elucidate Indole and Oxindole Alkaloids
More

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Nat. Prod. 2020, 83, 7, 2165-2177
  • Open Access
Article

The Chemistry of Kratom [Mitragyna speciosa]: Updated Characterization Data and Methods to Elucidate Indole and Oxindole Alkaloids
Click to copy article linkArticle link copied!

  • Laura Flores-Bocanegra
    Laura Flores-Bocanegra
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    More by Laura Flores-Bocanegra
    Orcidhttp://orcid.org/0000-0002-1393-7834
  • Huzefa A. Raja
    Huzefa A. Raja
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    More by Huzefa A. Raja
    Orcidhttp://orcid.org/0000-0002-0824-9463
  • Tyler N. Graf
    Tyler N. Graf
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    More by Tyler N. Graf
    Orcidhttp://orcid.org/0000-0003-4145-2815
  • Mario Augustinović
    Mario Augustinović
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    More by Mario Augustinović
  • E. Diane Wallace
    E. Diane Wallace
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    More by E. Diane Wallace
  • Shabnam Hematian
    Shabnam Hematian
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    More by Shabnam Hematian
    Orcidhttp://orcid.org/0000-0002-0788-7615
  • Joshua J. Kellogg
    Joshua J. Kellogg
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    More by Joshua J. Kellogg
    Orcidhttp://orcid.org/0000-0001-8685-0353
  • Daniel A. Todd
    Daniel A. Todd
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    More by Daniel A. Todd
  • Nadja B. Cech
    Nadja B. Cech
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    More by Nadja B. Cech
    Orcidhttp://orcid.org/0000-0001-6773-746X
  • Nicholas H. Oberlies*
    Nicholas H. Oberlies
    Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    *E-mail: [email protected]
    More by Nicholas H. Oberlies
    Orcidhttp://orcid.org/0000-0002-0354-8464
Open PDFSupporting Information (1)

Journal of Natural Products

Cite this: J. Nat. Prod. 2020, 83, 7, 2165–2177
Click to copy citationCitation copied!
https://doi.org/10.1021/acs.jnatprod.0c00257
Published June 29, 2020

Copyright © 2020 American Chemical Society and American Society of Pharmacognosy. This publication is licensed under these Terms of Use.

Request reuse permissions

Abstract

Click to copy section linkSection link copied!
High Resolution Image
Download MS PowerPoint Slide

Two separate commercial products of kratom [Mitragyna speciosa (Korth.) Havil. Rubiaceae] were used to generate reference standards of its indole and oxindole alkaloids. While kratom has been studied for over a century, the characterization data in the literature for many of the alkaloids are either incomplete or inconsistent with modern standards. As such, full 1H and 13C NMR spectra, along with HRESIMS and ECD data, are reported for alkaloids 1–19. Of these, four new alkaloids (7, 11, 17, and 18) were characterized using 2D NMR data, and the absolute configurations of 7, 17, and 18 were established by comparison of experimental and calculated ECD spectra. The absolute configuration for the N(4)-oxide (11) was established by comparison of NMR and ECD spectra of its reduced product with those for compound 7. In total, 19 alkaloids were characterized, including the indole alkaloid mitragynine (1) and its diastereoisomers speciociliatine (2), speciogynine (3), and mitraciliatine (4); the indole alkaloid paynantheine (5) and its diastereoisomers isopaynantheine (6) and epiallo-isopaynantheine (7); the N(4)-oxides mitragynine-N(4)-oxide (8), speciociliatine-N(4)-oxide (9), isopaynantheine-N(4)-oxide (10), and epiallo-isopaynantheine-N(4)-oxide (11); the 9-hydroxylated oxindole alkaloids speciofoline (12), isorotundifoleine (13), and isospeciofoleine (14); and the 9-unsubstituted oxindoles corynoxine A (15), corynoxine B (16), 3-epirhynchophylline (17), 3-epicorynoxine B (18), and corynoxeine (19). With the ability to analyze the spectroscopic data of all of these compounds concomitantly, a decision tree was developed to differentiate these kratom alkaloids based on a few key chemical shifts in the 1H and/or 13C NMR spectra.

Copyright © 2020 American Chemical Society and American Society of Pharmacognosy

Subjects

what are subjects
The scientific literature on the chemical composition of kratom [Mitragyna speciosa (Korth.) Havil. Rubiaceae] dates back nearly 100 years, when the most studied alkaloid from this plant, mitragynine (1), was reported in 1921. (1) The introduction to that paper concludes with the following prescient statements: “According to Redley . . . Mitragyne [sic] speciosa is used in Perak against the opium habit, whilst, according to Dr. P.P. Laidlaw, mitragynine is a local anaesthetic, which finding is of interest, since the alkaloid contains an ester grouping.” At that time, there was uncertainty on the use of kratom. Interestingly, a century later, this uncertainty continues, including in the scientific literature, the popular press, and even government regulatory bodies. Many questions persist such as, does kratom ameliorate pain, can it be used as an opioid substitute, does it relieve opioid withdrawal symptoms, does its use precipitate trips to the emergency room, and is kratom harmful, harmless, or somewhere in between? Addressing these questions requires a thorough understanding of the chemical composition of kratom.
In the past decade there has been an explosion in the biomedical literature regarding at least some of the above questions, particularly case reports (Figure S1). There are reports that speak to its ability to address pain, broadly defined. (2−5) However, there are a similar number that suggest that it has opioid-like properties and, thus, may be an addiction liability. (6−15) Toward that end, the U.S. Food and Drug Administration has threatened to classify kratom as a schedule I controlled substance more than once, although at the writing of this paper, it has not done so. (16−19)
As part of a project to study the potential for interactions between herbal medicines and drugs, (20−24) our team was charged with generating reference standards of the kratom alkaloids. In doing so, we found many challenges and opportunities, largely due to gaps in the literature. Extensive chemical studies have been performed over the last century, resulting in the isolation of at least 54 alkaloids from the plant (see Figure S2), starting with the isolation of the main alkaloid, mitragynine (1), in 1921 by Ellen Field. (1) More than four decades later, and over a series of three manuscripts, Becket et al. and Zacharias et al. worked on the isolation, structure elucidation, and absolute configuration of 1. (25−27) Contemporaneously, the mitragynine diastereoisomers speciociliatine (2) and speciogynine (3) were reported. (28) A dozen years later, the fourth diastereoisomer, mitraciliatine (4), was described from the leaves of M. speciosa. (29) Like many alkaloids, a majority of isolation studies on new compounds from kratom were carried out between the 1960s and 1980s. (30−32) However, due to the growing popularity of this plant near the end of the last century, there was a renewed interest, resulting in the isolation of additional alkaloids (particularly minor constituents, which could be isolated due to advances in HPLC). (33,34) Despite this, most of the pharmacological studies on constituents from kratom have focused on mitragynine (1) and 7-hydroxymitragynine (see Figure S1). In general, the tetracyclic indole and pentacyclic oxindole alkaloids isolated from M. speciosa embody a few variations, which, collectively, show the interrelatedness of these compounds (see Figure S2). Some key motifs of the 54 known compounds from M. speciosa include a hydroxy or methoxy group at C-9, unsaturation at C-3, C-5, or C-18, hydroxylation at C-7, and various configurations at C-3, C-7, and/or C-20 (see Figure S2). (30−32)
It was necessary to isolate standards for the alkaloids present in the plant, because even though there are over 50 kratom alkaloids reported, only 13 are commercially available (Figure S2). Moreover, in some cases we found that the quality of the commercial standards was not optimal, being mixtures, or were not even the correct compound. (35,36) From a pharmacological testing point of view, this is a serious problem, especially for scientists that do not have the training or collaborations to verify structural identity, as it could perpetuate erroneous findings in the literature. For these reasons, we strove to develop a series of reference standards, being able to isolate and characterize 19 kratom alkaloids (1–19), including four new analogues (7, 11, 17, and 18). In doing so, we quickly realized that the reported spectroscopy data for some of the known compounds were limited, as is the case for many natural products. (37−41) Thus, we took the opportunity to contribute by analyzing the NMR, HRESIMS, and ECD data for 1–19, comparing the key differences between analogues.

Results and Discussion

Click to copy section linkSection link copied!
While there are some challenges associated with acquiring kratom plant material, (42) two different sources could be obtained on the kilogram scale, which were termed “Green Maeng Da” and “White Jongkong” by the suppliers. These samples were slightly different in appearance, with the former being ground leaf fragments (internally coded as K49) and the latter being a fine powder (internally coded as K52) (see Figure S6). The taxonomy of these was examined using a combination of molecular methods, specifically DNA barcoding and maximum likelihood phylogenetic analysis. For the purpose of molecular identification, the most widely recommended loci were analyzed, including the plastid intergenic spacer trnH-psbA, matK, and the nuclear ribosomal internal transcribed spacer (ITS), since these three regions have been designated as the official DNA barcodes for the plant kingdom. (43,44) Of these, trnH-psbA is a widely used plastid marker, which displays a high rate of insertion and deletion and, as such, is widely used for plant barcoding studies. (45−47) All three regions indicated that samples K49 and K52 could be unequivocally identified as Mitragyna speciosa. Maximum likelihood analysis of the partial matK region placed both commercial samples in a strongly supported clade (100% bootstrap support) with the published sequences for M. speciosa (Figure S3). Importantly, this analysis included a partial matK sequence from a recently sequenced genome of M. speciosa (BioProject: PRJNA325670). In addition, a BLAST search of matK using the BOLDSYSTEMS database (version 4) showed that samples K49 and K52 had ≥99% sequence similarity to M. speciosa (Figures S4 and S5). As a confirmatory measure, maximum likelihood analysis using the ITS region also indicated that both samples formed a strongly supported clade (≥99% bootstrap support) with published sequence data of M. speciosa (Figure S6). Based on uncorrected p-distances calculated for trnH-psbA, there was ≥99% sequence similarity to sequences of M. speciosa. This means that samples K49 and K52 were more similar to sequences of M. speciosa and more dissimilar to sequences of M. diversifolia, M. hirsuta, and M. rotundifolia (Tables S1 and S2). In short, three different methods all indicated that these materials were derived from M. speciosa. The sequence data were deposited in GenBank: matK: MT114409 and MT114408, trnH-psbA: MT114410 and MT114411, and ITS: MT111840, MT111841, MT111842, and MT111843.
Even though the sources of kratom (i.e., K49 and K52) were demonstrated to be M. speciosa based on DNA barcoding, chromatographic profiles generated via UPLC-HRESIMS (Figure S7) showed clear differences in the profile of secondary metabolites. For instance, mitragynine (1) was the most abundant alkaloid in the K49 materials, while the K52 materials contained higher levels of speciofoline (12) and related alkaloids. While those differences may be somewhat surprising, varied chemical composition for different sources of M. speciosa has been documented, where plant age, environmental factors, and processing conditions impact on the suite of kratom alkaloids. (48,49) For example, in one published study the content of 1 derived from a Thai specimen was approximately five times higher than that derived from a Malaysian specimen. (50) Additionally, alkaloid differences between M. speciosa grown in Asia/Africa vs the United States have been noted. (49,51) Thus, for the purpose of generating structurally diverse kratom alkaloid reference standards, we selected sample K49 for the isolation of indole-type alkaloids and sample K52 for the isolation of oxindole-type alkaloids using an alkaloid partitioning scheme. The indole alkaloids mitragynine (1), speciociliatine (2), speciogynine (3), mitraciliatine (4), paynantheine (5), (52) isopaynantheine (6), (29) epiallo-isopaynantheine (7), mitragynine-N(4)-oxide (8), (53) speciociliatine-N(4)-oxide (9), (53) isopaynantheine-N(4)-oxide (10), (54) and epiallo-isopaynantheine-N(4)-oxide 11 were isolated from the Green Maeng Da product (K49; see Figure S8), while the oxindole alkaloids speciofoline (12), (55) isorotundifoleine (13), (56) isospeciofoleine (14), (57) corynoxine A (15), (58,59) corynoxine B (16), (59) 3-epirhynchophylline (17), 3-epicorynoxine B (18), and corynoxeine (19) were isolated from the White Jongkong product (K52; see Figure S9). Details of the structure elucidation for these compounds, including the identification of four new kratom alkaloids (i.e., 7, 11, 17, and 18), are presented below, using a suite of spectroscopic and spectrometric techniques (HRESIMS), including ECD. In doing so, a decision tree was developed that can be used to differentiate between these kratom alkaloids based on a few key signals in the 1H and/or 13C NMR spectra (Figure 1). This flow diagram was designed to be helpful for those with only a limited understanding of structure elucidation, focusing on key signals that serve to differentiate between the various kratom alkaloid chemotypes.

Figure 1

Figure 1. Decision tree for differentiating among 1–19 based on key NMR signals. As a single starting point, the 13C NMR signal for the lactam moiety is used to distinguish between oxindole (present) and indole (absent) kratom alkaloids. Once the broad structural class is determined, 1H NMR data can be used via a flowchart as a guide to elucidate the structure of these alkaloids.

High Resolution Image
Download MS PowerPoint Slide

Indole Alkaloids: Mitragynine (1) and Its Diastereoisomers (2–4)

Four diastereoisomers with a molecular formula of C23H30N2O4 were isolated, specifically mitragynine (1), speciociliatine (2), speciogynine (3), and mitraciliatine (4), all of which were verified via HRESIMS data, where the protonated molecule displayed m/z 399.2274, 399.2273, 399.2274, and 399.2275 ions, respectively (Figures S10–S13). While the absolute amounts likely vary in different kratom plant materials, the quantity of compound 1 isolated was at least 20 times greater than that for each of the other diastereoisomers (i.e., >450 mg of 1 vs ∼20 mg of 2, 3, or 4). The 1H and 13C NMR data matched with those reported previously, (60) and key characteristics included (1) eight sp2 signals in the 13C NMR spectrum assignable to the indole moiety (C-2 and C-7 to C-13); (2) two doublets (δH-10 6.44–6.49 and δH-12 6.87–7.01) and one triplet (δH-11 6.99–7.07), all corresponding to the indole moiety; (3) signals for the vinylic proton at C-17 (δC/δH 160.2–160.7/7.32–7.44); (4) three methoxy groups attached to C-9, C-17, and C-22 (δC/δH 51.1–61.9/3.66–3.89); and (5) the methyl group at C-19 (δC/δH 11.1–13.0/0.74–0.89). Importantly, a thorough analysis of the differences between the characteristic signals permitted the unequivocal identification of compounds 1–4. For example, as Lee and colleagues described, (61) when a deshielded proton singlet assignable to H-17 appeared at δH 7.43 or 7.44 (i.e., compounds 1 and 2, respectively), it was indicative of the α orientation of H-20. Alternatively, a more shielded chemical shift for H-17 (i.e., δH 7.32 and 7.35 for compounds 4 and 3, respectively) indicated the β orientation for H-20. (61) Additionally, the orientation of H-20 could be confirmed orthogonally via the chemical shift of C-18, at δC of 12.5 or 13.0 (i.e., compounds 2 and 1, respectively) for the α orientation and δC of 11.1 (i.e., for both 3 and 4) for the β orientation. On the other hand, the presence of a broad singlet at δH 4.40 or 4.80 (i.e., compounds 2 and 4) agreed with the β orientation for H-3, but a signal at δH 3.20 or 3.21 (i.e., compounds 1 and 3) indicated the opposite orientation for the same proton (i.e., H-3α). Indeed, the ΔδH-3 values of the α and β orientations depend on the dihedral angle and the distance between H-3 and the nitrogen lone pair. An anticoplanar arrangement, as seen in the axial H-3 of the trans-fused system in compound 1 or 3 (i.e., α orientation), leads to shielding relative to the syn-coplanar arrangement of the equatorial proton (i.e., β orientation) in compound 2 or 4, which have a dihedral angle of ∼60° with the nitrogen lone pair. The donation of electron density into the antibonding orbital (i.e., n → σ*) of the axial C–H bond (i.e., α orientation) effectively results in the weakening of that bond and strong shielding of the proton (Figure S18). (62,63) Key NMR signals for 1–4 are outlined (Table 1), and in addition, full 1D NMR spectra and tables are reported in the Supporting Information (Figures S14–S17 and Table S4). Moreover, ECD spectra presented an additional approach for confirming the absolute configuration for these corynanthe-type alkaloids. It has been established that the Cotton effect between 250 and 300 nm could be used to establish the orientation of H-3, where a negative Cotton effect correlates with the β orientation (i.e., compounds 2 and 4) and a positive Cotton effect for the α orientation for H-3 (i.e., compounds 1 and 3; see Figure S19). (61)
Table 1. Characteristic 1H and 13C NMR Data for Compounds 1–4 (CDCl3, 400 and 100 MHz, Respectively)a
 mitragynine (1)speciociliatine (2)speciogynine (3)mitraciliatine (4)
positionδCtypeδH (J in Hz)δCtypeδH (J in Hz)δCtypeδH (J in Hz)δCtypeδH (J in Hz)
361.3CH3.20, d (8.4)54.7CH4.40, bs61.9CH3.21, m53.9CH4.80, s
1099.9CH6.45, d (7.7)99.8CH6.47, d (7.7)99.8CH6.44, d (7.8)99.7CH6.49, d (7.6)
11122.0CH7.00, t (7.9)122.4CH7.02, t (8.0)122.4CH6.99, t (7.9)122.6CH7.07, t (7.9)
12104.3CH6.90, d (8.1)104.5CH6.91, d (8.1)104.5CH6.87, d (8.0)104.9CH7.01, d (8.0)
17160.7CH7.43, s160.6CH7.44, s160.4CH7.35, bs160.2CH7.32, s
1813.0CH30.87, t (7.3)12.5CH30.89, t (7.9)11.1CH30.85, t (7.2)11.1CH30.74, t (7.0)
9-OCH355.5CH33.87, s55.3CH33.88, s55.4CH33.85, s55.3CH33.89, s
17-OCH361.7CH33.73, s61.7CH33.78, s61.9CH33.72, s61.8CH33.77, s
22-OCH351.5CH33.71, s51.6CH33.66, s51.1CH33.72, s51.5CH33.68, s
NH  7.74, bs  8.00, bs  7.94, bs  8.98, bs
a

See Table S4 for a full comparison of the 1H and 13C NMR data for 1–4 (Supporting Information).

Indole Alkaloids: Paynantheine and Its Diastereoisomers (Compounds 5–7)

The structures of paynantheine (5) and isopaynantheine (6) were established by comparisons with literature data. (57) Their molecular formulas were confirmed by HRESIMS as C23H28N2O4, where the protonated molecule showed an m/z of 397.2119 and 397.2117, respectively (Figures S20 and S21). The NMR data of 5 and 6 resembled those for compounds 1–4, sharing the previously enumerated characteristic signals for the indole ring. The main difference was the absence of signals for the C-20 ethyl moiety and its replacement for a vinylic moiety, as evidenced by two doublets of doublets (δH 4.89–5.01) and a doublet of doublet of doublets or a doublet of triplets (δH 5.25–5.57), consistent with a Δ18(19) double bond (δC-18 115.7–116.7 and δC-19 137.9–139.4). As with 1–4, the orientation of H-3 was deduced from chemical shift data, where the H-3α orientation was noted for 5 (δH 3.20), while the more deshielded shift in 6 (δH 4.73) indicated the H-3β orientation. These assignments were supported by the ECD spectra, where 5 and 6 had opposite Cotton effects at 250–300 nm. Specifically, a negative Cotton effect confirmed the β orientation (i.e., 6) and a positive Cotton effect confirmed the α orientation (i.e., 5) for H-3 (see Figure S33). Comparisons of the key NMR signals for compounds 5 and 6 are shown in Table 2, and the full 1D NMR spectroscopic data are reported in the Supporting Information (Figures S23–S24 and Table S5).
Table 2. Characteristic 1H and 13C NMR Data for Compounds 5–7 (CDCl3, 400 and 100 MHz, Respectively)a
 paynantheine (5)isopaynantheine (6)epiallo-isopaynantheine (7)
positionδCtypeδH (J in Hz)δCtypeδH (J in Hz)δCtypeδH (J in Hz)
360.1CH3.20, m53.8CH4.73, bs53.9CH4.85, bs
1099.9CH6.45, d (7.8)99.7CH6.49, d (7.6)99.7CH6.49, d (7.8)
11122.1CH7.00, t (7.9)122.6CH7.07, t (7.9)122.9CH7.08, t (7.9)
12104.3CH6.88, d (8.0)105.0CH7.02, d (8.1)105.0CH7.01, d (8.1)
17160.0CH7.33, s160.2CH7.28, s160.3CH7.28, s
18115.7CH25.01, dd (17.3, 2.0)116.7CH24.96, dd (17.2, 1.8)117.2CH24.98, dd (17.3, 1.7)
   4.96, dd (10.4, 2.1)  4.89, dd (10.2, 1.8)  4.91, dd (10.3, 1.8)
19139.4CH5.55, dt (17.9, 9.3)137.9CH5.29, ddd (18.0, 10.3, 8.3)137.1CH5.27, ddd (18.0, 10.3, 8.3)
9-OCH355.4CH33.88, s55.3CH33.89, s55.3CH33.88, s
17-OCH361.7CH33.78, s61.7CH33.76, s61.7CH33.76, s
22-OCH351.5CH33.69, s51.4CH33.67, s51.5CH33.67, s
NH  7.85, s  8.91, s  9.12, s
a

See Table S5 for a full comparison of the 1H and 13C NMR data for 5–7 (Supporting Information).

Compound 7 was isolated as an optically active yellow powder (αD20 +41, c 0.1 CHCl3), with a molecular formula of C23H28N2O4, deduced by HRESIMS, where the protonated molecule showed an m/z of 397.2115 (Figure S22). The 1H and 13C NMR data of 7 resembled those of compounds 5 and 6, sharing all the characteristic signals for an indole alkaloid with Δ18(19) unsaturation (see Tables 2 and S5 and Figures S23–S25). These observations, along with differences in chromatographic retention times (5: 7.5 min, 6: 7.0 min, and 7: 9.0 min; see Figure S34), suggested that 7 was a new diastereoisomer of 5 and 6. The HSQC data, along with COSY and HMBC correlations, were used to elucidate the structure of 7 (Figures S26–S28). For example, three isolated spin systems (specifically, H-10/H-11/H-12, H2-5/H2-6, and H-3/H2-14/H-15/H-20/H2-21/H-19/H2-18) and key HMBC correlations (i.e., H-3 to C-2/C-7, H-17 to C-15/C-22, H2-18 to C-20, CH3O-9 to C-9, CH3O-17 to C-17, and CH3O-22 to C-22) were used to confirm the skeleton for the proposed structure (Figure 2).

Figure 2

Figure 2. Key correlations observed in the COSY and HMBC spectra for compounds 7, 17, and 18. The latter two have the same 2D structure and thus the same correlations.

High Resolution Image
Download MS PowerPoint Slide
To establish the absolute configuration of 7, several complementary lines of reasoning were used. For instance, the deshielded signal at 4.85 ppm suggested H-3β, since that was similar to the chemical shift for the same position in compounds 2 (δH-3 4.40), 4 (δH-3 4.80), and 6 (δH-3 4.73), all of which have been established to be H-3β. Moreover, biogenetic assumptions were used for the C-15 configuration, since all the indole alkaloids from M. speciosa (42 compounds, to date) have the H-15α orientation. (32) Those considerations narrowed the possibilities for compound 7 to either the pseudo (i.e., 3β, 15α, and 20β) or epiallo (i.e., 3β, 15α, and 20α) orientation. (61) The known compound isopaynantheine (6) has the pseudo configuration, and thus, compound 7 is the 20-epimer of 6 (i.e., H-20α), yielding an overall configuration of epiallo; those considerations were used to suggest the trivial name epiallo-isopaynantheine (7). In addition, ECD spectroscopy was used as an orthogonal probe of the proposed configuration. The spectrum for the epiallo configuration (i.e., 3β, 15α, and 20α) was calculated using a time-dependent DFT (TDDFT) method at the B3LYP/6-31G+(d) level of theory, demonstrating concordance, including the aforementioned negative Cotton effect at ca. 275 nm that confirmed the H-3β orientation (Figure 3). The NOESY spectra of compounds 6 and 7 were compared as well (Figures S29–S31). However, these data were inconclusive, since clear differences could not be discerned. This could be explained based on atomic distances, which were measured for the most stable conformers; in all cases these distances were <5 Å (Figure S31). Collectively, the amalgamation of NMR and ECD data and biogenetic considerations were used to establish the (3R,15S,20S) absolute configuration of the new indole alkaloid, epiallo-isopaynantheine (7).

Figure 3

Figure 3. Experimental ECD spectrum of 7 in CH3OH at 0.2 mg/mL (dashed line) and calculated ECD spectrum of (3R,15S,20S)-7 (dotted line).

High Resolution Image
Download MS PowerPoint Slide

N(4)-Oxides of Indole Alkaloids (8–11)

Compounds 8 and 9 had identical molecular formulas (C23H30N2O5), as determined by HRESIMS, where the protonated molecules displayed an m/z of 415.2234 (8) and 415.2237 (9) (see Figures S35 and S36). This indicated that 8 and 9 had one extra oxygen atom compared to the diastereoisomers 1–4. 1H and 13C NMR spectra of both had strong similarities to the spectroscopic data reported for mitragynine-N(4)-oxide, sharing the characteristic NMR signals for the N(4)-oxide indole alkaloids (δH-10 6.43, δH-11 6.99–7.03, δH-12 6.92–6.95, δC-17/δH-17 161.3–161.5/7.45–7.46, δC-18/δH-18 11.8–12.7/0.85–0.93, δC-21/δH-21 68.5–68.6/3.53–3.72, δC-5/δH-5 65.8–65.9/3.51–3.98, and three methoxy groups δC/δH 51.6–62.1/3.61–3.86). (30) The main difference between the spectra for compounds 8 and 9, relative to those discussed above for 1–4, was deshielding of the signals attributed to H-3, H2-5, and H2-21, which was caused by a coordinate covalent bond in the N(4)-oxide group. There is an important distinction with the N-oxides, relative to the other kratom alkaloids, in that the ΔδH-3 value is small (∼0.12 ppm) and does not correlate with the orientation of H-3. As noted in the discussion of 1–4, the ΔδH-3 values of diastereoisomers mainly depend on the extent of interaction between the nitrogen free electron pair and the C–H antibonding orbitals. However, for the N-oxides, such an effect is not possible, since the electron pair is shared with the oxygen (i.e., N+–O– group). For the N-oxides, the positive charge on the nitrogen has a strong electron-withdrawing inductive effect, resulting in decreased electron density regardless of whether the α-protons are axial or equatorial. In both compounds, the deshielded signal for the vinylic proton at δH-17 7.45–7.46 indicated the α orientation for H-20, analogous to compounds 1 and 2. In addition, H-15 was presumed to have the α orientation, based on the biogenetic considerations discussed for compound 7. Therefore, 8 and 9 could have the allo (i.e., 3α, 15α, and 20α) or the epiallo (i.e., 3β, 15α, and 20α) configurations. This illustrates another advantage of analyzing the ECD spectra of kratom alkaloids, particularly the Cotton effect at ca. 275 nm. Compounds 8 and 9 had opposite effects at ca. 275 nm, where a positive Cotton effect correlated with the H-3α orientation (i.e., 8) and a negative Cotton effect indicated the H-3β orientation (i.e., 9). In turn, these data allowed us to assign these compounds as mitragynine-N(4)-oxide (8) (30) and speciociliatine-N(4)-oxide (9). This is the first report of NMR characterization data for 9, and key NMR signals for 8 and 9 are collated in Table 3, with full 1D NMR data reported in the Supporting Information (see Figures S39 and S40 and Table S6).
Table 3. Characteristic 1H and 13C NMR Data for Compounds 8–11 (CDCl3, 400 and 100 MHz, Respectively)a
 mitragynine-N(4)-oxide (8)speciociliatine-N(4)-oxide (9)isopaynantheine-N(4)-oxide (10)epiallo-isopaynantheine-N(4)-oxide (11)
positionδCtypeδH (J in Hz)δCtypeδH (J in Hz)δCtypeδH (J in Hz)δCtypeδH (J in Hz)
366.9CH5.16, s66.0CH5.04, d (12.5)69.2CH5.04, bs69.6CH4.91, bs
1099.7CH6.43, d (7.7)99.8CH6.43, d (7.7)99.9CH6.49, d (7.8)99.8CH6.48 d (7.7
11123.3CH7.03, t (7.9)122.7CH6.99, t (7.9)123.8CH7.11, t (7.9)123.6CH7.10, t (7.9)
12105.2CH6.95, d (8.1)106.3CH6.92, bs105.1CH7.03, d (8.2)105.2CH7.04, d (8.1)
17161.5CH7.45, s161.3CH7.46, s160.5CH7.31, s160.5CH7.30, s
1812.7CH30.93, t (7.2)11.8CH30.85, t (7.4)118.0CH25.02, dd (17.5, 1.0)117.8CH25.02, d (17.2)
         4.95, dd (10.2, 1.7)  4.94, dd (10.3, 1.6)
9-OCH355.2CH33.85, s55.3CH33.86, s55.3CH33.88, s55.3CH33.87, s
17-OCH362.1CH33.80, s61.9CH33.85, s62.0CH33.80, s62.0CH33.79, s
22-OCH351.6CH33.61, s51.8CH33.68, s51.6CH33.68, s51.6CH33.68, s
NH  9.46, s     8.84, s   
a

See Table S6 for a full comparison for the 1H and 13C NMR data for 8–11 (Supporting Information).

A similar set of observations were used to assign the structures of compounds 10 and 11, which were isolated as orange powders with a molecular formula of C23H28N2O5 as calculated by HRESIMS via a protonated molecule with an m/z of 413.2079 (10) and 413.2077 (11) (Figures S37 and S38). For instance, the NMR data for 10 and 11 were similar to those reported for isopaynantheine-N(4)-oxide (Table 3). These NMR data also resembled those of 8 and 9, where the main difference was the lack of the C-20 ethyl group (10 and 11), which was replaced with a vinylic group (see Table 3). In both cases, the signals for the vinylic proton appeared at δH-17 7.30–7.31, which was similar to the shifts in compounds 6 and 7. Again, ECD data were helpful, where the negative Cotton effects at ca. 275 nm correlated with the H-3β orientation for both 10 and 11 (Figure S47). Additionally, a comparison of the ECD spectra of compounds 10 and 6 showed striking similarities; the same was true when comparing compounds 11 and 7 (see Figure S46). Therefore, compound 10 had the pseudo configuration (3β, 15α, and 20β; i.e., as seen in 6) and 11 had the epiallo configuration (3β, 15α, and 20α; i.e., as seen in 7). To confirm the absolute configuration of the new compound 11, the method described by Shellard and colleagues (53) was used. Briefly, 11 was reduced by addition of H2SO4, and the reaction product should correspond to the indole alkaloid without the oxide. Indeed, the 1H NMR spectrum for the reduced product of 11 matched the spectrum of 7 (Figure S46). Collectively, these data permitted the characterization of these compounds as isopaynantheine-N(4)-oxide (10) and the new kratom alkaloid epiallo-isopaynantheine-N(4)-oxide (11). The spectroscopic data for both are reported in the Supporting Information (Figures S41–S45 and Table S6).

Oxindole Alkaloids: 9-Hydroxylated Oxindoles like Speciofoline (12–14)

Compound 12 had a molecular formula of C22H28N2O5, based on the protonated HRESIMS molecule with an m/z of 401.2067 (Figure S48). Comparison of the NMR data with key NMR signals in the 1H and 13C spectra reported previously permitted the identification of this compound as speciofoline (12) (Table 4). (55,56) This compound, which is one of the main alkaloids present in kratom (e.g., >55 mg isolated in this study), was first reported in 1963. (55) We have included the full spectroscopic data for 12 to serve as a reference point when analyzing the spectroscopic data for some of the more minor oxindole alkaloids. For instance, the C-ring (i.e., the pyrollidine ring) of 12 is connected to the γ-lactam (i.e., B-ring) through a C-7 spiro carbon, and this results in characteristic signals in the 13C NMR spectrum at δC 180.2 and 57.3 for the carbonyl in the oxindole ring and the spiro C-7 carbon, respectively (Table 4); the lactam signal, in particular, serves to quickly differentiate between indole and oxindole alkaloids (see Figure 1). Other important NMR signals, which are similar to those discussed above for the indole alkaloids, include (1) signals for the indole system (δH-10 6.35, δH-11 7.05 and δH-12 6.53); (2) a vinylic H-17 (δC/δH 159.8/7.38); (3) two methoxy groups at C-17 and C-22 (δC/δH 61.3/3.79 and δC/δH 51.7/3.65, respectively), and (4) a methyl group (δC-18/δH-18 12.3/0.83). Key NMR signals for 12 are tabulated (Table 4), and the full 1D NMR spectroscopic data are reported in the Supporting Information (Figure S51 and Table S7).
Table 4. Characteristic 1H and 13C NMR Data for Compounds 12–14 (CDCl3, 500 and 125 MHz, Respectively)a
 speciofoline (12)isorotundifoleine (13)isospeciofoleine (14)
positionδCtypeδH (J in Hz)δCtypeδH (J in Hz)δCtypeδH (J in Hz)
2180.2C 177.7C 179.1C 
363.8CH3.06, dd (11.7, 3.6)66.6CH3.39, dd (12.5, 3.6)68.7CH2.68, dd (11.6, 3.2)
757.3C 55.9C 57.5C 
9154.6C 155.1C 154.6C 
10111.9CH6.35, d (7.6)112.1CH6.30, dd (7.6, 0.8)111.4CH6.36, dd (7.6, 0.7)
11129.6CH7.05, t (8.0)129.2CH7.02, dd (8.3, 7.7)129.6CH7.06, dd (8.3, 7.7)
12101.1CH6.53, d (8.3)100.3CH6.52, dd (8.5, 0.8)101.0CH6.58, d (8.3)
17159.8CH7.38, s159.8CH7.27, s159.9CH7.19, s
1812.3CH30.83, d (7.4)116.4CH25.01, m 4.96, m116.4CH24.97, m 4.95, m
1924.2CH21.21, dqd (14.0, 6.8, 2.8)138.8CH5.43, dt (18.7, 9.1)138.6CH5.49, dt (17.3, 9.5)
17-OCH361.3CH33.79, s61.7CH33.79, s61.5CH33.71, s
22-OCH351.7CH33.65, s51.3CH33.68, s51.2CH33.59, s
NH  8.44, s  7.45,s  7.60, s
a

See Table S7 for a full comparison of the 1H and 13C NMR data for 12–14 (Supporting Information).

Additionally, two other 9-hydroxylated oxindole alkaloids were isolated and characterized as isorotundifoleine (13) and isospeciofoleine (14). The molecular formula for both isomers was C22H26N2O5 as measured by HRESIMS based on protonated molecules with m/z values of 399.1909 and 399.1906, respectively (Figures S49 and S50). The structures were elucidated by comparing the NMR data with those reported previously (Table 4), (56,57) and the full assignment of the 1H and 13C NMR spectroscopic data for both are reported in the Supporting Information (Figures S52 and S53 and Table S7); this is the first report of comprehensive NMR data for 13. The NMR data for both 13 and 14 resembled those described above for speciofoline (12), with a major difference being the absence of the methyl group (i.e., C-18 in 12 at δC/δH 12.3/0.83), which was replaced by the Δ18(19) double bond (δC/δH 116.4/4.95–5.01 and δC/δH 138.6–138.8/5.43–5.49, respectively, for 13 and 14). As with the indole alkaloids, ECD spectra were instrumental in assigning the configuration of these compounds, especially for analyzing the C-7 spiro center. According to the literature, the negative Cotton effect at 290 nm confirmed the (7R) configuration in compounds 12 and 13, and the positive Cotton effect agreed with the (7S) configuration in compound 14. Additionally, the negative Cotton effect around 250 nm confirmed the H-3β orientation in compounds 12 and 14, whereas the opposite Cotton effect demonstrated the H-3α orientation in 13. These results agreed with the rules for ECD spectra for the 9-hydroxylated oxindole alkaloids, and a calculated ECD spectrum was generated for 12 as a confirmatory measure (see Figure S54). (56,64)

Oxindole Alkaloids: 9-Unsubstituted Oxindoles Such as Corynoxine A (15–19)

Two closely related isomers, 15 and 16, were isolated with a molecular formula of C22H28N2O4, based on HRESIMS protonated molecules with m/z values of 385.2119 (i.e., 15) and 385.2127 (i.e., 16) (Figures S55 and S56). The compounds were characterized using 1H and 13C NMR data as corynoxine A (15) and corynoxine B (16), based on concordance with published data for synthetic standards of these compounds (Tables 5 and S8 and Figures S60 and S61). (65) In addition, the NMR data for 15 and 16 resembled those described for 12, with the main difference being replacement of the C-9 phenolic group with an aromatic proton, which resulted in a pattern of two doublets and two triplets of doublets for the protons in the oxindole ring (H-9 to H-12, see Table 5). Both 15 and 16 had the allo configuration (i.e., 3α, 15α, and 20α), with opposite configurations at the spiro C-7, being (7S) for 15 and (7R) for 16. As Trager and colleagues reported, (64) the configuration at C-7 can be deduced based on the chemical shift for the H-9 signal. For instance, when presuming the allo configuration, the presence of a deshielded signal for H-9 (δH 7.45) confirmed the (7S) configuration for 15 and the (7R) configuration in 16 due to the more shielded signal for H-9 (δH7.19). While 15 was stable, an interesting challenge with compound 16 was its interconversion to 15 over a period of about 8 days in CDCl3 (see Figure S62). As reported previously, (66) the epimerization process increases under acidic conditions via an intermolecular Mannich reaction, resulting in a ratio of ∼70:30 of 15 and 16, respectively (see Figure S62). As such, only the ECD spectrum of 15 is reported, supporting the (7S) and the allo configurations based on negative Cotton effects around 290 and 250 nm (Figure S76).
Table 5. Characteristic 1H and 13C NMR Data for Compounds 15–19 (CDCl3, 500 and 125 MHz, Respectively)a
 corynoxine A (15)corynoxine B (16)3-epirhynchophylline (17)3-epicorynoxine B (18)corynoxeine (19)
positionδCtypeδH (J in Hz)δCtypeδH (J in Hz)δCtypeδH (J in Hz)δCtypeδH (J in Hz)δCtypeδH (J in Hz)
2182.4C 182.3C 181.2C 182.2C 181.0C 
373.2CH2.41, dd (11.3, 2.7)76.5CH2.24, bd (11.2)77.4CH2.19, dd (11.4, 2.4)77.0CH2.19, d (10.9)75.2CH2.30, dd (11.3, 2.5)
9125.0CH7.45, d (7.4)123.2CH7.19, d (7.4)123.3CH7.20, d (7.5)123.4CH7.20, d (7.8)123.5CH7.22, d (7.8)
10122.5CH7.05, td (7.6, 1.0)122.5CH7.01, td (7.5, 1.0)122.5CH7.02, td (7.6, 1.0)122.9CH7.02, td (7.5)122.7CH7.05, td (7.6, 1.0)
11127.4CH7.17, td (7.7, 1.3)127.9CH7.16, td (7.7, 1.0)127.8CH7.16, td (7.7, 1.2)128.1CH7.17, t (7.7)128.0CH7.18, td (7.7, 1.2)
12109.5CH6.86, d (7.7)109.5CH6.87, d (7.7)109.1CH6.81, d (7.7)109.6CH6.80, d (7.7)109.2CH6.82, d (7.7)
1813.0CH30.87, t (7.4)13.4CH30.86, t (7.4)13.5CH30.86, t (7.4)13.3CH30.86, t (7.3)115.6CH24.95, ddd (17.2, 2.01, 0.8) 4.90, dd (10.2, 2.1)
1919.4CH21.10, dqd (15.7, 7.8, 2.9) 1.65, dq (14.3, 7.2)19.3CH21.77, ddq (14.2, 11.1, 7.1) 1.18, m19.3CH21.78, ddq (13.6, 11.2, 7.2) 1.18, dq (14.7, 7.7)19.8CH21.80, m 1.17, dq (14.5, 7.3)139.6CH5.51, dt (18.0, 9.1)
17-OCH361.2CH33.51, s61.6CH33.57, s61.7CH33.67, s61.7CH33.69, s61.7CH33.74, s
22-OCH351.3CH33.59, s51.4CH33.61, s51.4CH33.63, s51.4CH33.63, s51.4CH33.62, s
NH  8.40, s  8.91, s  7.62, s  7.33, s  7.53, s
a

See Table S8 for a full comparison of the 1H and 13C NMR data for 15–19 (Supporting Information).

Compounds 17 and 18 were isolated as optically active powders ([α]D23 −30 (c 0.1, CHCl3) and [α]D24 −46 (c 0.1, CHCl3), respectively). Their molecular formulas were established as C22H28N2O4 based on the HRESIMS protonated molecule with m/z values of 385.2119 (i.e., 17) and 385.2120 (i.e., 18) (Figures S57 and S58). The 1H and 13C NMR spectra of these compounds were similar to those of 15 and 16 (Table 5). These data, along with their different retention times (17: 2.76 min and 18: 2.87 min) (see Figures S57 and S58), suggested that 17 and 18 were new isomers of 15 and 16. The HSQC data, along with COSY and HMBC correlations, were used to confirm the proposed structures. In both cases, three isolated spin systems (specifically H-9/H-10/H-11/H-12, H2-5/H2-6, and H-3/H2-14/H-15/H-20/H2-21/H2-19/H3-18) and key HMBC correlations (i.e., H-3 to C-2/C-7, H-17 to C-15/C-22, H3-18 to C-20, CH3O-17 to C-17, and CH3O-22 to C-22) were used to confirm the 2D structures of 17 and 18 (see Figures 2 and S63–S66 and S69–S72). Similar to the discussion for 6 and 7, the correlations observed in the NOESY spectra for 17 and 18 were not useful to determine the relative configuration for these compounds (Figures S67 and S73). The absolute configuration of these molecules was proposed based on ECD experiments, following the rules described for the 9-unsubstituted oxindole alkaloids. In particular, the related isomer rhyncophylline served as a reference, since the crystal structure for this compound has been published and the ECD data were well described. (64,67) For instance, both 17 and 18 had the (7R) configuration, based on positive Cotton effects around 290 nm, and the H-3β orientation, as noted by positive Cotton effects around 250 nm (Figure S76). Using biogenetic reasoning for the H-15α orientation, along with the evidence observed in the ECD data, we deduced that compounds 17 and 18 should have the pseudo (i.e., 3β, 15α, and 20β) or epiallo (i.e., 3β, 15α, and 20α) configurations. To evaluate that presumption, the ECD spectra for the diastereoisomers at C-20 were calculated using a TDDFT method at the B3LYP/6-31G+(d) level of theory. The results showed that the calculated ECD spectrum for H-20β matched with the ECD spectrum for 17, and similarly, the calculated ECD spectrum for an analogue with the H-20α orientation matched with the ECD spectrum for compound 18 (Figure 4). NMR data, biogenetic considerations, and the examination of ECD spectra were used to establish the absolute configuration of the new oxindole alkaloids (3R,7R,15S,20R)-3-epirhynchophylline (17) and (3R,7R,15S,20S)-3-epicorynoxine B (18).

Figure 4

Figure 4. (A) Experimental ECD spectra of 17 in CH3OH at 0.2 mg/mL (dashed lines) and calculated ECD spectrum of (3R,7R,15S,20R)-17 (dotted lines). (B) Experimental ECD spectra of 18 in CH3OH at 0.2 mg/mL (dashed lines) and calculated ECD spectrum of (3R,7R,15S,20S)-18 (dotted lines).

High Resolution Image
Download MS PowerPoint Slide
Compound 19 was isolated as a white powder, and its molecular formula was established as C22H26N2O4, based on the HRESIMS protonated molecule with an m/z of 383.1964 (Figure S59). The NMR data for this compound showed strong similarities to the data of 15–18, where the main differences were the absence of the signals for the C-20 ethyl group, which was replaced by a vinylic group (Tables 5 and S8). The NMR data (Figure S75 and Table S8) matched with those reported for corynoxeine. (68) ECD data corroborated the H-3α orientation based on the negative Cotton effect around 250 nm, and the (7R) configuration based on the positive Cotton effect around 290 (Figure S76).
To add complementary data to the structural characterization of the kratom alkaloids, an attempt was made to analyze compounds 1, 6, 7, 15, 17, and 18 by VCD, so as to examine a range of both indole and oxindole alkaloids. However, in all cases the similarities between calculated and experimental data were low, ranging between 57.7% and 70.0% (Table S9). In contrast, prominent recent VCD results published in this Journal report similarities ranging from 74.1% to 98.5%. (69−73) In particular, we were surprised at the lack of concordance with the data for mitragynine (1), since it has been so well characterized, including by X-ray crystallography. (27) Thus, the purity of 1, 6, 7, 15, 17, and 18, was examined after the completion of the VCD studies, and indeed, it was obvious that the compounds decomposed during the experiments (see Figure S77). On the basis of the 1H NMR spectra (data not shown), we hypothesize that epimers were formed, likely as a result of the VCD data being recorded at elevated temperatures in CHCl3 for up to 18 h; the epimerization potential of these compounds has been reported. (66) While disappointing, we determined that analysis of VCD spectra is not helpful for this class of compounds, at least with current technologies, due to their lack of stability under the analytical conditions.
In summary, 19 reference standards were isolated from kratom plant materials, including the two new indole alkaloids 7 and 11 and the two new oxindole alkaloids 17 and 18. To characterize their structures, including absolute configuration, a combination of mass spectrometry and NMR and ECD spectroscopy was utilized. An added benefit of analyzing the NMR spectroscopy data for a suite of closely related compounds was that it facilitated the development of a decision tree (Figure 1). Using only a few key NMR signals, even a relative novice should be able to narrow the possible structures for at least these kratom alkaloids, and an expert is encouraged to examine a full suite of NMR data in relation to those reported in the Supporting Information. It is our hope that improvements in the structural characterization of the kratom alkaloids will result in more clarity in the biomedical literature on this interesting class of compounds.

Experimental Section

Click to copy section linkSection link copied!

General Experimental Procedures

Optical rotations were obtained in CHCl3 using a Rudolph Research Autopol III polarimeter. UV and ECD spectra were acquired on a Varian Cary 100 Bio UV–vis spectrophotometer and an Olis DSM 17 CD spectrophotometer, respectively. A ChiralIR-2X dual-source, dual-polarization-modulated FT-VCD spectrometer was used to carry out IR and VCD measurements. NMR experiments were conducted using either a JEOL ECA-500 NMR spectrometer operating at 500 MHz for 1H and 125 MHz for 13C or a JEOL ECS-400 NMR spectrometer equipped with a high-sensitivity JEOL Royal probe operating at 400 MHz for 1H and 100 MHz for 13C; the residual solvent signals were utilized for referencing. HRESIMS was performed on a Thermo LTQ Orbitrap XL mass spectrometer equipped with an electrospray ionization source. UPLC was carried out on a Waters Acquity system with data collected and analyzed using Thermo Xcalibur software. HPLC was carried out using a Varian ProStar HPLC system equipped with ProStar 210 pumps and a ProStar 335 photodiode array detector (PDA), with data collected and analyzed using Galaxie Chromatography Workstation software (version 1.9.3.2). For preparative HPLC, a series of Phenomenex columns were used, including a Kinetex C18 (5 μm; 250 × 21.2 mm), a Luna CN (5 μm; 250 × 21.2 mm), and a Luna PFP (5 μm; 250 × 21.2 mm) all at a 20 mL/min flow rate. For UPLC, a Waters BEH C18 column (1.7 μm; 50 × 2.1 mm) was used with a 0.6 mL/min flow rate. Flash chromatography was performed on a Teledyne ISCO CombiFlash Rf 200 using various sizes of Silica Gold columns and monitored by UV and evaporative light-scattering detectors.

Plant Material, DNA Extraction, PCR, and Sequencing for Molecular Identification

The commercial kratom products used to prepare extracts [i.e., Green Maeng Da (K49, batch: M-1005, 4 kg) and White Jongkong (K52, batch: BN-1006, 1 kg)] were identified by DNA barcoding. The manufacturers reported these as both from Southeast Asia, with K49 being chipped leaf materials and K52 being a fine powder. Samples were handled using methods described previously for the DNA barcoding of commercial mushroom products. (74) Briefly, one scintillation vial was made from each product (see Figure S6), where the vial was filled with plant material from the top and middle layers of the commercial product, and these were labeled with product name, lot number, and batch number and stored at ambient temperature in a bench drawer. For DNA extractions, approximately 5 mg of plant powder was taken from the scintillation vial and transferred to a bashing bead tube with DNA lysis buffer provided by Zymo Research Quick-DNA plant/seed miniprep DNA extraction kit. DNA was extracted using procedures outlined in the Zymo Research plant DNA extraction kit. The plastid gene matK was PCR amplified with primer combination matK-xf and matK-MALP; (75,76) for psbA-trnH primer combination psbA-trnH (77) and for nuclear ITS, primer combinations ITS-u1 and ITS-u4 (78) were used for PCR and sequencing. All PCRs were amplified on an Applied Biosystems Veriti thermal cycler using PuReTaq Ready-To-Go PCR beads (GE Healthcare) with the above primers. The PCR reaction was carried out in 25 μL containing 5 μL of template DNA, 2.5 μL of BSA, 2.5 μL of 50% DMSO, and 1 μL of each forward and reverse primer at a concentration of 10 μM. The rest of the volume was made up to 25 μL by adding molecular biology grade water from Fisher Scientific. PCR thermocycler parameters for all fragments are outlined (Table S3). The PCR products were then run on an ethidium bromide-stained 1% agarose gel (Fisher Scientific) along with a 1 kb DNA ladder (Promega) to estimate the size of the amplified band. PCR products were purified using a Wizard SV gel and PCR clean-up system. Sanger sequencing of the purified PCR products was performed at Eurofins Genomics (http://www.operon.com/default.aspx) using BigDye Terminator v3.1 cycle sequencing. The sequencing was accomplished bidirectionally using both strands with the same primers used for the PCR amplification. Sequences were generated on an Applied Biosystems 3730XL high-throughput capillary sequencer. For both sequencing reactions, approximately 15 μL of PCR template was used along with 2 μM sequencing primers. Sequences were assembled with Sequencher 5.3 (Gene Codes), optimized, and then corrected manually when necessary; the latter step was to ensure that the computer algorithm was assigning proper base calls. Each sequence fragment was subjected to an individual NCBI GenBank, Basic Local Alignment Search Tool (BLAST) search as well as the BOLDSYSTEMS database to verify identity.

BLAST Search and DNA Barcoding

For identification of kratom plant material via DNA barcoding, one plastid region (matK) was utilized for plant identification by BLAST searching against the BOLDSYSTEMS database version 4. In addition, the sequences of matK were compared against an authentic partial sequence of matK from the Mitragyna speciosa genome assembly (Center for Food Safety and Applied Nutrition (CFSAN), part of the USDA). Uncorrected p-distances were calculated in Geneious, a bioinformatics desktop software package (http://www.biomatters.com), for sequences obtained from the psbA-trnH plastid region, which is considered as one of the most variable regions of angiosperm plants, as well as for the nuclear ITS region for the published sequence data from GenBank for Mitragyna spp. (79−81) including M. speciosa and the newly obtained sequences in this study. The p-distances were obtained by dividing the number of nucleotide differences by the total number of nucleotides being compared. An arbitrary cut-off proxy of ≥98–100% was applied as a criterion to designate similar species; therefore, to be considered the same species based on psbA-trnH and ITS sequence comparison, the taxa being compared would have ≥98% sequence similarity.

Molecular Phylogenetic Analysis

Maximum likelihood analysis was performed separately for both the nuclear ITS and the plastid matK region to place the kratom samples into a phylogenetic framework with published sequences of M. speciosa. Methods for maximum likelihood analysis have been outlined previously. (82)Nauclea officinalis (Rubiaceae) was used as an outgroup taxon in both nuclear ITS and matK analyses.

Extraction and Isolation of Kratom Alkaloids from Green Maeng Da

The kratom plant material (Green Maeng Da, 4 kg; Figure S8) was extracted with 10 L of CHCl3–CH3OH (1:1) and 500 mL of 10% aqueous KOH by maceration over 24 h at room temperature. The mixture was filtered, and the solvent was evaporated under reduced pressure. The dried extract was reconstituted in a solution of 1 M HCl and hexanes (1:1), transferred into a separatory funnel, and shaken vigorously. The hexanes phase was drawn off, the pH of the aqueous phase was adjusted to 9.0 with dropwise addition of concentrated NH4OH, and the alkaloids were extracted as the free base with CHCl3; after washing with neutral water, the organic phase was dried to yield 12 g of the alkaloid extract. This material was fractionated by normal-phase flash chromatography using a silica column (120 g) and a gradient solvent system of hexanes–CHCl3–CH3OH at a flow rate of 85 mL/min over 67 min to yield 11 pooled fractions.
Fraction 4 (500 mg) was subjected to reverse-phase HPLC using a CN column and a gradient system of 40:60 to 100:0 of CH3OH–H2O (10 mM NH4OAc in both phases) over 20 min with a flow rate of 20 mL/min. This process yielded eight subfractions, and fraction 8 was identified as compound 1 (450.5 mg).
Fraction 9 (1.1 g) was fractionated by normal-phase flash chromatography using a silica column (12 g) and a gradient system of hexanes–EtOAc–CH3OH using a flow rate of 30 mL/min to generate four subfractions. Subfraction 2 (40 mg) was purified by preparative HPLC over a CN column using a gradient of 70:30 to 100:0 of CH3OH–H2O (10 mM NH4OAc in both phases) over 20 min with a flow rate of 20 mL/min. This process yielded compounds 4 (13.1 mg) and 6 (15.2 mg). Subfraction 4 (800 mg) was subjected to flash chromatography using a silica column (12 g) via a gradient of CHCl3–CH3OH (10 mM NH4OAc in both phases) over 60 min with a flow rate of 30 mL/min to generate five fractions (F9-4_1 through F9-4_5). Fraction F9-4_3 was subjected to preparative HPLC over a Kinetex column using a gradient of 60:40 to 70:30 of CH3OH–H2O (10 mM NH4OAc in both phases) over 30 min with a flow rate of 20 mL/min; three fractions were collected, and the first fraction was characterized as compound 2 (20.5 mg). Fraction F9-4_4 (300 mg) was subjected to flash chromatography using a silica column (4 g) and a gradient of hexanes–acetone–CH3OH over 20 min at a flow rate of 18 mL/min to generate eight fractions. The second fraction was resolved by preparative HPLC over a CN column using a gradient of 50:50 to 100:0 of CH3OH–H2O (10 mM NH4OAc in both phases) over 20 min with a flow rate of 20 mL/min; this process yielded 16.5 mg of compound 7. The seventh fraction (16 mg) from F9-4_4 was subjected to preparative HPLC using a CN column and a gradient of 40:60 to 90:10 of CH3OH–H2O (10 mM NH4OAc in both phases) over 20 min with a flow rate of 20 mL/min; two fractions were collected, and the first fraction was characterized as compound 11 (2.3 mg). Fraction F9-4_5 (40 mg) was subjected to preparative HPLC over a Kinetex column with a gradient of 50:50 to 100:0 of CH3OH–H2O (10 mM NH4OAc in both phases) over 35 min with a flow rate of 20 mL/min; the third fraction was identified as 8 (10.5 mg).
Fraction 6 (680 mg) was subjected to a second fractionation using flash chromatography over a silica column (12 g) and a gradient of CHCl3–CH3OH (10 mM NH4OAc in both phases) over 60 min with a flow rate of 30 mL/min to generate five subfractions. Subfraction 1 (47 mg) was subjected to preparative HPLC over a CN column and a gradient system of 55:45 to 100:0 CH3OH–H2O (10 mM NH4OAc in both phases) over 25 min; the first and second fractions were identified as 5 (9.8 mg) and 3 (18.3 mg), respectively.
Fraction 8 (1.3 g) was fractionated by flash chromatography using a silica column (12 g) with a gradient of CHCl3–CH3OH (10 mM NH4OAc in both phases) over 25 min with a flow rate of 30 mL/min to generate four subfractions. Subfractions 3 (12.8 mg) and 4 (7.0 mg) were purified by preparative HPLC over a CN column and a gradient system of 50:50 to 100:0 CH3OH–H2O (10 mM NH4OAc in both phases) over 15 min at a flow rate of 20 mL/min to yield compounds 9 (5.7 mg) and 10 (4.5 mg), respectively.

Extraction and Isolation of Kratom Alkaloids from White Jongkong

The plant material (White Jongkong, 1 kg; Figure S9) was extracted exhaustively using the same procedure described above, to obtain 1.0 g of the dried extract. Normal-phase flash chromatography was used to separate the extract using a silica column (24 g) and a gradient system of hexanes–CHCl3–CH3OH over 52 min at a flow rate of 35 mL/min to generate 13 fractions. Fractions 3 (100 mg) and 4 (80 mg) were purified, separately, by preparative HPLC using a PFP column and a gradient of 70:30 to 100:0 CH3OH–H2O (10 mM NH4OAc in both phases) over 20 min at a flow rate of 20 mL/min to yield 38.2 mg of 15 (from fraction 3) and, separately, 52.5 mg of 16 and 3.5 mg of 13 (from fraction 4).
Fraction 5 (81 mg) was subjected to preparative HPLC over a PFP column using a gradient of 70:30 to 100:0 CH3OH–H2O (10 mM NH4OAc in both phases) over 20 min at a flow rate of 20 mL/min to generate nine subfractions, and subfraction 4 was identified as compound 12 (55.0 mg).
Fractions 6 (156 mg) and 7 (84 mg) were combined based upon their similar HPLC chromatographic profiles. The resulting fraction (240 mg) was resolved by flash chromatography over a silica column (12 g) using a gradient of hexanes–CHCl3–CH3OH over 25 min at a flow rate of 18 mL/min to generate 11 subfractions. Subfraction 2 (10.0 mg) was subjected to semipreparative HPLC over a PFP column using a gradient of 50:50 to 100:0 CH3OH–H2O (10 mM NH4OAc in both phases) over 20 min at a flow rate of 4.0 mL/min, yielding 17 (2.0 mg). Subfraction 4 (15 mg) was subjected to preparative HPLC over a PFP column using a gradient of 60:40 to 100:0 CH3OH–H2O (10 mM NH4OAc in both phases) over 20 min at a flow rate of 20.0 mL/min, yielding 14 (3.6 mg). Subfraction 5 (13 mg) was subjected to preparative HPLC over a PFP column using a gradient of 50:50 to 100:0 CH3OH–H2O (10 mM NH4OAc in both phases) over 20 min at a flow rate of 20.0 mL/min to generate four subfractions, where subfractions 2 and 3 were identified as 19 (1.7 mg) and 18 (1.1 mg), respectively.

Epiallo-isopaynantheine (7):

yellowish solid powder; [α]D20 +41 (c 0.1, CHCl3); UV (CH3OH) λmax (log ε) 233 (3.7), 339 (2.9) nm; 1H and 13C NMR see Table 2 and Table S5; HRESIMS m/z 397.2115 [M + H]+ (calcd for C23H29N2O4, 397.2127).

Epiallo-isopaynantheine-N(4)-oxide (11):

orange powder; [α]D23 +33 (c 0.1, CHCl3); UV (CH3OH) λmax (log ε) 219 (3.2), 244 (3.9) nm; 1H and 13C NMR see Table 3 and Table S6; HRESIMS m/z 413.2077 [M + H]+ (calcd for C23H29N2O5, 413.2076).

3-Epirhyncophylline (17):

white powder; [α]D23 −30 (c 0.1, CHCl3); UV (CH3OH) λmax (log ε) 219 (3.3), 244 (3.6) nm; 1H and 13C NMR see Table 5 and Table S8; HRESIMS m/z 385.2119 [M + H]+ (calcd for C22H29N2O4, 385.2127).

3-Epicorynoxine B (18):

white powder; [α]D24 −46 (c 0.1, CHCl3); UV (CH3OH) λmax (log ε) 217 (3.4), 246 (3.7) nm; 1H and 13C NMR see Table 5 and Table S8; HRESIMS m/z 385.2120 [M + H]+ (calcd for C22H29N2O4, 385.2127).

Computational Methods

The minimum energy structures were built with Spartan’10 software (Wavefunction Inc., Irvine, CA, USA). The conformational analysis was performed using the Monte Carlo search protocol under the MMFF94 molecular mechanics force field.
For the ECD prediction, the resulting conformers were minimized using the DFT method at the B3LYP/6-311G+(2d,p) level of theory. Then, the TDDFT method at the B3LYP/6-31G+(d) level of theory was employed for ECD calculations. The calculated excitation energy (nm) and rotatory strength in dipole velocity and dipole length forms were simulated into an ECD curve. All calculations were performed employing the Gaussian’09 program package (Gaussian Inc., Wallingford, CT, USA).

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00257.

  • 1H NMR, 13C NMR, and HRESIMS data for compounds 1–19; 2D NMR data (COSY, HSQC, and HMBC) for new compounds 7, 11, 17, and 18; ECD data for compounds 1–14 and 16–19 (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!
  • Corresponding Author
  • Authors
    • Laura Flores-Bocanegra - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States;  Orcidhttp://orcid.org/0000-0002-1393-7834
    • Huzefa A. Raja - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States;  Orcidhttp://orcid.org/0000-0002-0824-9463
    • Tyler N. Graf - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States;  Orcidhttp://orcid.org/0000-0003-4145-2815
    • Mario Augustinović - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    • E. Diane Wallace - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    • Shabnam Hematian - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States;  Orcidhttp://orcid.org/0000-0002-0788-7615
    • Joshua J. Kellogg - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States;  Orcidhttp://orcid.org/0000-0001-8685-0353
    • Daniel A. Todd - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
    • Nadja B. Cech - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States;  Orcidhttp://orcid.org/0000-0001-6773-746X
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

Click to copy section linkSection link copied!

This project was supported by the National Institutes of Health/National Center for Complementary and Integrative Health via the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center, U54 AT008909), including an Administrative Supplement for Validation Studies of Analytical Methods for Dietary Supplements and Natural Products. We thank our colleagues from UNC Greensboro (S. Knowles, Z. Al Subeh, and K. Cank) for evaluating the NMR decision tree.

References

Click to copy section linkSection link copied!

This article references 82 other publications.

  1. 1
    Field, E. J. Chem. Soc., Trans. 1921, 119, 887– 891,  DOI: 10.1039/CT9211900887
    Google Scholar
    1
    Mitragynine and mitraversine, two new alkaloids from species of Mitragyne
    Field, Ellen
    Journal of the Chemical Society, Transactions (1921), 119 (), 887-91CODEN: JCHTA3; ISSN:0368-1645.
    Mitragyne speciosa, extd. with alc., the alc. residue dissolved in AcOH and dild. to ppt. resin and chlorophyll and then made alk. with NH4OH, gave an amorphous ppt., from an AcOH soln. of which picric acid ppts. mitragynine picrate, C22H31O5N.C6H3O7N3, orange-red slender needles from glacial AcOH, or MeOH, m. 223-4°. Mitragynine, amorphous crysts., b5 230-40°, m. 102-6°, contains 3 MeO groups. Hydrochloride, rhombic leaflets from alc.-Et2O, m. 243°. Acetate, slender silky needles from AcOH-Et2O, m. 142°. Trichloroacetate, C22H31O5N.CCl3CO2H, needles from Me2CO-Et2O, m. .157°. The hydrolysis product of the acetate with EtONa is a dicarboxylic acid, C17H22N(OMe)-(CO2H)2, m. 280°. Distd. with CaO, a green oil was obtained from which a red picrate was prepd., m. 218°. Mitragynine may be a deriv. of indole or at least undergoes decompn. with the formation of such a substance. M. diversifolia, treated with alc. and AcOH as above, the AcOH soln. poured into H2O, made alk., extd. with Et2O, the Et2O extd. with 10% AcOH and this ext. made alk. gave 0.27% of the wt. of the leaves of mitraversine, C22H26O4N2, m. 237°. It contains 2 MeO groups. Hydrochloride, rhombic leaflets, m. 208-10°.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaB3MXhsFejsw%253D%253D&md5=4fff795e629ece791683dc1e20fe7ba2
  2. 2
    Vermaire, D. J.; Skaer, D.; Tippets, W. A. A. Pract. 2019, 12, 103– 105,  DOI: 10.1213/XAA.0000000000000857
    Google Scholar
    2
    Kratom and General Anesthesia: A Case Report and Review of the Literature
    Vermaire Deborah J; Skaer Deborah; Tippets William
    A&A practice (2019), 12 (4), 103-105 ISSN:.
    Kratom is a botanical substance derived from the Mitragyna speciosa plant, which grows naturally in Southeast Asia. Its active compounds include alkaloids with psychoactive and opioid properties. Low doses act as a stimulant, while higher doses cause analgesia and euphoria. As a drug of abuse, there are reports of seizure, acute psychosis, and death. Both the US Food and Drug Administration and the Drug Enforcement Agency warn against the use of kratom. Here is the first reported case of an anesthetic in a patient using kratom for chronic pain.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c7is1Sltw%253D%253D&md5=c4c6358769a2681fa5d432e565ba8a24
  3. 3
    Schmuhl, K. K.; Gardner, S. M.; Cottrill, C. B.; Bonny, A. E. Subst. Abus. 2019, 1– 4,  DOI: 10.1080/08897077.2019.1671945
    Google Scholar
    3
    Home induction and outpatient treatment of kratom use disorder with buprenorphine-naloxone: A case report in a young adult
    Schmuhl Kelsey K; Schmuhl Kelsey K; Cottrill Casey B; Gardner Spencer M; Cottrill Casey B; Bonny Andrea E
    Substance abuse (2019), (), 1-4 ISSN:.
    Background: The use of the natural product, kratom, has increased significantly in recent years. The active compounds in kratom have been shown to produce both opioid and stimulant-like effects. While kratom is marketed as a safe, non-addictive method to treat pain and opioid withdrawal, there have been reports demonstrating that kratom is physiologically addictive and linked to overdose deaths. A limited number of case-reports are available describing treatment of kratom use disorder in middle-aged adults, generally in the context of chronic pain and in inpatient settings. Our case is unique in that we describe outpatient treatment of kratom use disorder in a young adult with comorbid attention deficit hyperactivity disorder (ADHD) and in the absence of chronic pain. Case: A 20-year-old college student with ADHD presented to an office-based opioid agonist treatment clinic (OBOT) for treatment of kratom use disorder. He was unable to attend inpatient or residential substance use treatment due to work and school obligations. Additionally, he had stopped taking his prescribed stimulant due to cardiac side effects. The OBOT team successfully initiated buprenorphine-naloxone (BUP/NAL) sublingual films via home induction to treat his kratom use disorder. The patient is being monitored monthly with plans to slowly taper his BUP/NAL dose as tolerated. Discussion: We present a case of a young adult male with kratom use disorder, complicated by a diagnosis of ADHD, successfully treated with BUP/NAL via home induction. The patient is currently kratom-free, reports improved mood and sleep patterns since initiating BUP/NAL, and is able to once again tolerate his ADHD stimulant medication. Healthcare providers should be aware of the use of kratom and consider utilizing BUP/NAL to treat dependence to this botanical drug.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MjgvFemtw%253D%253D&md5=eedc1ff52346299b8be5d9893014f7b0
  4. 4
    Coe, M. A.; Pillitteri, J. L.; Sembower, M. A.; Gerlach, K. K.; Henningfield, J. E. Drug Alcohol Depend. 2019, 202, 24– 32,  DOI: 10.1016/j.drugalcdep.2019.05.005
    Google Scholar
    4
    Kratom as a substitute for opioids: Results from an online survey
    Coe, Marion A.; Pillitteri, Janine L.; Sembower, Mark A.; Gerlach, Karen K.; Henningfield, Jack E.
    Drug and Alcohol Dependence (2019), 202 (), 24-32CODEN: DADEDV; ISSN:0376-8716. (Elsevier Ireland Ltd.)
    Kratom is a South Eastern Asian tree whose leaves are used to make tea-like brews or swallowed in powd. form for various health and well-being reasons including to relieve pain and opioid withdrawal. It is important to learn more about the potential public health impact of kratom in the context of the opioid epidemic. An anonymous online survey of kratom users was conducted in Sept. 2017 through the American Kratom Assocn. and assocd. social media sites. Kratom was used primarily to relieve pain (endorsed by 48% of respondents), for anxiety, PTSD, or depression (22%), to increase energy or focus (10%) and to help cut down on opioid use and/or relieve withdrawal (10%). Over 90% of respondents who used it in place of opioids indicated that it was helpful to relieve pain, reduce opioid use, and relieve withdrawal. The reported incidence of bad adverse reactions was 13%, and reactions were overwhelmingly mild and self-managed. Respondents reported using kratom for conditions which often require use of opioids, including pain and redn. of opioid use. The high self-reported efficacy and low incidence of adverse reactions assocd. with kratom use suggest that it may provide a potential alternative to opioids for some persons even though it has not been evaluated in multi-center clin. trials or approved for any therapeutic purpose. Further study of kratom, including systematic characterization of its safety and efficacy for various conditions is warranted.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlejurvN&md5=879225fc2c5d7f7e617a63b695623eb9
  5. 5
    Buresh, M. J. Addict. Med. 2018, 12, 481– 483,  DOI: 10.1097/ADM.0000000000000428
    Google Scholar
    There is no corresponding record for this reference.
  6. 6
    Corkery, J. M.; Streete, P.; Claridge, H.; Goodair, C.; Papanti, D.; Orsolini, L.; Schifano, F.; Sikka, K.; Korber, S.; Hendricks, A. J. Psychopharmacol. 2019, 33, 1102– 1123,  DOI: 10.1177/0269881119862530
    Google Scholar
    6
    Characteristics of deaths associated with kratom use
    Corkery John M; Papanti Duccio; Orsolini Laura; Schifano Fabrizio; Sikka Kanav; Streete Peter; Claridge Hugh; Goodair Christine; Korber Sophie; Hendricks Amy
    Journal of psychopharmacology (Oxford, England) (2019), 33 (9), 1102-1123 ISSN:.
    BACKGROUND: Kratom (Mitragyna speciosa Korth) use has increased in Western countries, with a rising number of associated deaths. There is growing debate about the involvement of kratom in these events. AIMS: This study details the characteristics of such fatalities and provides a 'state-of-the-art' review. METHODS: UK cases were identified from mortality registers by searching with the terms 'kratom', 'mitragynine', etc. Databases and online media were searched using these terms and 'death', 'fatal*', 'overdose', 'poisoning', etc. to identify additional cases; details were obtained from relevant officials. Case characteristics were extracted into an Excel spreadsheet, and analysed employing descriptive statistics and thematic analysis. RESULTS: Typical case characteristics (n = 156): male (80%), mean age 32.3 years, White (100%), drug abuse history (95%); reasons for use included self-medication, recreation, relaxation, bodybuilding, and avoiding positive drug tests. Mitragynine alone was identified/implicated in 23% of cases. Poly substance use was common (87%), typically controlled/recreational drugs, therapeutic drugs, and alcohol. Death cause(s) included toxic effects of kratom ± other substances; underlying health issues. CONCLUSIONS: These findings add substantially to the knowledge base on kratom-associated deaths; these need systematic, accurate recording. Kratom's safety profile remains only partially understood; toxic and fatal levels require quantification.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mvps1Gluw%253D%253D&md5=3c7117b77f7cf98ad5b17be0bf1c4c6d
  7. 7
    Murthy, P.; Clark, D. Paediatr. Child. Health. 2019, 24, 12– 14,  DOI: 10.1093/pch/pxy084
    Google Scholar
    7
    An unusual cause for neonatal abstinence syndrome
    Murthy Prashanth; Clark Deborah
    Paediatrics & child health (2019), 24 (1), 12-14 ISSN:1205-7088.
    Neonatal abstinence syndrome (NAS) secondary to maternal drug use is a well-recognized clinical entity. We present a novel case of moderately severe NAS in a term infant whose mother was self-medicating with kratom tea. The baby required oral morphine for NAS. After 12 days in neonatal intensive care unit, she was discharged on oral morphine which was discontinued after 2 months. Kratom, a psychoactive herb with opioid activity, has traditionally been used as a stimulant to boost energy, cure cough, depression, pain, sickness and a substitute for opium. Although well known in South East Asia and Africa, this drug is less familiar to physicians in North America. It is undetectable by standard urine drug screening and is being sold as a legal herbal remedy. This is the first report of a newborn developing significant NAS after maternal use of kratom tea. We believe physicians should be aware of this 'new' risk to newborns.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cfmtlSmsg%253D%253D&md5=4ebad4fae131d4bb125b95e6b0917470
  8. 8
    Mackay, L.; Abrahams, R. Can. Fam. Physician 2018, 64, 121– 122
    Google Scholar
    8
    Novel case of maternal and neonatal kratom dependence and withdrawal
    Mackay Lindsay; Abrahams Ronald
    Canadian family physician Medecin de famille canadien (2018), 64 (2), 121-122 ISSN:.
    There is no expanded citation for this reference.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MritF2rsw%253D%253D&md5=26f086b960e337d2f8aee7ad9b257491
  9. 9
    Cumpston, K. L.; Carter, M.; Wills, B. K. Am. J. Emerg. Med. 2018, 36, 166– 168,  DOI: 10.1016/j.ajem.2017.07.051
    Google Scholar
    9
    Clinical outcomes after Kratom exposures: A poison center case series
    Cumpston Kirk L; Carter Michael; Wills Brandon K
    The American journal of emergency medicine (2018), 36 (1), 166-168 ISSN:.
    There is no expanded citation for this reference.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cfhvVOnsQ%253D%253D&md5=608813d7671b9d89732389fa4ce7ddc3
  10. 10
    Castillo, A.; Payne, J. D.; Nugent, K. Proc. (Bayl. Univ. Med. Cent.) 2017, 30, 355– 357,  DOI: 10.1080/08998280.2017.11929647
    Google Scholar
    10
    Posterior reversible leukoencephalopathy syndrome after kratom ingestion
    Castillo Austin; Payne J Drew; Nugent Kenneth
    Proceedings (Baylor University. Medical Center) (2017), 30 (3), 355-357 ISSN:0899-8280.
    Posterior reversible encephalopathy syndrome has been associated with hypertension, preeclampsia, cancer chemotherapy, and drugs of abuse, such as amphetamine and methamphetamine. We report a young man who suddenly developed severe headache, disorientation, and aphasia following ingestion of kratom and Adderall. Computed tomography and magnetic resonance imaging of his head revealed foci of vasogenic edema in the posterior occipital lobes, frontal lobes, and brainstem. In addition, he had a small area of hemorrhage in the left posterior occipital lobe. Lumbar puncture revealed an increased number of red blood cells but no other abnormalities. His initial blood pressure was elevated but returned to normal during hospitalization. This case suggests that kratom can cause posterior reversible encephalopathy syndrome and needs to be considered when patients present to emergency centers with headaches, confusion, and visual disturbances.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cjjvVWnuw%253D%253D&md5=2391f9bb57ab0c0598c9020ddf9d50cd
  11. 11
    Galbis-Reig, D. Wmj. 2016, 115, 49– 52
    Google Scholar
    11
    A Case Report of Kratom Addiction and Withdrawal
    Galbis-Reig David
    WMJ : official publication of the State Medical Society of Wisconsin (2016), 115 (1), 49-52; quiz 53 ISSN:1098-1861.
    Kratom, a relatively unknown herb among physicians in the western world, is advertised on the Internet as an alternative to opioid analgesics, as a potential treatment for oploid withdrawal and as a "legal high" with minimal addiction potential. This report describes a case of kratom addiction in a 37-year-old woman with a severe oploid-like withdrawal syndrome that was managed successfully with symptom-triggered clonidine therapy and scheduled hydroxyzine. A review of other case reports of kratom toxicity, the herb's addiction potential, and the kratom withdrawal syndrome is discussed. Physicians in the United States should be aware of the growing availability and abuse of kratom and the herb's potential adverse health effects, with particular attention to kratom's toxicity, addictive potential, and associated withdrawal syndrome.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fotFahtQ%253D%253D&md5=23312a82e7b101ac8fb58acc64d5b33e
  12. 12
    Karinen, R.; Fosen, J. T.; Rogde, S.; Vindenes, V. Forensic Sci. Int. 2014, 245, e29-e32  DOI: 10.1016/j.forsciint.2014.10.025
    Google Scholar
    There is no corresponding record for this reference.
  13. 13
    Forrester, M. B. J. Addict. Dis. 2013, 32, 396– 400,  DOI: 10.1080/10550887.2013.854153
    Google Scholar
    13
    Kratom exposures reported to Texas poison centers
    Forrester Mathias B
    Journal of addictive diseases (2013), 32 (4), 396-400 ISSN:.
    Kratom use is a growing problem in the United States. Kratom exposures reported to Texas poison centers between January 1998 and September 2013 were identified. No kratom exposures were reported from 1998 to 2008 and 14 exposures were reported from 2009 to September 2013. Eleven patients were male, and 11 patients were in their 20s. The kratom was ingested in 12 patients, inhaled in 1, and both ingested and inhaled in 1. Twelve patients were managed at a healthcare facility and the remaining 2 were managed at home.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3lsVChsg%253D%253D&md5=804dd16635e981eb82f7bb1b5befaa9d
  14. 14
    Holler, J. M.; Vorce, S. P.; McDonough-Bender, P. C.; Magluilo, J., Jr.; Solomon, C. J.; Levine, B. J. Anal. Toxicol. 2011, 35, 54– 9,  DOI: 10.1093/anatox/35.1.54
    Google Scholar
    14
    A Drug Toxicity Death Involving Propylhexedrine and Mitragynine
    Holler, Justin M.; Vorce, Shawn P.; McDonough-Bender, Pamela C.; Magluilo, Joseph, Jr.; Solomon, Carol J.; Levine, Barry
    Journal of Analytical Toxicology (2011), 35 (1), 54-59CODEN: JATOD3; ISSN:0146-4760. (Preston Publications)
    A death involving abuse of propylhexedrine and mitragynine is reported. Propylhexedrine is a potent α-adrenergic sympathomimetic amine found in nasal decongestant inhalers. The decedent was found dead in his living quarters with no signs of phys. trauma. Anal. of his computer showed information on kratom, a plant that contains mitragynine, which produces opiumlike effects at high doses and stimulant effects at low doses, and a procedure to conc. propylhexedrine from over-the-counter inhalers. Toxicol. results revealed the presence of 1.7 mg/L propylhexedrine and 0.39 mg/L mitragynine in his blood. Both drugs, as well as acetaminophen, morphine, and promethazine, were detected in the urine. Quant. results were achieved by gas chromatog.-mass spectrometry monitoring selected ions for the propylhexedrine heptafluorobutyryl deriv. Liq. chromatog.-tandem mass spectrometry in multiple reactions monitoring mode was used to obtain quant. results for mitragynine. The cause of death was ruled propylhexedrine toxicity, and the manner of death was ruled accidental. Mitragynine may have contributed as well, but as there are no published data for drug concns., the medical examiner did not include mitragynine toxicity in the cause of death. This is the first known publication of a case report involving propylhexedrine and mitragynine. (c) 2011 Preston Publications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1yktr0%253D&md5=f3b49903ef9a8ae4c3d8256321326707
  15. 15
    McWhirter, L.; Morris, S. Eur. Addict. Res. 2010, 16, 229– 31,  DOI: 10.1159/000320288
    Google Scholar
    15
    A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence
    McWhirter Laura; Morris Siobhan
    European addiction research (2010), 16 (4), 229-31 ISSN:.
    Kratom (Mitragyna speciosa) has been used for medicinal and recreational purposes. It has reported analgesic, euphoric and antitussive effects via its action as an agonist at opioid receptors. It is illegal in many countries including Thailand, Malaysia, Myanmar, South Korea and Australia; however, it remains legal or uncontrolled in the UK and USA, where it is easily available over the Internet. We describe a case of kratom dependence in a 44-year-old man with a history of alcohol dependence and anxiety disorder. He demonstrated dependence on kratom with withdrawal symptoms consisting of anxiety, restlessness, tremor, sweating and cravings for the substance. A reducing regime of dihydrocodeine and lofexidine proved effective in treating subjective and objective measures of opioid-like withdrawal phenomena, and withdrawal was relatively short and benign. There are only few reports in the literature of supervised detoxification and drug treatment for kratom dependence. Our observations support the idea that kratom dependence syndrome is due to short-acting opioid receptor agonist activity, and suggest that dihydrocodeine and lofexidine are effective in supporting detoxification.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cfivFensQ%253D%253D&md5=45fce464c0d99e13ca326f39a47a61b6
  16. 16
    The New York Times. April 17, 2019. https://www.nytimes.com/2019/04/17/us/kratom-overdose-deaths.html (accessed October 25, 2019).
    Google Scholar
    There is no corresponding record for this reference.
  17. 17
    U.S. Food & Drug Administration. February 21, 2018 https://www.fda.gov/news-events/press-announcements/fda-oversees-destruction-and-recall-kratom-products-and-reiterates-its-concerns-risks-associated (accessed October 25, 2019).
    Google Scholar
    There is no corresponding record for this reference.
  18. 18
    United States Drug Enforcement Administration. August 30, 2016. https://www.dea.gov/press-releases/2016/08/30/dea-announces-intent-schedule-kratom (accessed October 25, 2019).
    Google Scholar
    There is no corresponding record for this reference.
  19. 19
    Forbes. October 13, 2016. https://www.forbes.com/sites/davidkroll/2016/08/30/dea-to-place-kratom-mitragynine-on-schedule-i-premature-move-may-compromise-research-benefits/#679fe47d2b8f (accessed October 25, 2019).
    Google Scholar
    There is no corresponding record for this reference.
  20. 20
    Johnson, E. J.; González-Peréz, V.; Tian, D.-D.; Lin, Y. S.; Unadkat, J. D.; Rettie, A. E.; Shen, D. D.; McCune, J. S.; Paine, M. F. Drug Metab. Dispos. 2018, 46, 1046– 1052,  DOI: 10.1124/dmd.118.081273
    Google Scholar
    20
    review Selection of priority natural products for evaluation as potential precipitants of natural product-drug interactions: a NaPDI center recommended approach
    Johnson, Emily J.; Gonzalez-Perez, Vanessa; Tian, Dan-Dan; Lin, Yvonne S.; Unadkat, Jashvant D.; Rettie, Allan E.; Shen, Danny D.; McCune, Jeannine S.; Paine, Mary F.
    Drug Metabolism & Disposition (2018), 46 (7), 1046-1052CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)
    A review. Pharmacokinetic interactions between natural products (NPs) and conventional medications (prescription and nonprescription) are a long-standing but understudied problem in contemporary pharmacotherapy. Consequently, there are no established methods for selecting and prioritizing com. available NPs to evaluate as precipitants of NP-drug interactions (NPDIs). As such, NPDI discovery remains largely a retrospective, bedside-to-bench process. This Recommended Approach, developed by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), describes a systematic method for selecting NPs to evaluate as precipitants of potential clin. significant pharmacokinetic NPDIs. Guided information-gathering tools were used to score, rank, and triage NPs from an initial list of 47 candidates. Triaging was based on the presence and/or absence of an NPDI identified in a clin. study (=20% or <20% change in the object drug area under the concn. vs. time curve, resp.), as well as mechanistic and descriptive in vitro and clin. data. A qual. decision-making tool, termed the fulcrum model, was developed and applied to 11 high-priority NPs for rigorous study of NPDI risk. Application of this approach produced a final list of five high-priority NPs, four of which are currently under investigation by the NaPDI Center.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFSgurrJ&md5=3f77ddff421bd6c0141faf5889f39e5e
  21. 21
    Tian, D.-D.; Kellogg, J. J.; Okut, N.; Oberlies, N. H.; Cech, N. B.; Shen, D. D.; McCune, J. S.; Paine, M. F. Drug Metab. Dispos. 2018, 46, 552,  DOI: 10.1124/dmd.117.079491
    Google Scholar
    21
    Identification of intestinal UDP-glucuronosyltransferase inhibitors in green tea (Camellia sinensis) using a biochemometric approach: application to raloxifene as a test drug via in vitro to in vivo extrapolation
    Tian, Dan-Dan; Kellogg, Joshua J.; Okut, Nese; Oberlies, Nicholas H.; Cech, Nadja B.; Shen, Danny D.; McCune, Jeannine S.; Paine, Mary F.
    Drug Metabolism & Disposition (2018), 46 (5), 552-560CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)
    Green tea (Camellia sinensis) is a popular beverage worldwide, raising concern for adverse interactions when co-consumed with conventional drugs. Like many botanical natural products, green tea contains numerous polyphenolic constituents that undergo extensive glucuronidation. As such, the UDP-glucuronosyltransferases (UGTs), particularly intestinal UGTs, represent potential first-pass targets for green tea-drug interactions. Candidate intestinal UGT inhibitors were identified using a biochemometrics approach, which combines bioassay and chemometric data. Exts. and fractions prepd. from four widely consumed teas were screened (20-180 mg/mL) as inhibitors of UGT activity (4-methylumbelliferone glucuronidation) in human intestinal microsomes; all demonstrated concn.-dependent inhibition. A biochemometrics-identified fraction rich in UGT inhibitors from a representative tea was purified further and subjected to second-stage biochemometric anal. Five catechins were identified as major constituents in the bioactive subfractions and prioritized for further evaluation. Of these catechins, (-)epicatechin gallate and (-)-epigallocatechin gallate showed concn.-dependent inhibition, with IC50 values (105 and 59 μ M, resp.) near or below concns. measured in a cup (240 mL) of tea (66 and 240 μ M, resp.). Using the clin. intestinal UGT substrate raloxifene, the Ki values were ∼1.0 and 2.0 μ M, resp. Using estd. intestinal lumen and enterocyte inhibitor concns., a mechanistic static model predicted green tea to increase the raloxifene plasma area under the curve up to 6.1- and 1.3-fold, resp. Application of this novel approach, which combines biochemometrics with in vitro-in vivo extrapolation, to other natural product-drug combinations will refine these procedures, informing the need for further evaluation via dynamic modeling and clin. testing.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOjsLjN&md5=0cb38e0a92e89525d97c360e3ed8a239
  22. 22
    Gufford, B. T.; Chen, G.; Lazarus, P.; Graf, T. N.; Oberlies, N. H.; Paine, M. F. Drug Metab. Dispos. 2014, 42, 1675– 1683,  DOI: 10.1124/dmd.114.059451
    Google Scholar
    22
    Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation
    Gufford, Brandon T.; Chen, Gang; Lazarus, Philip; Graf, Tyler N.; Oberlies, Nicholas H.; Paine, Mary F.
    Drug Metabolism & Disposition (2014), 42 (10), 1675-1683, 9 pp.CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)
    Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying dietary substance-drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/exts. (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize addnl. perpetrators of dietary substance-drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/exts. inhibited UGT activity by >50% in at least one enzyme source, prompting IC50 detn. The IC50 values of 13 constituents/exts. (≤10 mM with at least one enzyme source) were well below intestinal tissue concns. or concns. in relevant juices, suggesting that these diet derived substances can inhibit intestinal UGTs at clin. achievable concns. Evaluation of the effect of inhibitor depletion on IC50 detn. demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify dietary substance-drug interactions that warrant advanced modeling and simulation to inform clin. assessment.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1yqur3K&md5=9616e20dd42c3ff1177b99d967987428
  23. 23
    Kellogg, J. J.; Paine, M. F.; McCune, J. S.; Oberlies, N. H.; Cech, N. B. Nat. Prod. Rep. 2019, 36, 1196– 1221,  DOI: 10.1039/C8NP00065D
    Google Scholar
    23
    Selection and characterization of botanical natural products for research studies: a NaPDI center recommended approach
    Kellogg, Joshua J.; Paine, Mary F.; McCune, Jeannine S.; Oberlies, Nicholas H.; Cech, Nadja B.
    Natural Product Reports (2019), 36 (8), 1196-1221CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
    A review. Covering: up to the end of 2018 Dietary supplements, which include botanical (plant-based) natural products, constitute a multi-billion-dollar industry in the US. While there is general agreement that rigorous scientific studies are needed to evaluate the safety and efficacy of botanical natural products used by consumers, researchers conducting such studies face a unique set of challenges. Botanical natural products are inherently complex mixts., with compn. that differs depending on myriad factors including variability in genetics, cultivation conditions, and processing methods. Unfortunately, many studies of botanical natural products are carried out with poorly characterized study material, such that the results are irreproducible and difficult to interpret. This review provides recommended approaches for addressing the crit. questions that researchers must address prior to in vitro or in vivo (including clin.) evaluation of botanical natural products. We describe selection and authentication of botanical material and identification of key biol. active compds., and compare state-of-the-art methodologies such as untargeted metabolomics with more traditional targeted methods of characterization. The topics are chosen to be of maximal relevance to researchers, and are reviewed critically with commentary as to which approaches are most practical and useful and what common pitfalls should be avoided.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFKmurg%253D&md5=cb245ca58f01bfc4979389687a8b6451
  24. 24
    Brantley, S. J.; Gufford, B. T.; Dua, R.; Fediuk, D. J.; Graf, T. N.; Scarlett, Y. V.; Frederick, K. S.; Fisher, M. B.; Oberlies, N. H.; Paine, M. F. CPT: Pharmacometrics Syst. Pharmacol. 2014, 3, 107,  DOI: 10.1038/psp.2013.69
    Google Scholar
    24
    Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb-Drug Interaction
    Brantley, S. J.; Gufford, B. T.; Dua, R.; Fediuk, D. J.; Graf, T. N.; Scarlett, Y. V.; Frederick, K. S.; Fisher, M. B.; Oberlies, N. H.; Paine, M. F.
    CPT: Pharmacometrics & Systems Pharmacology (2014), 3 (March), e107CODEN: CPSPBR; ISSN:2163-8306. (Nature Publishing Group)
    Herb-drug interaction predictions remain challenging. Physiol. based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb-drug interactions using the semipurified milk thistle prepn., silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and ([ital: null])-warfarin AUC by 5% and 4%, resp. A proof-of-concept clin. study confirmed minimal interaction between high-dose silibinin and both midazolam and ([ital: null])-warfarin (9 and 13% increase in AUC, resp.). Unexpectedly, ([ital: null])-warfarin AUC decreased (by 15%), but this is unlikely to be clin. important. Application of this PBPK modeling framework to other herb-drug interactions could facilitate development of guidelines for quant. prediction of clin. relevant interactions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Whtr7N&md5=e6e01ffb3c177cc872746270a174ee33
  25. 25
    Beckett, A. H.; Shellard, E. J.; Tackie, A. N. Planta Med. 1965, 13, 241– 246,  DOI: 10.1055/s-0028-1100118
    Google Scholar
    25
    Mitragyna species of Asia. IV. Alkaloids of leaves of Mitragyna speciosa. Isolation of mitragynine and speciofoline
    Beckett, Arnold H.; Shellard, Edward J.; Tackie, A. N.
    Planta Medica (1965), 13 (), 241-6CODEN: PLMEAA; ISSN:0032-0943.
    CA 66: 11091s. The alkaloids mitragynine and speciofoline (described for the first time) are isolated from the ethanol ext. of dry leaves of M. speciosa by column chromatog. using Al2O3 and eluting with ether and CHCl3 and various salts of mitragynine are prepd. Mitragynine, C23H30N2O4.EtOH, m. 97-8°, [α]20D -127° (c 2, CHCl3), gives a blue color when treated with vanillin and HCl; picrate m. 224.5° (MeOH); HCl salt m. 246-8° (ether/alc.); perchlorate m. 245-6° (glacial HOAc); HI salt m. 232-3° (ether/alc.); trichloroacetate m. 157° (acetone/ether); oxalate m. 219-20° (60% alc.); acetate m. 172° (Ac2O-ether); HBr salt m. 246-7° (ether/alc.); trinitrobenzene deriv. m. 146-7° (MeOH); cinnamate m. 155-6° (MeCOEt). Speciofoline, C22H28N2O5, m. 235-6°, [α]22D -102.9° (c 2, CHCl3), gives a light orange color when treated with vanillin and HCl; HBr salt m. 219-21° (alc.).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXksVequr4%253D&md5=550a1dedbab6932827d627b2d4d7ea9f
  26. 26
    Beckett, A.; Shellard, E.; Phillipson, J.; Lee, C. M. Planta Med. 1966, 14, 277– 288,  DOI: 10.1055/s-0028-1100055
    Google Scholar
    26
    Mitragyna species of Asia. VII. Indole alkaloids from the leaves of Mitragyna speciosa Korth
    Beckett, Arnold H.; Shellard, Edward J.; Phillipson, John D.; Lee, Calvin M.
    Planta Medica (1966), 14 (3), 277-88CODEN: PLMEAA; ISSN:0032-0943.
    cf. preceding abstr. Five addnl. alkaloids have been isolated from M. speciosa. Previously known and described are ajmalicine and corynantheidine; new are speciogynine, paynantheine, and speciociliatine. They are all derived from I, and their distinguishing features are tabulated. [TABLE OMITTED]
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXhtFSqsw%253D%253D&md5=15e5817323b9378d7bbae019b9493987
  27. 27
    Zacharias, D.; Rosenstein, R.; Jeffrey, G. Acta Crystallogr. 1965, 18, 1039– 1043,  DOI: 10.1107/S0365110X65002499
    Google Scholar
    27
    The structure of mitragynine hydroiodide
    Zacharias, David E.; Rosenstein, R. D.; Jeffrey, G. A.
    Acta Crystallographica (1965), 18 (6), 1039-43CODEN: ACCRA9; ISSN:0365-110X.
    C23H30N2O4, is an alkaloid contg. the indolo[2,3-a]quinolizine ring system substituted with methoxyl, ethyl, and methyl β-methoxyacryloyl groups. The structure was unknown at the beginning of this investigation, but was subsequently reported from a chem. study (Joshi, et al., CA 59, 3974f). This x-ray analysis confirms the conclusions of the chem. work and also shows that the methoxycarbonyl and methoxyl groups have a trans configuration about the double bond in the acrylyl moiety. The x-ray analysis was carried out on crystals of the hydroiodide which are orthorhombic with a 11.51, b 7.87, c 26.69 A.; space group is P212121. The heavy-atom method was used with 3-dimensional Fourier syntheses and structure factors computed 1st on an IBM 1620 and subsequently on an IBM 7070 computer. Two successive refinements with progressive addn. of the light atoms gave the complete structure. Subsequent refinement with isotropic temp. factors on all atoms gave an R index of 0.12.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXkt1Wjsbg%253D&md5=cd58e800e3ee1971902f8986af70d1fa
  28. 28
    Beckett, A. H.; Shellard, E. J.; Phillipson, J. D.; Lee, C. M. Planta Med. 1966, 14, 277– 288,  DOI: 10.1055/s-0028-1100055
    Google Scholar
    28
    Mitragyna species of Asia. VII. Indole alkaloids from the leaves of Mitragyna speciosa Korth
    Beckett, Arnold H.; Shellard, Edward J.; Phillipson, John D.; Lee, Calvin M.
    Planta Medica (1966), 14 (3), 277-88CODEN: PLMEAA; ISSN:0032-0943.
    cf. preceding abstr. Five addnl. alkaloids have been isolated from M. speciosa. Previously known and described are ajmalicine and corynantheidine; new are speciogynine, paynantheine, and speciociliatine. They are all derived from I, and their distinguishing features are tabulated. [TABLE OMITTED]
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXhtFSqsw%253D%253D&md5=15e5817323b9378d7bbae019b9493987
  29. 29
    Shellard, E.; Houghton, P.; Resha, M. Planta Med. 1978, 34, 253– 263,  DOI: 10.1055/s-0028-1097448
    Google Scholar
    29
    The mitragyna species of Asia. Part XXXII. The distribution of alkaloids in young plants of Mitragyna speciosa Korth grown from seed obtained from Thailand
    Shellard, E. J.; Houghton, P. J.; Resha, Masechaba
    Planta Medica (1978), 34 (3), 253-63CODEN: PLMEAA; ISSN:0032-0943.
    The major indole alkaloids, in young plants of M. speciosa, as distinct from those in the mature plants, are those possessing C-3Hβ with isocorynantheidine, isopaynantheine, and mitraciliatine (found for the first time in M. speciosa) being the dominant ones although speciogynine, a C-3Hα alkaloid, occurred in the major quantities. The oxindole alkaloids rhynchociline and ciliaphylline were also found in M. speciosa for the first time, although not in the leaves, while specionoxeine and isospecionoxeine were found for the first time in this species obtained from Thailand.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXmvFSquw%253D%253D&md5=e1990f35860b03f28211a44318e778c0
  30. 30
    Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi, N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto, L. T.; Watanabe, K.; Murayama, T.; Horie, S. J. Med. Chem. 2002, 45, 1949– 1956,  DOI: 10.1021/jm010576e
    Google Scholar
    30
    Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands
    Takayama, Hiromitsu; Ishikawa, Hayato; Kurihara, Mika; Kitajima, Mariko; Aimi, Norio; Ponglux, Dhavadee; Koyama, Fumi; Matsumoto, Kenjiro; Moriyama, Tomoyuki; Yamamoto, Leonard T.; Watanabe, Kazuo; Murayama, Toshihiko; Horie, Syunji
    Journal of Medicinal Chemistry (2002), 45 (9), 1949-1956CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Mitragynine is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compd., synthesis of some derivs., evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compds. for μ-, δ-, and κ-receptors were detd. in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivs. of mitragynine, i.e., mitragynine pseudoindoxyl (I) and 7-hydroxymitragynine, were found as opioid agonists with higher potency than morphine in the expt. with guinea pig ileum. In addn., I induced an analgesic activity in the tail flick test in mice.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitVOjur0%253D&md5=df2bbc1f913e4d8404a9e27375b3c993
  31. 31
    Takayama, H. Chem. Pharm. Bull. 2004, 52, 916– 928,  DOI: 10.1248/cpb.52.916
    Google Scholar
    31
    Chemistry and pharmacology of analgesic indole alkaloids from the Rubiaceous plant, Mitragyna speciosa
    Takayama, Hiromitsu
    Chemical & Pharmaceutical Bulletin (2004), 52 (8), 916-928CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)
    A review. The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochem. studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compds. were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of mitragynine, the major constituent of this plant, and its analogs were found in in vitro and in vivo expts. and the mechanisms underlying the analgesic activity were clarified. The essential structural features of mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacol. evaluation of the natural and synthetic derivs. Among the mitragynine derivs., 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvVKktbk%253D&md5=7f8c2d9978db7f60516f517988d3e014
  32. 32
    Takayama, H.; Kitajima, M.; Kogure, N. Curr. Org. Chem. 2005, 9, 1445– 1464,  DOI: 10.2174/138527205774370559
    Google Scholar
    32
    Chemistry of indole alkaloids related to the corynanthe-type from Uncaria, Nauclea and Mitragyna plants
    Takayama, Hiromitsu; Kitajima, Mariko; Kogure, Noriyuki
    Current Organic Chemistry (2005), 9 (15), 1445-1464CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
    A review. A no. of monoterpenoid indole and oxindole alkaloids were isolated from botanical sources, and many of them were found to possess significant pharmacol. activities and are utilized as key lead compds. in new drug development. In this review, the recent results of our phytochem. and synthetic studies of indole alkaloids having the Corynanthe-type related skeleton from genera Uncaria, Nauclea, and Mitragyna, which are classified under tribe Cinchoneae, family Rubiaceae, are described.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVakt7rO&md5=e6e271e70a1a641f97cd4fbe4690b33e
  33. 33
    Marston, A.; Hostettmann, K. Nat. Prod. Rep. 1991, 8, 391– 413,  DOI: 10.1039/np9910800391
    Google Scholar
    33
    Modern separation methods
    Marston, A.; Hostettmann, K.
    Natural Product Reports (1991), 8 (4), 391-413CODEN: NPRRDF; ISSN:0265-0568.
    A review with 269 refs. on chromatog. methods used for the isolation of natural products.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlslygt7w%253D&md5=e319628376d8d5bcef662c9e0b82e210
  34. 34
    Stead, P. Isolation by Preparative HPLC. In Natural Products Isolation; Cannell, R. J. P., Ed.; Humana Press: Totowa, NJ, 1998; pp 165– 208.
    Google Scholar
    There is no corresponding record for this reference.
  35. 35
    Betz, J. M.; Brown, P. N.; Roman, M. C. Fitoterapia 2011, 82, 44– 52,  DOI: 10.1016/j.fitote.2010.09.011
    Google Scholar
    35
    Accuracy, precision, and reliability of chemical measurements in natural products research
    Betz, Joseph M.; Brown, Paula N.; Roman, Mark C.
    Fitoterapia (2011), 82 (1), 44-52CODEN: FTRPAE; ISSN:0367-326X. (Elsevier B.V.)
    A review. Natural products chem. is the discipline that lies at the heart of modern pharmacognosy. The field encompasses qual. and quant. anal. tools that range from spectroscopy and spectrometry to chromatog. Among other things, modern research on crude botanicals is engaged in the discovery of the phytochem. constituents necessary for therapeutic efficacy, including the synergistic effects of components of complex mixts. in the botanical matrix. In the phytomedicine field, these botanicals and their contained mixts. are considered the active pharmaceutical ingredient (API), and pharmacognosists are increasingly called upon to supplement their mol. discovery work by assisting in the development and utilization of anal. tools for assessing the quality and safety of these products. Unlike single-chem. entity APIs, botanical raw materials and their derived products are highly variable because their chem. and morphol. depend on the genotypic and phenotypic variation, geog. origin and weather exposure, harvesting practices, and processing conditions of the source material. Unless controlled, this inherent variability in the raw material stream can result in inconsistent finished products that are under-potent, over-potent, and/or contaminated. Over the decades, natural product chemists have routinely developed quant. anal. methods for phytochems. of interest. Quant. methods for the detn. of product quality bear the wt. of regulatory scrutiny. These methods must be accurate, precise, and reproducible. Accordingly, this review discusses the principles of accuracy (relationship between exptl. and true value), precision (distribution of data values), and reliability in the quantitation of phytochems. in natural products.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVKls70%253D&md5=d785954b667d5111d972b6db8229af3f
  36. 36
    Li, S.; Yuan, W.; Deng, G.; Wang, P.; Yang, P.; Aggarwal, B. Pharm. Crops 2011, 2, 28– 54,  DOI: 10.2174/2210290601102010028
    Google Scholar
    36
    Chemical composition and product quality control of turmeric (Curcuma longa L.)
    Li, Shiyou; Yuan, Wei; Deng, Guangrui; Wang, Ping; Yang, Peiying; Aggarwal, Bharat B.
    Pharmaceutical Crops (2011), 2 (), 28-54CODEN: PCHRBU; ISSN:2210-2906. (Bentham Science Publishers Ltd.)
    A review. Chem. constituents of various tissues of turmeric (Curcuma longa L.) have been extensively investigated. To date, at least 235 compds., primarily phenolic compds. and terpenoids have been identified from the species, including 22 diarylheptanoids and diarylpentanoids, eight phenylpropene and other phenolic compds., 68 monoterpenes, 109 sesquiterpenes, five diterpenes, three triterpenoids, four sterols, two alkaloids, and 14 other compds. Curcuminoids (diarylheptanoids) and essential oils are major bioactive ingredients showing various bioactivities in in vitro and in vivo bioassays. Curcuminoids in turmeric are primarily accumulated in rhizomes. The essential oils from leaves and flowers are usually dominated by monoterpenes while those from roots and rhizomes primarily contained sesquiterpenes. The contents of curcuminoids in turmeric rhizomes vary often with varieties, locations, sources, and cultivation conditions, while there are significant variations in compn. of essential oils of turmeric rhizomes with varieties and geog. locations. Further, both curcuminoids and essential oils vary in contents with different extn. methods and are unstable with extn. and storage processes. As a result, the quality of com. turmeric products can be markedly varied. While curcumin (1), demethoxycurcumin (2), and bisdemethoxycurcumin (5) have been used as marker compds. for the quality control of rhizomes, powders, and ext. ("curcumin") products, Ar-turmerone (99), α-turmerone (100), and β-turmerone (101) may be used to control the product quality of turmeric oil and oleoresin products. Authentication of turmeric products can be achieved by chromatog. and NMR techniques, DNA markers, with morphol. and anat. data as well as GAP and other information available.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1GjtbfO&md5=c80633c79db31449ddb1511f394084fa
  37. 37
    Napolitano, J. G.; Lankin, D. C.; Chen, S. N.; Pauli, G. F. Magn. Reson. Chem. 2012, 50, 569– 575,  DOI: 10.1002/mrc.3829
    Google Scholar
    37
    Complete 1H NMR spectral analysis of ten chemical markers of Ginkgo biloba
    Napolitano, Jose G.; Lankin, David C.; Chen, Shao-Nong; Pauli, Guido F.
    Magnetic Resonance in Chemistry (2012), 50 (8), 569-575CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
    The complete and unambiguous 1H NMR assignments of ten marker constituents of Ginkgo biloba are described. The comprehensive 1H NMR profiles (fingerprints) of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, bilobalide, quercetin, kaempferol, isorhamnetin, isoquercetin, and rutin in DMSO-d6 were obtained through the examn. of 1D 1H NMR and 2D 1H,1H-COSY data, in combination with 1H iterative full spin anal. (HiFSA). The computational anal. of discrete spin systems allowed a detailed characterization of all the 1H NMR signals in terms of chem. shifts (δH) and spin-spin coupling consts. (JHH), regardless of signal overlap and higher order coupling effects. The capability of the HiFSA-generated 1H fingerprints to reproduce exptl. 1H NMR spectra at different field strengths was also evaluated. As a result of this anal., a revised set of 1H NMR parameters for all ten phyto-constituents was assembled. Furthermore, precise 1H NMR assignments of the sugar moieties of isoquercetin and rutin are reported for the first time. Copyright © 2012 John Wiley & Sons, Ltd.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XovFWktrc%253D&md5=cc60c88c73582ede4354478fdb0bd4c6
  38. 38
    Niemitz, M.; Laatikainen, R.; Chen, S. N.; Kleps, R.; Kozikowski, A. P.; Pauli, G. F. Magn. Reson. Chem. 2007, 45, 878– 882,  DOI: 10.1002/mrc.2061
    Google Scholar
    38
    Complete 1H NMR spectral fingerprint of huperzine A
    Niemitz, Matthias; Laatikainen, Reino; Chen, Shao-Nong; Kleps, Robert; Kozikowski, Alan P.; Pauli, Guido F.
    Magnetic Resonance in Chemistry (2007), 45 (10), 878-882CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
    Complete anal. of the 1H NMR spectrum of huperzine A, 1-amino-13-ethylidene-11-methyl-6-aza-tricyclo[7.3.1.02,7]trideca-2 (7),3,10-trien-5-one, a Lycopodium alkaloid and anti-Alzheimer drug lead contg. an ABCD(E)(MN)(OP)X3Y3-type system of 15 nonexchangeable protein spins, is reported for the 1st time, and earlier assignments are cor. The complete 1H parameter set of 11 chem. shifts clarifies the diastereotopism of both methylgene groups, and provides a total of 38 obsd. H,H-couplings including 31 long-range (4-6J) connectivities. The NMR data is consistent with the comparatively rigid alicyclic backbone predicted by mol. mechanics calcns., and forms the basis for 1H NMR fingerprint anal. for the purpose of dereplication, purity anal., and elucidation of structural analogs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFOnu7jI&md5=10ad38b5be5ec06b1aa23d157a80b1d9
  39. 39
    Seebacher, W.; Simic, N.; Weis, R.; Saf, R.; Kunert, O. Magn. Reson. Chem. 2003, 41, 636– 638,  DOI: 10.1002/mrc.1214
    Google Scholar
    39
    Complete assignments of 1H and 13C NMR resonances of oleanolic acid, 18α-oleanolic acid, ursolic acid and their 11-oxo derivatives
    Seebacher, Werner; Simic, Nebojsa; Weis, Robert; Saf, Robert; Kunert, Olaf
    Magnetic Resonance in Chemistry (2003), 41 (8), 636-638CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
    Complete assignments of 1H and 13C NMR chem. shifts for oleanolic acid, 18α-oleanolic acid, ursolic acid and their 11-oxo derivs. based on 1H, 13C, 2-dimensional DQF-COSY, NOESY, HSQC, HMBC and HSQC-TOCSY expts. were achieved.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlvFSiur8%253D&md5=051177f19ad71ea06339ab6508322618
  40. 40
    Sy-Cordero, A. A.; Pearce, C. J.; Oberlies, N. H. J. Antibiot. 2012, 65, 541– 9,  DOI: 10.1038/ja.2012.71
    Google Scholar
    40
    Revisiting the enniatins: a review of their isolation, biosynthesis, structure determination and biological activities
    Sy-Cordero, Arlene A.; Pearce, Cedric J.; Oberlies, Nicholas H.
    Journal of Antibiotics (2012), 65 (11), 541-549CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)
    A review. Enniatins are cyclohexadepsipeptides isolated largely from Fusarium species of fungi, although they have been isolated from other genera, such as Verticillium and Halosarpheia. They were first described over 60 years ago, and their range of biol. activities, including antiinsectan, antifungal, antibiotic and cytotoxic, drives contemporary interest. To date, 29 enniatins have been isolated and characterized, either as a single compd. or mixts. of inseparable homologs. Structurally, these depsipeptides are biosynthesized by a multifunctional enzyme, termed enniatin synthetase, and are composed of six residues that alternate between N-Me amino acids and hydroxy acids. Their structure elucidation can be challenging, particularly for enniatins isolated as inseparable homologs; however, several strategies and tools have been utilized to solve these problems. Currently, there is one drug that has been developed from a mixt. of enniatins, fusafungine, which is used as a topical treatment of upper respiratory tract infections by oral and/or nasal inhalation. Given the range of biol. activities obsd. for this class of compds., research on enniatins will likely continue. This review strives to digest the past studies, as well as, describe tools and techniques that can be utilized to overcome the challenges assocd. with the structure elucidation of mixts. of enniatin homologs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslagsLrE&md5=13828a23868b277d1460b1f71b83ee73
  41. 41
    Kao, D.; Flores-Bocanegra, L.; Raja, H. A.; Darveaux, B. A.; Pearce, C. J.; Oberlies, N. H. Phytochemistry 2020, 172, 112238,  DOI: 10.1016/j.phytochem.2019.112238
    Google Scholar
    41
    New tricks for old dogs: Two new macrocyclic trichothecene epimers and absolute configuration of 16-hydroxyverrucarin B
    Kao, Diana; Flores-Bocanegra, Laura; Raja, Huzefa A.; Darveaux, Blaise A.; Pearce, Cedric J.; Oberlies, Nicholas H.
    Phytochemistry (Elsevier) (2020), 172 (), 112238CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Ltd.)
    Two new compds., 3'-epi-16-hydroxyverrucarin A and 3'-epiverrucarin X, have been isolated and identified, and the characterization data of a series of known trichothecenes have been refined. The interesting structure and potent biol. activities of macrocyclic trichothecenes have been of interest to the scientific community for several decades. However, some of the characterization data for the older analogs of this class are not well documented, either because of a lack of abs. configuration or a lack of clarity in the NMR data, largely due to technol. limitations at the time they were discovered. NMR techniques, application of Mosher's esters anal., and electronic CD were used here both to refine the characterization of known trichothecenes, as well as to uncover new structures. These studies demonstrate strategies that can be used to interrogate the characterization data of well-known secondary metabolites, thereby gaining greater insight into methods that can be used to refine previous literature.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFCit74%253D&md5=aa2d8e50cc193e861824af06d896d93b
  42. 42
    https://www.fda.gov/news-events/public-health-focus/fda-and-kratom (accessed January 20, 2020).
    Google Scholar
    There is no corresponding record for this reference.
  43. 43
    Hollingsworth, M. L.; Andra Clark, A.; Forrest, L. L.; Richardson, J.; Pennington, R. T.; Long, D. G.; Cowan, R.; Chase, M. W.; Gaudeul, M.; Hollingsworth, P. M. Mol. Ecol. Resour. 2009, 9, 439– 457,  DOI: 10.1111/j.1755-0998.2008.02439.x
    Google Scholar
    43
    Selecting barcoding loci for plants: evaluation of seven candidate loci with species-level sampling in three divergent groups of land plants
    Hollingsworth, Michelle L.; Clark, Alex Andra; Forrest, Laura L.; Richardson, James; Pennington, R. Toby; Long, David G.; Cowan, Robyn; Chase, Mark W.; Gaudeul, Myriam; Hollingsworth, Peter M.
    Molecular Ecology Resources (2009), 9 (2), 439-457CODEN: MEROCJ; ISSN:1755-098X. (Wiley-Blackwell)
    There has been considerable debate, but little consensus regarding locus choice for DNA barcoding land plants. This is partly attributable to a shortage of comparable data from all proposed candidate loci on a common set of samples. In this study, we evaluated the seven main candidate plastid regions (rpoC1, rpoB, rbcL, matK, trnH-psbA, atpF-atpH, psbK-psbI) in three divergent groups of land plants [Inga (angiosperm); Araucaria (gymnosperm); Asterella s.l. (liverwort)]. Across these groups, no single locus showed high levels of universality and resolvability. Interspecific sharing of sequences from individual loci was common. However, when multiple loci were combined, fewer barcodes were shared among species. Evaluation of the performance of previously published suggestions of particular multilocus barcode combinations showed broadly equiv. performance. Minor improvements on these were obtained by various new three-locus combinations involving rpoC1, rbcL, matK and trnH-psbA, but no single combination clearly outperformed all others. In terms of abs. discriminatory power, promising results occurred in liverworts (e.g. c. 90% species discrimination based on rbcL alone). However, Inga (rapid radiation) and Araucaria (slow rates of substitution) represent challenging groups for DNA barcoding, and their corresponding levels of species discrimination reflect this (upper est. of species discrimination = 69% in Inga and only 32% in Araucaria; mean = 60% averaging all three groups). DNA sequence and amino acid sequences of these seven candidate plastid loci from various plants are deposited in GenBank/EMBL/DDBJ under various accession nos., including ACCNs in range AM919789-AM919982, ACCNs in range AM919986-AM920060, ACCNs in range AM920063-AM920083, AM920086-AM920111, AM920113-AM920150, AM920152-AM920192, AM920194-AM920223, ACCNs in range AM920226-AM920247, AM920249-AM920308, AM920310, ACCNs in range AM921997-AM922019, AM922021-AM922096, FJ173458-FJ173802 and FJ205612-FJ205615.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjvVKgtbs%253D&md5=b887641922b574f4e665757fdc086583
  44. 44
    Kress, W. J.; Wurdack, K. J.; Zimmer, E. A.; Weigt, L. A.; Janzen, D. H. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 8369– 8374,  DOI: 10.1073/pnas.0503123102
    Google Scholar
    44
    Use of DNA barcodes to identify flowering plants
    Kress, W. John; Wurdack, Kenneth J.; Zimmer, Elizabeth A.; Weigt, Lee A.; Janzen, Daniel H.
    Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (23), 8369-8374CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Methods for identifying species by using short orthologous DNA sequences, known as "DNA barcodes," have been proposed and initiated to facilitate biodiversity studies, identify juveniles, assoc. sexes, and enhance forensic analyses. The cytochrome c oxidase 1 sequence, which has been found to be widely applicable in animal barcoding, is not appropriate for most species of plants because of a much slower rate of cytochrome c oxidase 1 gene evolution in higher plants than in animals. We therefore propose the nuclear internal transcribed spacer region and the plastid trnH-psbA intergenic spacer as potentially usable DNA regions for applying barcoding to flowering plants. The internal transcribed spacer is the most commonly sequenced locus used in plant phylogenetic investigations at the species level and shows high levels of interspecific divergence. The trnH-psbA spacer, although short (≈450-bp), is the most variable plastid region in angiosperms and is easily amplified across a broad range of land plants. Comparison of the total plastid genomes of tobacco and deadly nightshade enhanced with trials on widely divergent angiosperm taxa, including closely related species in seven plant families and a group of species sampled from a local flora encompassing 50 plant families (for a total of 99 species, 80 genera, and 53 families), suggest that the sequences in this pair of loci have the potential to discriminate among the largest no. of plant species for barcoding purposes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlsV2mtbY%253D&md5=4cb6c3928c04e884cfad4636b8f550f5
  45. 45
    Kress, W. J.; Erickson, D. L. PLoS One 2007, 2, e508  DOI: 10.1371/journal.pone.0000508
    Google Scholar
    There is no corresponding record for this reference.
  46. 46
    Li, X.; Yang, Y.; Henry, R. J.; Rossetto, M.; Wang, Y.; Chen, S. Biol. Rev. 2015, 90, 157– 166,  DOI: 10.1111/brv.12104
    Google Scholar
    46
    Plant DNA barcoding: from gene to genome
    Li Xiwen; Yang Yang; Henry Robert J; Rossetto Maurizio; Wang Yitao; Chen Shilin
    Biological reviews of the Cambridge Philosophical Society (2015), 90 (1), 157-66 ISSN:.
    DNA barcoding is currently a widely used and effective tool that enables rapid and accurate identification of plant species; however, none of the available loci work across all species. Because single-locus DNA barcodes lack adequate variations in closely related taxa, recent barcoding studies have placed high emphasis on the use of whole-chloroplast genome sequences which are now more readily available as a consequence of improving sequencing technologies. While chloroplast genome sequencing can already deliver a reliable barcode for accurate plant identification it is not yet resource-effective and does not yet offer the speed of analysis provided by single-locus barcodes to unspecialized laboratory facilities. Here, we review the development of candidate barcodes and discuss the feasibility of using the chloroplast genome as a super-barcode. We advocate a new approach for DNA barcoding that, for selected groups of taxa, combines the best use of single-locus barcodes and super-barcodes for efficient plant identification. Specific barcodes might enhance our ability to distinguish closely related plants at the species and population levels.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crnsFygsA%253D%253D&md5=850019e10c4794b3f62af11a7116b6a5
  47. 47
    Ebihara, A.; Nitta, J. H.; Ito, M. PLoS One 2010, 5, e15136  DOI: 10.1371/journal.pone.0015136
    Google Scholar
    There is no corresponding record for this reference.
  48. 48
    Brown, P. N.; Lund, J. A.; Murch, S. J. J. Ethnopharmacol. 2017, 202, 302– 325,  DOI: 10.1016/j.jep.2017.03.020
    Google Scholar
    48
    A botanical, phytochemical and ethnomedicinal review of the genus Mitragyna korth: Implications for products sold as kratom
    Brown, Paula N.; Lund, Jensen A.; Murch, Susan J.
    Journal of Ethnopharmacology (2017), 202 (), 302-325CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
    The genus Mitragyna (Rubiacaeae) has been traditionally used in parts of Africa, Asia and Oceania. In recent years, there has been increased interest in species of Mitragyna with the introduction of products to western markets and regulatory uncertainty. This paper reviewed the traditional ethnomedicinal uses of leaves for species belonging to the genus Mitragyna with ref. to the botany and known chem. in order to highlight areas of interest for products currently being sold as kratom. A literature search was conducted using Web of Science, Google Scholar, the Royal Museum for Central Africa, Internet Archive, Hathi Trust, and Biodiversity Heritage Library search engines in the spring of 2015, fall of 2016 and winter of 2017 to document uses of bark, leaf and root material.Leaves of M. speciosa (kratom) had the most common documented ethnomedicinal uses as an opium substitute or remedy for addiction. Other species of Mitragyna were reportedly used for treating pain, however the mode of prepn. was most often cited as topical application. Other uses of Mitragyna included treatment of fever, skin infections, and as a mild anxiolytic. Mitragyna species have been used medicinally in various parts of the world and that there is significant traditional evidence of use. Modern products that include formulations as topical application of liniments, balms or tinctures may provide effective alternatives for treatment of certain types of pains. Future research is required to establish safety and toxicol. limits, medicinal chem. parameters and the potential for different physiol. responses among varying genetic populations to support regulatory requirements for Mitragyna spp.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvFensLo%253D&md5=c9df1fd21f5ec044209f79747a9c83fc
  49. 49
    Raffa, R. B. Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-opium Source; CRC Press, 2014.
    Google Scholar
    There is no corresponding record for this reference.
  50. 50
    Takayama, H.; Kurihara, M.; Kitajima, M.; Said, I. M.; Aimi, N. Tetrahedron 1998, 54, 8433– 8440,  DOI: 10.1016/S0040-4020(98)00464-5
    Google Scholar
    50
    New indole alkaloids from the leaves of Malaysian Mitragyna speciosa
    Takayama, Hiromitsu; Kurihara, Mika; Kitajima, Mariko; Said, Ikram M.; Aimi, Norio
    Tetrahedron (1998), 54 (29), 8433-8440CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
    Three new monoterpenoid indole alkaloids; 3,4,5,6-tetradehydromitragynine, mitralactonal, and mitrasulgynine which contain a sulfonate function were isolated, in addn. to seven known compds., from the leaves of the Malaysian Mitragyna speciosa.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXksFCqsL0%253D&md5=205189645b9873bf89413b306820c16f
  51. 51
    León, F.; Habib, E.; Adkins, J. E.; Furr, E. B.; McCurdy, C. R.; Cutler, S. J. Nat. Prod. Commun. 2009, 4, 907– 910,  DOI: 10.1177/1934578X0900400705
    Google Scholar
    51
    Phytochemical characterization of the leaves of Mitragyna speciosa grown in USA
    Leon, Francisco; Habib, Eman; Adkins, Jessica E.; Furr, Edward B.; McCurdy, Christopher R.; Cutler, Stephen J.
    Natural Product Communications (2009), 4 (7), 907-910CODEN: NPCACO; ISSN:1934-578X. (Natural Product Inc.)
    Mitragyna speciosa (Rubiaceae) has traditionally been used in the tropical regions of Asia, Africa and Indonesia as a substitute for opium. Indole alkaloids are the most common compds. that have been isolated. We investigated the constituents of the leaves of M. speciosa that was grown at the University of Mississippi. Several alkaloids were isolated, including ajmalicine, corynantheidine, isomitraphylline, mitraphylline, paynantheine, isocorynantheidine, 7-hydroxymitragynine and mitragynine, but their percentages were lower than those in a com. Thai sample of "kratom". In addn., we isolated the flavonoid epicatechin, a saponin daucosterol, the triterpenoid saponins quinovic acid 3-O-β-D-quinovopyranoside, quinovic acid 3-O-β-D-glucopyranoside, as well as several glycoside derivs. including 1-O-feruloyl-β-D-glucopyranoside, benzyl-β-D-glucopyranoside, 3-oxo-α-ionyl-O-β-D-glucopyranoside, roseoside, vogeloside, and epivogeloside. This is the first report of the last group of compds. having been isolated from a Mitragyna species. Biol. studies are currently underway to test these compds. for opioid activity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptlemsr0%253D&md5=d2f6822e5eb7f95e581203e8fe408398
  52. 52
    Beckett, A.; Shellard, E.; Phillipson, J.; Lee, C. M. J. Pharm. Pharmacol. 1965, 17, 753– 755,  DOI: 10.1111/j.2042-7158.1965.tb07599.x
    Google Scholar
    52
    Alkaloids from Mitragyna speciosa
    Beckett, A. H.; Shellard, E. J.; Phillipson, J. D.; Lee, Calvin M.
    Journal of Pharmacy and Pharmacology (1965), 17 (11), 753-5CODEN: JPPMAB; ISSN:0022-3573.
    Alkaloids were isolated from a MeOH ext. of the leaves of M. speciosa. The picrates gave mitragynine, corynantheidine, isomitraphylline, and speciophylline (I). The picrate mother liquors gave ajmalicine, speciogynine (II), and psynantheine (III). I is an oxoindole alkaloid with a structure similar to mitraphylline. The N.M.R. spectrum placed the ester methoxy group at 6.62 τ. II and III were found to be indoles. The structure of II is similar to mitragynine. A methoxy group in the 9-position of II and III is suggested. Ir bands were found for II and III between 2700 and 2800 cm.-1 There was no C3H multiplet in the N.M.R. above 6.0 τ. III had no 3-proton triplet for the C-CH3 in the 9.1 τ region. III had multiplets for 3 protons in the olefinic region 5.2-4.2 τ. III is a 9-methoxy deriv. of corynantheine-type structure.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XhtFKmsQ%253D%253D&md5=e9f443eff29e09974983bd10a8cc2756
  53. 53
    Shellard, E. J.; Hougton, P. J.; Resha, M. Planta Med. 1978, 33, 223– 227,  DOI: 10.1055/s-0028-1097379
    Google Scholar
    53
    The Mitragyna species of Asia. Part XXX: Oxidation products of mitragynine and speciociliatine
    Shellard, E. J.; Houghton, P. J.; Resha, M.
    Planta Medica (1978), 33 (3), 223-7CODEN: PLMEAA; ISSN:0032-0943.
    Oxidn. of mitragynine and speciociliatine with Me3COCl gave a mixt. of mitragynine oxindole A, mitragynine oxindole B, and speciociliatine oxindole B (I). Oxidn. of mitragynine with m-ClC6H4C(O)OOH gave the oxidn. products II and III.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXls1ersLc%253D&md5=5e3c3af680b5bb4a384778ae9b10bf9d
  54. 54
    Cao, X.-F.; Wang, J.-S.; Wang, X.-B.; Luo, J.; Wang, H.-Y.; Kong, L.-Y. Phytochemistry 2013, 96, 389– 396,  DOI: 10.1016/j.phytochem.2013.10.002
    Google Scholar
    54
    Monoterpene indole alkaloids from the stem bark of Mitragyna diversifolia and their acetylcholine esterase inhibitory effects
    Cao, Xing-Fen; Wang, Jun-Song; Wang, Xiao-Bing; Luo, Jun; Wang, Hong-Ying; Kong, Ling-Yi
    Phytochemistry (Elsevier) (2013), 96 (), 389-396CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Ltd.)
    Five monoterpene indole alkaloids, mitradiversifoline, with a unique rearranged skeleton, specionoxeine-N(4)-oxide, 7-hydroxyisopaynantheine, 3-dehydropaynantheine, and 3-isopaynantheine-N(4)-oxide, and 10 known ones, were isolated from Mitragyna diversifolia. All the isolates were evaluated for their inhibition of acetylcholinesterase activities, and four showed moderate activities, with IC50 values of 4.1, 5.2, 10.2, and 10.3 μM, resp.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs12lurnF&md5=1eb77ffabd69d63823cfa445da76acc6
  55. 55
    Beckett, A. H.; Lee, C. M.; Tackie, A. N. Tetrahedron Lett. 1963, 4, 1709– 1714,  DOI: 10.1016/S0040-4039(01)90899-8
    Google Scholar
    There is no corresponding record for this reference.
  56. 56
    Hemingway, S. R.; Houghton, P. J.; Phillipson, J. D.; Shellard, E. J. Phytochemistry 1975, 14, 557– 563,  DOI: 10.1016/0031-9422(75)85128-4
    Google Scholar
    56
    9-Hydroxyrhynchophylline-type oxindole alkaloids
    Hemingway, Sarah R.; Houghton, Peter J.; Phillipson, J. David; Shellard, Edward J.
    Phytochemistry (Elsevier) (1975), 14 (2), 557-63CODEN: PYTCAS; ISSN:0031-9422.
    Speciofoline (I) was assigned the epiallo B configuration on the basis of isomerization studies, NMR and CD spectra, and 3 new speciofoline isomers, mitrafoline (II) (allo A), isomitrafoline (III) (allo B) and isospeciofoline (epiallo A) (IV) were isolated from Mitragyna speciosa. Rotundifoleine (V) and isorotundifoleine (VI), were sepd. as minor products from crystalline samples of rotundifoline and isorotundifoline (VII) resp., previously isolated from M. parvifolia. A transient product observed during the isomerization of (VII) was identifed as the pseudo B isomer, 3-epiisorotundifoline (VIII).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXktFSmtrc%253D&md5=053167f5f15d8ece4688363437e3edba
  57. 57
    Ali, Z.; Demiray, H.; Khan, I. A. Tetrahedron Lett. 2014, 55, 369– 372,  DOI: 10.1016/j.tetlet.2013.11.031
    Google Scholar
    57
    Isolation, characterization, and NMR spectroscopic data of indole and oxindole alkaloids from Mitragyna speciosa
    Ali, Zulfiqar; Demiray, Hatice; Khan, Ikhlas A.
    Tetrahedron Letters (2014), 55 (2), 369-372CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    A new indole alkaloid, 7β-hydroxy-7H-mitraciliatine (I) and a new oxindole alkaloid, isospeciofoleine (II) together with 4 known alkaloids were isolated from Mitragyna speciosa and characterized by NMR, CD, and MS spectroscopic data analyses. The 1H and 13C NMR spectroscopic data of isospeciofoline (3), isorotundifoline (4), paynantheine (5), and 3-isopaynantheine (6) were also reported for the first time.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOmt77P&md5=2aa62ffa9ab5bcbb32d389c2ec59bd32
  58. 58
    Cu, N. Bull. Soc. Chim. Fr. 1957, 1292– 1294
    Google Scholar
    58
    Alkaloids of Pseudocinchona africana. Corynoxeine and corynoxine, two new oxindole alkaloids. Identity of rhynchophylline and dihydrocornyoxeine
    Cu, Nguyen An; Goutarel, Robert; Janot, Maurice-Marie
    Bulletin de la Societe Chimique de France (1957), (), 1292-4CODEN: BSCFAS; ISSN:0037-8968.
    The residual alkaloidal material after sepn. of corynanthine, corynanthidine, corynantheine, dihydrocorynantheine, and corynantheidine from the bark of P. africana was chromatographed on Al2O3 to give β-yohimbine and 2 new alkaloids, corynoxeine (I), C22H26N2O4, m. 210°, [α]D 23° (c 1.0, C5H5N), -21.5 ± 2° (c 1.0, CHCl3), [α]Hg -31.5 ± 1° (CHCl3), and corynoxine (II), C22H28N2O4, m. 166-8°, [α]D -14 ± 3° (c 1.0, C5H5N), [α]D -3° (c 1.75, CHCl3). I had 2 MeO groups and an active H atom but no N-Me or C-Me groups and was reduced with Pd to dihydrocorynoxeine (Ia), C22H28N2O4, m. 210°, [α]D -17 ± 2° (CHCl3), [α]Hg -15.5° (c 0.92, CHCl3), contg. a C-Me group (Kuhn-Roth), and oxidized by CrO3 to EtCO2H, showing the presence of an HC:CH2 group in I. I and Ia had superimposable UV spectra characterized by a band at 2-5 mμ (log ε 4.28) not displaced by the bathochromic shift in alk. media in the region 260-300 mμ. The UV absorption spectrum is formed by the summation of 2 nonconjugated chromaphores, MeO2CC:CHOMe, absorbing at 245 mμ, and a 3,3'-disubstituted oxindole. Confirmation was provided by the IR spectrum of I characterized by 4 strong bands at 5.8, 5.9, 6.1, 6.2 μ, and a band at 11 μ not present in the spectrum of Ia. Ia hydrolyzed by 2N KOH in MeOH gave an amphoteric acid with the grouping HO2CC:CHOMe, hydrolyzed with 2N H2SO4 to a β-aldehydic acid, decarboxylated in the course of the reaction to an amorphous aldehyde "dihydrocorynoxeinal," C19H24N2O2, [α]D 22 ± 2° (CHCl3), not contg. an MeO group and with a typical oxindole spectrum, reduced according to Wolff-Kischner to dihydrocorynoxeinane, C19H26N2O, m. 70°, [α]D 24 ± 2° (CHCl3), with a typical oxindole spectrum. II had a C-Me and 2 MeO groups and an active H atom but no N-Me group, and was not reduced by Pd, showing the presence of a CH2CH2 chain. The UV spectrum was superimposable on that of I and showed the same bathochromic shift in alk. media. The IR spectrum had the same characteristics as that of I in the region 6 μ though the 2 CO bands were united in a broad band at 5.9 μ. The same degrdn. sequence as given for Ia converted II to corynoxinal (IIa), C19H24N2O2, [α]D -16 ± 2° (CHCl3), [α]Hg -15 ± 1° (c 2.0, CHCl3), and corynoxinane (IIb), C19H26N2O, m. 70°, [α]D -25 ± 2° (c 1.0, CHCl3), [α]Hg -27 ± 2° (c 1.13, CHCl3). IIa and IIb had no MeO groups and gave oxindole UV absorption spectra. The IR spectrum of IIa was identical with that of dihydrocorynoxeinal in which the 2 CO groups formed a broad band at 5.9 μ, the 6.1 μ band disappeared, but the 6.2 μ dihydroindole band was conserved. Similarly, the IR spectra of IIb and dihydrocorynoxeinane were identical. Rhynchophylline, isolated from Adina rubrostipulata (cf. Kates and Marion, C.A. 45, 6646b), m. 210°, [α]D -18 ± 2° (CHCl3), IR spectrum superimposable on that of Ia, and is apparently identical with Ia. Structures are proposed for I and II which should lead to the further elucidation of the typically oxindolic alkaloid, gelsemine.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG1cXltVOjtQ%253D%253D&md5=2eb62b9270e0f36241e58623521e7e48
  59. 59
    Shellard, E. Planta Med. 1978, 34, 26– 36,  DOI: 10.1055/s-0028-1097410
    Google Scholar
    59
    The Mitragyna species of Asia. Part XXXI. The alkaloids of Mitragyna speciosa Korth from Thailand
    Shellard, E. J.; Houghton, P. J.; Resha, Masechaba
    Planta Medica (1978), 34 (1), 26-36CODEN: PLMEAA; ISSN:0032-0943.
    In addn. to the previously reported alkaloids from M. speciosa a no. of addnl. oxindole alkaloids were isolated, 3 of which are new. These have been named mitrafoline, isomitrafoline,and isospeciofoline. Mitragynine oxindoles A and B were found for the first time in plant material while corynoxeine and the corynoxines were found for the first time in the genus Mitragyna. Examn. of 13 monthly samples of leaves showed that mitragynine and paynantheine remained the dominant indole alkaloids of the mature plant throughout the entire period of collection.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXmtFWqtb8%253D&md5=1553e6db0fd95665c839d7c7270e51cd
  60. 60
    Kitajima, M.; Misawa, K.; Kogure, N.; Said, I. M.; Horie, S.; Hatori, Y.; Murayama, T.; Takayama, H. J. Nat. Med. 2006, 60, 28– 35,  DOI: 10.1007/s11418-005-0001-7
    Google Scholar
    60
    A new indole alkaloid, 7-hydroxyspeciociliatine, from the fruits of Malaysian Mitragyna speciosa and its opioid agonistic activity
    Kitajima, Mariko; Misawa, Kaori; Kogure, Noriyuki; Said, Ikram M.; Horie, Syunji; Hatori, Yoshio; Murayama, Toshihiko; Takayama, Hiromitsu
    Journal of Natural Medicines (2006), 60 (1), 28-35CODEN: JNMOBN ISSN:. (Springer Tokyo)
    A new indole alkaloid, 7-hydroxyspeciociliatine (1), was isolated from the fruits of Malaysian Mitragyna speciosa Korth., together with 11 known indole and oxindole alkaloids (3-13). The structure of the new compd. was detd. by spectroscopic anal. and chem. conversion. The opioid agonistic activity of the new alkaloid was investigated in guinea-pig ileum expts. The compd. was found to have a weak stimulatory effect on μ-opioid receptors.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitlGrur8%253D&md5=3f631d44d1b13ec103b955169bbd42f4
  61. 61
    Lee, C. M.; Trager, W. F.; Beckett, A. H. Tetrahedron 1967, 23, 375– 385,  DOI: 10.1016/S0040-4020(01)83323-8
    Google Scholar
    61
    Corynantheidine-type alkaloids. II. Absolute configuration of mitragynine, speciociliatine, mitraciliatine and speciogynine
    Lee, Calvin M.; Trager, William F.; Beckett, Arnold H.
    Tetrahedron (1967), 23 (1), 375-85CODEN: TETRAB; ISSN:0040-4020.
    cf. preceeding abstr. The abs. configuration of mitragynine (allo), speciociliatine (I) (epiallo), mitraciliatine (pseudo), and speciogynine (normal) was detd. from ir, N.M.R., O.R.D., and circular dichroism data; all have the C-15 hydrogen α. Moreover, the preferred conformation of each configuration was established. The abs. configuration of any ring substituted or unsubstituted corynantheidine-type alkaloid of unknown configuration can be detd. by use of the phys. criteria presented. 25 references.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXjvVWjsQ%253D%253D&md5=99b353d6b9c7a5ad8f8b7aeacda25441
  62. 62
    1H NMR Properties of Piperidine Derivatives. In Studies in Organic Chemistry; Rubiralta, M.; Giralt, E.; Diez, A., Eds.; Elsevier, 1991; Vol. 43, pp 34– 87.
    Google Scholar
    There is no corresponding record for this reference.
  63. 63
    Alkorta, I.; Elguero, J. Magn. Reson. Chem. 2004, 42, 955– 961,  DOI: 10.1002/mrc.1460
    Google Scholar
    63
    A GIAO/DFT study of 1H, 13C and 15N shieldings in amines and its relevance in conformational analysis
    Alkorta, Ibon; Elguero, Jose
    Magnetic Resonance in Chemistry (2004), 42 (11), 955-961CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
    The 1H, 13C and 15N abs. shieldings of 13 amines were calcd. at the GIAO/B3LYP/6-311++G** level. For some compds. (ethylamine, piperidine and 1-methylpiperidine) two conformations were calcd. The 13C and 15N data could be correctly correlated with exptl. chem. shifts, allowing the conformation of 1-methylpiperidine to be established. The 1H NMR abs. shieldings, although less well correlated with δ values, were used to account for the anisotropy effects of the N lone pair.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpvVygsrc%253D&md5=12282fdb9c6636e09056b621597a0fd7
  64. 64
    Trager, W.; Lee, C. M.; Phillipson, J.; Haddock, R.; Dwuma-Badu, D.; Beckett, A. Tetrahedron 1968, 24, 523– 543,  DOI: 10.1016/0040-4020(68)88002-0
    Google Scholar
    64
    Configurational analysis of rhynchophylline-type oxindole alkaloids. Absolute configuration of ciliaphylline, rhynchociline, specionoxeine, isospecionoxeine, rotundifoline and isorotundifoline
    Trager, William F.; Lee, Calvin M.; Phillipson, John D.; Haddock, R. E.; Dwuma-Badu, D.; Beckett, Arnold H.
    Tetrahedron (1968), 24 (2), 523-43CODEN: TETRAB; ISSN:0040-4020.
    From a general configurational and conformational anal. of rhynchophyllinoid alkaloids, unique phys. criteria are developed that differentiate between the 8 possible configurational types. The criteria are applied to 6 rhynchophylline-type alkaloids of unknown configurations and show that ciliaphylline I (R = OMe, R' = Et), specionoxeine I (R = OMe, R' = CH:CH2), and isorotundifoline I (R = OH, R' = Et) have the normal B configuration while rhynchociline I (R = OMe, R' = Et), isospecionoxeine I (R = OMe, R' = CH:CH2), and rotundifoline I (R = OH, R' = Et) have the normal A configuration. All 6 alkaloids have the C-15 Hα abs. stereochemistry.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXjvFyrsw%253D%253D&md5=d61a4f4e0c73af38c7aa4487b125374c
  65. 65
    Xu, J.; Shao, L.-D.; Li, D.; Deng, X.; Liu, Y.-C.; Zhao, Q.-S.; Xia, C. J. Am. Chem. Soc. 2014, 136, 17962– 17965,  DOI: 10.1021/ja5121343
    Google Scholar
    65
    Construction of Tetracyclic 3-Spirooxindole through Cross-Dehydrogenation of Pyridinium: Applications in Facile Synthesis of (±)-Corynoxine and (±)-Corynoxine B
    Xu, Jun; Shao, Li-Dong; Li, Dashan; Deng, Xu; Liu, Yu-Chen; Zhao, Qin-Shi; Xia, Chengfeng
    Journal of the American Chemical Society (2014), 136 (52), 17962-17965CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A facile and straightforward method was developed to construct the fused tetracyclic 3-spirooxindole skeleton, which exists widely in natural products. The formation of the tetracyclic 3-spirooxindole structure was achieved through a transition-metal-free intramol. cross-dehydrogenative coupling of pyridinium, which were formed in situ by the condensation of 3-(2-bromoethyl)indolin-2-one derivs. with 3-substituted pyridines. As examples of the application of this new methodol., two potentially medicinal natural products, (±)-corynoxine (I) and (±)-corynoxine B, were efficiently synthesized in five scalable steps.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOgsL%252FP&md5=9b0366aabeba2e1ec21590d3528f3733
  66. 66
    Berner, M.; Tolvanen, A.; Jokela, R. Acid-catalysed Epimerization of Bioactive Indole Alkaloids and Their Derivatives. In Studies in Natural Products Chemistry; Atta ur Raman, Ed.; Elsevier, 2001; Vol. 25, pp 3– 42.
    Google Scholar
    There is no corresponding record for this reference.
  67. 67
    Laus, G.; Wurst, K. Helv. Chim. Acta 2003, 86, 181– 187,  DOI: 10.1002/hlca.200390009
    Google Scholar
    67
    X-ray crystal structure analysis of oxindole alkaloids
    Laus, Gerhard; Wurst, Klaus
    Helvetica Chimica Acta (2003), 86 (1), 181-187CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
    The single-crystal X-ray structures of speciophylline, mitraphylline, and rhynchophylline, oxindole alkaloids from the Peruvian climbing vine Uncaria tomentosa (Rubiaceae), were detd. The three compds. show N ···H-N hydrogen bonding, which has not been obsd. in the crystal structures of the related alkaloids pteropodine and isopteropodine. In the tetracyclic alkaloid rhynchophylline, the side chain is rotated out of the ring plane into a position perpendicular to it. This is in contrast to the situation of the pentacyclic analog mitraphylline, which possesses a conformationally rigid tricyclic core. This conformational difference possibly causes the competitive antagonism of these two types of alkaloids.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXht1OjtLs%253D&md5=b452333e36ae340e374488d4af001ebd
  68. 68
    Wanner, M. J.; Ingemann, S.; van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2013, 2013, 1100– 1106,  DOI: 10.1002/ejoc.201201505
    Google Scholar
    68
    Total Synthesis of the Spirocyclic Oxindole Alkaloids Corynoxine, Corynoxine B, Corynoxeine, and Rhynchophylline
    Wanner, Martin J.; Ingemann, Steen; van Maarseveen, Jan H.; Hiemstra, Henk
    European Journal of Organic Chemistry (2013), 2013 (6), 1100-1106CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Racemic total syntheses of four spirocyclic oxindole alkaloids are reported. The general starting material was an N-2-butenylated 2-hydroxytryptamine, which underwent a base-mediated Mannich spirocyclization with a functionalized aldehyde to generate the C-ring. The second key step was a Pd-catalyzed cyclization of an α-keto ester enolate (in the original aldehyde) onto an allylic carbonate (in the N-substituent) to form the D-ring. The stereoselectivities of the key steps were moderate, but the isomers were readily purified, so that the natural products could be conveniently prepd., three of them for the first time.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkvFKrsQ%253D%253D&md5=3f2a4d0ec2a87db3d274f51d91d9edc6
  69. 69
    Reinhardt, J. K.; Klemd, A. M.; Danton, O.; De Mieri, M.; Smieško, M.; Huber, R.; Bürgi, T.; Gründemann, C.; Hamburger, M. J. Nat. Prod. 2019, 82, 1424– 1433,  DOI: 10.1021/acs.jnatprod.8b00791
    Google Scholar
    69
    Sesquiterpene lactones from Artemisia argyi: Absolute configuration and immunosuppressant activity
    Reinhardt, Jakob K.; Klemd, Amy M.; Danton, Ombeline; De Mieri, Maria; Smiesko, Martin; Huber, Roman; Burgi, Thomas; Grundemann, Carsten; Hamburger, Matthias
    Journal of Natural Products (2019), 82 (6), 1424-1433CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    A library of exts. from plants used in Chinese Traditional Medicine was screened for inhibition of T lymphocyte proliferation. An Et acetate ext. from aerial parts of Artemisia argyi showed promising activity and was submitted to HPLC-based activity profiling to track the active compds. From the most active time window, three guaianolides (1, 2, and 5) and two seco-tanapartholides (3 and 4) were identified and, in a less active time window, five new sesquiterpene lactones (8-11, 17), along with six known sesquiterpene lactones and two known flavonoids. The abs. configurations of compds. 1, 2, 5-10, 13-15, 17, and 18 were established by comparison of exptl. with calcd. electronic CD (ECD) spectra. For seco-tanapartholides B (3) and A (4), ECD yielded ambiguous results, and their abs. configurations were detd. by comparing exptl. and calcd. vibrational CD (VCD) spectra. Compds. 1-5 showed significant, noncytotoxic inhibition of T lymphocyte proliferation, with IC50 values between 1.0 and 3.7 μM.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFWgtLnN&md5=e20016f1a8dcfaf2b6d839d23b6052d4
  70. 70
    Bustos-Brito, C.; Joseph-Nathan, P.; Burgueño-Tapia, E.; Martínez-Otero, D.; Nieto-Camacho, A.; Calzada, F.; Yépez-Mulia, L.; Esquivel, B.; Quijano, L. J. Nat. Prod. 2019, 82, 1207– 1216,  DOI: 10.1021/acs.jnatprod.8b00952
    Google Scholar
    70
    Structure and absolute configuration of abietane diterpenoids from Salvia clinopodioides: Antioxidant, antiprotozoal, and antipropulsive activities
    Bustos-Brito, Celia; Joseph-Nathan, Pedro; Burgueno-Tapia, Eleuterio; Martinez-Otero, Diego; Nieto-Camacho, Antonio; Calzada, Fernando; Yepez-Mulia, Lilian; Esquivel, Baldomero; Quijano, Leovigildo
    Journal of Natural Products (2019), 82 (5), 1207-1216CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    The aerial parts of Salvia clinopodioides afforded abietanes 1a, 2a, and 3 (clinopodiolides A-C), two of which possess an unusual lactol moiety at C-19-C-20, together with an icetexane named clinopodiolide D (4a). Their structures were established by spectroscopic means, mainly 1H and 13C NMR, including 1D and 2D homo- and heteronuclear expts. The antioxidant, antiprotozoal, and antidiarrheal effects of the isolates were evaluated. Compds. 2a and 3 showed better effects than α-tocopherol in the inhibition of lipid peroxidn. with IC50 (μM) = 5.9 ± 0.1 and 2.7 ± 0.2, resp., and moderate activity in the DPPH assay. All tested compds. showed moderate antiamoebic and antigiardial activity, as well as a good antipropulsive effect.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXovVyrtrk%253D&md5=7eaa3667d58910da0e9d9bcbc430dd12
  71. 71
    El-Kashef, D. H.; Daletos, G.; Plenker, M.; Hartmann, R.; Mándi, A.; Kurtán, T.; Weber, H.; Lin, W.; Ancheeva, E.; Proksch, P. J. Nat. Prod. 2019, 82, 2460– 2469,  DOI: 10.1021/acs.jnatprod.9b00125
    Google Scholar
    71
    Polyketides and a Dihydroquinolone Alkaloid from a Marine-Derived Strain of the Fungus Metarhizium marquandii
    El-Kashef, Dina H.; Daletos, Georgios; Plenker, Malte; Hartmann, Rudolf; Mandi, Attila; Kurtan, Tibor; Weber, Horst; Lin, Wenhan; Ancheeva, Elena; Proksch, Peter
    Journal of Natural Products (2019), 82 (9), 2460-2469CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    Three new natural products, including 2 butenolide derivs. and 1 dihydroquinolone deriv., together with 9 known natural products were isolated from a marine-derived strain of the fungus Metarhizium marquandii. The structures of the new compds. were unambiguously deduced by spectroscopic means including HRESIMS and 1D/2D NMR spectroscopy, ECD, VCD, OR measurements and calcns. The abs. configuration of marqualide (I) was detd. by a combination of modified Mosher's method with TDDFT-ECD calcns. at different levels, which revealed the importance of intramol. hydrogen-bonding in detg. the ECD features. The (3R,4R) abs. configuration of aflaquinolone I (II), detd. by OR, ECD, and VCD calcns., was opposite to the (3S,4S) abs. configuration of the related aflaquinolones A-G suggesting that the fungus Metarhizium marquandii produces aflaquinolone I with a different configuration (chiral switching). The abs. configuration of the known natural product, terrestric acid hydrate, was likewise detd. for the 1st time. TDDFT-ECD calcns. allowed detn. of the abs. configuration of its chirality center remote from the stereogenic unsatd. γ-lactone chromophore. ECD calcns. aided by solvent models revealed the importance of intramol. hydrogen bond networks in stabilizing conformers and detg. relations between ECD transitions and abs. configurations.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1Shsb7E&md5=5dccd962459d630ad8bf6e75e7e05558
  72. 72
    Cao, F.; Meng, Z.-H.; Mu, X.; Yue, Y.-F.; Zhu, H.-J. J. Nat. Prod. 2019, 82, 386– 392,  DOI: 10.1021/acs.jnatprod.8b01030
    Google Scholar
    72
    Absolute Configuration of Bioactive Azaphilones from the Marine-Derived Fungus Pleosporales sp. CF09-1
    Cao, Fei; Meng, Zhi-Hui; Mu, Xing; Yue, Yu-Fei; Zhu, Hua-Jie
    Journal of Natural Products (2019), 82 (2), 386-392CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    Investigation of the marine-derived fungus Pleosporales sp. CF09-1 cultured in modified PDB medium led to the isolation of 6 new azaphilone derivs., pleosporalones B and C (I ad II) and plosporalones E-H, and 1 known analog pleosporalone D. The abs. configurations of C-2' and C-3' in pleosporalone D were assigned by a vibrational CD method. The C-11 relative configurations for the pair of C-11 epimers (pleosporalones E and F) were established by comparing the magnitude of the computed 13C NMR chem. shifts (Δδcalcd) with the exptl. 13C NMR values (Δδexp) for the epimers. Antiphytopathogenic and anti-Vibrio activities were evaluated. I exhibited potent antifungal activities against the fungi Alternaria brassicicola and Fusarium oxysporum with the same MIC value of 1.6 μg/mL, which were stronger than the pos. control ketoconazole among these compds. Addnl., I displayed significant activity against the fungus Botryosphaeria dothidea (MIC, 3.1 μg/mL). Pleosporalone G and F displayed moderate anti-Vibrio activities against Vibrio anguillarum and Vibrio parahemolyticus, with MIC values of 13 and 6.3 μg/mL for pleosporalone G and 6.3 and 25 μg/mL for pleosporalone F, resp.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisValtbo%253D&md5=2dacc6f58de96fdcf98afd98a29e96ce
  73. 73
    Arreaga-González, H. M.; Rodríguez-García, G.; del Río, R. E.; Ferreira-Sereno, J. A.; García-Gutiérrez, H. A.; Cerda-García-Rojas, C. M.; Joseph-Nathan, P.; Gómez-Hurtado, M. A. J. Nat. Prod. 2019, 82, 3394– 3400,  DOI: 10.1021/acs.jnatprod.9b00734
    Google Scholar
    73
    Configurational Variation of a Natural Compound within Its Source Species. The Unprecedented Case of Areolal in Piptothrix areolare
    Arreaga-Gonzalez, Hector M.; Rodriguez-Garcia, Gabriela; del Rio, Rosa E.; Ferreira-Sereno, Jose A.; Garcia-Gutierrez, Hugo A.; Cerda-Garcia-Rojas, Carlos M.; Joseph-Nathan, Pedro; Gomez-Hurtado, Mario A.
    Journal of Natural Products (2019), 82 (12), 3394-3400CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    The exceptional case of a natural compd. that shows drastic abs. configuration variations within the same species was examd. Sequential samples of areolal (1) isolated from Piptothrix areolare showed dextrorotatory (ee 32%), almost racemic (ee 4%), levorotatory (ee 82%), and again dextrorotatory (ee 10%) values. Enantiomeric compns. of this epoxythymol deriv. were detd. from individual plant specimens collected from the same geog. location over a 46-day period, which were processed using the same extn. and isolation methods. Detection of this unusual phenomenon was possible by anal. of NMR data recorded in the presence of BINOL as a chiral solvating agent. The abs. configuration of (-)-(8S)-areolal followed from vibrational CD data of an enantiomerically enriched sample, while single-crystal X-ray diffraction and supramol. analyses revealed interactions that diminish the crystal entropy in rac-1. These results might be related with environmental factors and biochem. processes, suggesting the need of strict evaluations of enantiomeric compn. of natural products that could be considered for human applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFyqtrvI&md5=859eb605770ad2114e636e1f0b443a27
  74. 74
    Raja, H. A.; Baker, T. R.; Little, J. G.; Oberlies, N. H. Food Chem. 2017, 214, 383– 392,  DOI: 10.1016/j.foodchem.2016.07.052
    Google Scholar
    74
    DNA barcoding for identification of consumer-relevant mushrooms: A partial solution for product certification?
    Raja, Huzefa A.; Baker, Timothy R.; Little, Jason G.; Oberlies, Nicholas H.
    Food Chemistry (2017), 214 (), 383-392CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
    One challenge in the dietary supplement industry is confirmation of species identity for processed raw materials, i.e. those modified by milling, drying, or extn., which move through a multilevel supply chain before reaching the finished product. This is particularly difficult for samples contg. fungal mycelia, where processing removes morphol. characteristics, such that they do not present sufficient variation to differentiate species by traditional techniques. To address this issue, we have demonstrated the utility of DNA barcoding to verify the taxonomic identity of fungi found commonly in the food and dietary supplement industry; such data are crit. for protecting consumer health, by assuring both safety and quality. By using DNA barcoding of nuclear ribosomal internal transcribed spacer (ITS) of the rRNA gene with fungal specific ITS primers, ITS barcodes were generated for 33 representative fungal samples, all of which could be used by consumers for food and/or dietary supplement purposes. In the majority of cases, we were able to sequence the ITS region from powd. mycelium samples, grocery store mushrooms, and capsules from com. dietary supplements. After generating ITS barcodes utilizing std. procedures accepted by the Consortium for the Barcode of Life, we tested their utility by performing a BLAST search against authenticate published ITS sequences in GenBank. In some cases, we also downloaded published, homologous sequences of the ITS region of fungi inspected in this study and examd. the phylogenetic relationships of barcoded fungal species in light of modern taxonomic and phylogenetic studies. We anticipate that these data will motivate discussions on DNA barcoding based species identification as applied to the verification/certification of mushroom-contg. dietary supplements.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtF2hurnP&md5=c0b2f3c4a4f86f9fdc38532010a1207c
  75. 75
    Dunning, L. T.; Savolainen, V. Bot. J. Linn. Soc. 2010, 164, 1– 9,  DOI: 10.1111/j.1095-8339.2010.01071.x
    Google Scholar
    There is no corresponding record for this reference.
  76. 76
    Ford, C. S.; Ayres, K. L.; Toomey, N.; Haider, N.; Van Alphen Stahl, J.; Kelly, L. J.; Wikström, N.; Hollingsworth, P. M.; Duff, R. J.; Hoot, S. B. Bot. J. Linn. Soc. 2009, 159, 1– 11,  DOI: 10.1111/j.1095-8339.2008.00938.x
    Google Scholar
    There is no corresponding record for this reference.
  77. 77
    Pawar, R. S.; Handy, S. M.; Cheng, R.; Shyong, N.; Grundel, E. Planta Med. 2017, 83, 921– 936,  DOI: 10.1055/s-0043-107881
    Google Scholar
    77
    Assessment of the Authenticity of Herbal Dietary Supplements: Comparison of Chemical and DNA Barcoding Methods
    Pawar, Rahul S.; Handy, Sara M.; Cheng, Raymond; Shyong, Nicole; Grundel, Erich
    Planta Medica (2017), 83 (11), 921-936CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
    About 7 % of the U. S. population reports using botanical dietary supplements. Increased use of such supplements has led to discussions related to their authenticity and quality. Reports of adulteration with substandard materials or pharmaceuticals are of concern because such substitutions, whether inadvertent or deliberate, may reduce the efficacy of specific botanicals or lead to adverse events. Methods for verifying the identity of botanicals include macroscopic and microscopic examns., chem. anal., and DNA-based methods including DNA barcoding. Macroscopic and microscopic examns. may fail when a supplement consists of botanicals that have been processed beyond the ability to provide morphol. characterizations. Chem. anal. of specific marker compds. encounters problems when these compds. are not distinct to a given species or when purified ref. stds. are not available. Recent investigations describing DNA barcoding anal. of botanical dietary supplements have raised concerns about the authenticity of the supplements themselves as well as the appropriateness of using DNA barcoding techniques with finished botanical products. We collected 112 market samples of frequently consumed botanical dietary supplements of ginkgo, soy, valerian, yohimbe, and St. John's wort and analyzed each for specific chem. markers (i.e., flavonol glycosides, total isoflavones, total valerenic acids, yohimbine, and hypericins, resp.). We used traditional DNA barcoding techniques targeting the nuclear ITS2 gene and the chloroplast gene psbA-trnH on the same samples to det. the presence of DNA of the labeled ingredient. We compared the results obtained by both methods to assess the contribution of each in detg. the identity of the samples.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVCqu7Y%253D&md5=db2e07475b5fccc221b191802bcc6e2e
  78. 78
    Cheng, T.; Xu, C.; Lei, L.; Li, C.; Zhang, Y.; Zhou, S. Mol. Ecol. Resour. 2016, 16, 138– 149,  DOI: 10.1111/1755-0998.12438
    Google Scholar
    78
    Barcoding the kingdom plantae: new PCR primers for ITS regions of plants with improved universality and specificity
    Cheng, Tao; Xu, Chao; Lei, Li; Li, Changhao; Zhang, Yu; Zhou, Shiliang
    Molecular Ecology Resources (2016), 16 (1), 138-149CODEN: MEROCJ; ISSN:1755-098X. (Wiley-Blackwell)
    The internal transcribed spacer (ITS) of nuclear ribosomal DNA is one of the most commonly used DNA markers in plant phylogenetic and DNA barcoding analyses, and it has been recommended as a core plant DNA barcode. Despite this popularity, the universality and specificity of PCR primers for the ITS region are not satisfactory, resulting in amplification and sequencing difficulties. By thoroughly surveying and analyzing the 18S, 5.8S and 26S sequences of Plantae and Fungi from GenBank, we designed new universal and plant-specific PCR primers for amplifying the whole ITS region and a part of it (ITS1 or ITS2) of plants. In silico analyses of the new and the existing ITS primers based on these highly representative data sets indicated that (i) the newly designed universal primers are suitable for over 95% of plants in most groups; and (ii) the plant-specific primers are suitable for over 85% of plants in most groups without amplification of fungi. A total of 335 samples from 219 angiosperm families, 11 gymnosperm families, 24 fern and lycophyte families, 16 moss families and 17 fungus families were used to test the performances of these primers. In vitro PCR produced similar results to those from the in silico analyses. Our new primer pairs gave PCR improvements up to 30% compared with common-used ones. The new universal ITS primers will find wide application in both plant and fungal biol., and the new plant-specific ITS primers will, by eliminating PCR amplification of nonplant templates, significantly improve the quality of ITS sequence information collections in plant mol. systematics and DNA barcoding.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitV2jsbbL&md5=690069c351bb33c712638c8d5ec07bc0
  79. 79
    Löfstrand, S. D.; Krüger, Å.; Razafimandimbison, S. G.; Bremer, B. Syst. Bot. 2014, 39, 304– 315,  DOI: 10.1600/036364414X678116
    Google Scholar
    There is no corresponding record for this reference.
  80. 80
    Razafimandimbison, S. G.; Bremer, B. Am. J. Bot. 2002, 89, 1027– 1041,  DOI: 10.3732/ajb.89.7.1027
    Google Scholar
    80
    Phylogeny and classification of Naucleeae S.L. (Rubiaceae) inferred from molecular (ITS, rBCL, and tRNT-F) and morphological data
    Razafimandimbison, Sylvain G.; Bremer, Birgitta
    American Journal of Botany (2002), 89 (7), 1027-1041CODEN: AJBOAA; ISSN:0002-9122. (Botanical Society of America)
    Parsimony analyses of the tribe Naucleeae sensu lato (s.l.) using the noncoding internal transcribed spacer (ITS) regions of nuclear rDNA, the protein-coding rbcL and noncoding trnT-F regions of chloroplast DNA, and morphol. data were performed to construct new intratribal classification, test the monophyly of previous subtribal circumscriptions, and evaluate the generic status of Naucleeae s.l. Fifty-two ITS, 45 rbcL, and 55 trnT-F new sequences are published here. Our study supports the monophyly of the subtribes Anthocephalidae, Mitragynae, Uncariae all sensu Haviland and Naucleinae sensu Ridsdale. There was no support for Cephalanthidae sensu Haviland and Adininae sensu Ridsdale. Naucleeae can be subdivided into six highly supported and morphol. distinct subtribes. Breoniinae, Cephalanthinae, Corynantheinae, Naucleinae, and Mitragyninae, Uncarinae, plus one, Adininae, which is poorly supported. The relationships among these subtribes were largely unresolved. We maintain the following 22 genera: Adina, Adinauclea, Breonadia, Breonia, Burttdavya, Cephalanthus, Gyrostipula, Haldina, Janotia, Ludekia, Metadina, Mitragyna, Myrmeconauclea, Nauclea, Neolamarckia, Neonauclea, Ochreinauclea, Pausinystalia, Pertusadina, Sarcocephalus, Sinoadina, and Uncaria. Pseudocinchona is reestablished. Corynanthe is restricted to C. paniculata and Hallea is reincluded in Mitragyna. Our results were inconclusive for assessing the relationships among Adina, Adinauclea, Metadina, and Pertusadina due to lack of resoln.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislejtg%253D%253D&md5=dc6e3d53a33203c56391d5ec5e4cce17
  81. 81
    Tnah, L.; Lee, S.; Tan, A.; Lee, C.; Ng, K.; Ng, C.; Farhanah, Z. N. Food Control 2019, 95, 318– 326,  DOI: 10.1016/j.foodcont.2018.08.022
    Google Scholar
    81
    DNA barcode database of common herbal plants in the tropics: a resource for herbal product authentication
    Tnah, L. H.; Lee, S. L.; Tan, A. L.; Lee, C. T.; Ng, K. K. S.; Ng, C. H.; Nurul Farhanah, Z.
    Food Control (2019), 95 (), 318-326CODEN: FOOCEV; ISSN:0956-7135. (Elsevier Ltd.)
    Ensuring the authenticity of raw materials used in herbal manufg. is a key step prior to material processing. As species authentication is fundamental in the confirmation of herbal product quality, DNA barcoding techniques represent an efficient method for detecting plant-based adulterants in traded herbal products. Through this study, we established a DNA barcoding authentication system for 112 common herbal plant species in the tropics, which can be used for species identification and authentication. The DNA barcode ref. database for the authentication system was generated using rbcL for primary differentiation, and trnH-psbA for secondary differentiation. The performance of the barcodes in resolving species was evaluated using similarity BLAST, phylogenetic tree reconstruction and by estg. the barcoding gap. In this study, the multigene tiered approach for DNA barcoding is proven robust with high species-level resoln. (96.4%). Upon completion of the DNA barcoding authentication system, 30 herbal products from the local market were tested for their authenticity using this approach. Recovery of DNA barcodes from the herbal products was 73.4%, of which 56.7% of the products tested were authentic, whereas 10% of the herbal products were substituted with other plant taxa and 6.7% were contaminated. To this end, authentication of herbal products is challenging, but with the establishment of a new DNA barcoding authentication system for common herbal plants in the tropics, the existing quality assurance and adulteration screening programs employed by regulatory agencies could be significantly strengthened.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsF2mu7fF&md5=9216e652ad786af7bed161b0391c30bc
  82. 82
    Raja, H. A.; Miller, A. N.; Pearce, C. J.; Oberlies, N. H. J. Nat. Prod. 2017, 80, 756– 770,  DOI: 10.1021/acs.jnatprod.6b01085
    Google Scholar
    82
    Fungal Identification Using Molecular Tools: A Primer for the Natural Products Research Community
    Raja, Huzefa A.; Miller, Andrew N.; Pearce, Cedric J.; Oberlies, Nicholas H.
    Journal of Natural Products (2017), 80 (3), 756-770CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    A review. Fungi are morphol., ecol., metabolically, and phylogenetically diverse. They are known to produce numerous bioactive mols., which makes them very useful for natural products researchers in their pursuit of discovering new chem. diversity with agricultural, industrial, and pharmaceutical applications. Despite their importance in natural products chem., identification of fungi remains a daunting task for chemists, esp. those who do not work with a trained mycologist. The purpose of this review is to update natural products researchers about the tools available for mol. identification of fungi. In particular, we discuss (1) problems of using morphol. alone in the identification of fungi to the species level; (2) the three nuclear ribosomal genes most commonly used in fungal identification and the potential advantages and limitations of the ITS region, which is the official DNA barcoding marker for species-level identification of fungi; (3) how to use NCBI-BLAST search for DNA barcoding, with a cautionary note regarding its limitations; (4) the numerous curated mol. databases contg. fungal sequences; (5) the various protein-coding genes used to augment or supplant ITS in species-level identification of certain fungal groups; and (6) methods used in the construction of phylogenetic trees from DNA sequences to facilitate fungal species identification. We recommend that, whenever possible, both morphol. and mol. data be used for fungal identification. Our goal is that this review will provide a set of standardized procedures for the mol. identification of fungi that can be utilized by the natural products research community.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis1agtr8%253D&md5=5da43eae011fd414b20212e0f6d57072

Cited By

Click to copy section linkSection link copied!
Citation Statements
Explore this article's citation statements on scite.ai
powered by  Scite

This article is cited by 77 publications.

  1. Xing He, Kangli Liu, Shengnan Yan, Yue Wang, Yuqin Jiang, Xinying Zhang, Xuesen Fan. Synthesis of 1,7-Fused Indolines Tethered with Spiroindolinone Based on C–H Activation Strategy with Air as a Sustainable Oxidant. The Journal of Organic Chemistry 2024, 89 (3) , 1880-1897. https://doi.org/10.1021/acs.joc.3c02630
  2. Weiming Hu, Jiali Huang, Gang Gao, Wenting Guo, Fujun Yin, Yang Sun, Jingjiao Huang, Chuanzhou Tao, Li Tao, Huayou Hu. Palladium-Catalyzed Dearomatization of Indoles with Alkynes: Construction of Spirocyclohexaneindolenines. The Journal of Organic Chemistry 2023, 88 (15) , 11335-11345. https://doi.org/10.1021/acs.joc.3c01041
  3. Larissa C. Laforest, Michelle A. Kuntz, Siva Rama Raju Kanumuri, Sushobhan Mukhopadhyay, Abhisheak Sharma, Sarah E. O’Connor, Christopher R. McCurdy, Satya Swathi Nadakuduti. Metabolite and Molecular Characterization of Mitragyna speciosa Identifies Developmental and Genotypic Effects on Monoterpene Indole and Oxindole Alkaloid Composition. Journal of Natural Products 2023, 86 (4) , 1042-1052. https://doi.org/10.1021/acs.jnatprod.3c00092
  4. Zeinab Y. Al Subeh, Laura Flores-Bocanegra, Huzefa A. Raja, Joanna E. Burdette, Cedric J. Pearce, Nicholas H. Oberlies. Embellicines C-E: Macrocyclic Alkaloids with a Cyclopenta[b]fluorene Ring System from the Fungus Sarocladium sp.. Journal of Natural Products 2023, 86 (3) , 596-603. https://doi.org/10.1021/acs.jnatprod.2c01048
  5. Carsten Schotte, Yindi Jiang, Dagny Grzech, Thu-Thuy T. Dang, Larissa C. Laforest, Francisco León, Marco Mottinelli, Satya Swathi Nadakuduti, Christopher R. McCurdy, Sarah E. O’Connor. Directed Biosynthesis of Mitragynine Stereoisomers. Journal of the American Chemical Society 2023, 145 (9) , 4957-4963. https://doi.org/10.1021/jacs.2c13644
  6. Lingkai Kong, Wenyue Tian, Zhiyan Liu, Ting Xu, Haoyue Wen, Zihan Chen, Jin Gao, Li-Ping Bai. TfOH-Catalyzed Cascade C–H/N–H Chemo-/Regioselective Annulation of Indole-2-carboxamides with Benzoquinones for the Construction of Anticancer Tetracyclic Indolo[2,3-c]quinolinones. The Journal of Organic Chemistry 2022, 87 (12) , 7955-7967. https://doi.org/10.1021/acs.joc.2c00598
  7. Beibei Zhang, Xiaoxian Li, Zhenkang Ai, Bingyue Zhao, Zhenyang Yu, Yunfei Du. Chemoselective Synthesis of Sulfenylated Spiroindolenines from Indolyl-ynones via Organosulfenyl Chloride-Mediated Dearomatizing Spirocyclization. Organic Letters 2022, 24 (1) , 390-394. https://doi.org/10.1021/acs.orglett.1c04063
  8. Soumen Chakraborty, Rajendra Uprety, Samuel T. Slocum, Takeshi Irie, Valerie Le Rouzic, Xiaohai Li, Lisa L. Wilson, Brittany Scouller, Amy F. Alder, Andrew C. Kruegel, Michael Ansonoff, Andras Varadi, Shainnel O. Eans, Amanda Hunkele, Abdullah Allaoa, Sanjay Kalra, Jin Xu, Ying Xian Pan, John Pintar, Bronwyn M. Kivell, Gavril W. Pasternak, Michael D. Cameron, Jay P. McLaughlin, Dalibor Sames, Susruta Majumdar. Oxidative Metabolism as a Modulator of Kratom’s Biological Actions. Journal of Medicinal Chemistry 2021, 64 (22) , 16553-16572. https://doi.org/10.1021/acs.jmedchem.1c01111
  9. Soumen Chakraborty, Jeffrey F. DiBerto, Abdelfattah Faouzi, Sarah M. Bernhard, Anna M. Gutridge, Steven Ramsey, Yuchen Zhou, Davide Provasi, Nitin Nuthikattu, Rahul Jilakara, Melissa N. F. Nelson, Wesley B. Asher, Shainnel O. Eans, Lisa L. Wilson, Satyanarayana M. Chintala, Marta Filizola, Richard M. van Rijn, Elyssa B. Margolis, Bryan L. Roth, Jay P. McLaughlin, Tao Che, Dalibor Sames, Jonathan A. Javitch, Susruta Majumdar. A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects. Journal of Medicinal Chemistry 2021, 64 (18) , 13873-13892. https://doi.org/10.1021/acs.jmedchem.1c01273
  10. Soumen Chakraborty, Rajendra Uprety, Amal E. Daibani, Valerie L. Rouzic, Amanda Hunkele, Kevin Appourchaux, Shainnel O. Eans, Nitin Nuthikattu, Rahul Jilakara, Lisa Thammavong, Gavril W. Pasternak, Ying-Xian Pan, Jay P. McLaughlin, Tao Che, Susruta Majumdar. Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom. ACS Chemical Neuroscience 2021, 12 (14) , 2661-2678. https://doi.org/10.1021/acschemneuro.1c00149
  11. Nelson Jeng-Yeou Chear, Francisco León, Abhisheak Sharma, Siva Rama Raju Kanumuri, Grant Zwolinski, Khalil A. Abboud, Darshan Singh, Luis F. Restrepo, Avi Patel, Takato Hiranita, Surash Ramanathan, Aidan J. Hampson, Lance R. McMahon, Christopher R. McCurdy. Exploring the Chemistry of Alkaloids from Malaysian Mitragyna speciosa (Kratom) and the Role of Oxindoles on Human Opioid Receptors. Journal of Natural Products 2021, 84 (4) , 1034-1043. https://doi.org/10.1021/acs.jnatprod.0c01055
  12. Taslima Begum, Mohd Hafiz Arzmi, Murni Nazira Sarian, Syed Adnan Ali Shah, Syed Najmul Hejaz Azmi, ABM Helal Uddin, Alfi Khatib, Qamar Uddin Ahmed. A review on multi-therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7-hydroxymitragynine: Experimental evidence and future perspectives. Kuwait Journal of Science 2025, 52 (2) , 100381. https://doi.org/10.1016/j.kjs.2025.100381
  13. Taslima Begum, Mohd Hafiz Arzmi, Alfi Khatib, A.B.M. Helal Uddin, Maryam Aisyah Abdullah, Kamal Rullah, Siti Zaiton Mat So’ad, Nur Fatihah Zulaikha Haspi, Murni Nazira Sarian, Humaira Parveen, Sayeed Mukhtar, Qamar Uddin Ahmed. A review on Mitragyna speciosa (Rubiaceae) as a prominent medicinal plant based on ethnobotany, phytochemistry and pharmacological activities. Natural Product Research 2025, 39 (6) , 1636-1652. https://doi.org/10.1080/14786419.2024.2371564
  14. Niklāvs Ūdris, Rebeka Ločmele, Juris Pelšs, Anastasija Ture, Guna Sakaine, Artis Kinēns, Gints Smits. Enantiopure piperidines via stereoselective Ireland–Claisen rearrangement: entry into corynanthe alkaloids. Organic Chemistry Frontiers 2025, 12 (6) , 1945-1950. https://doi.org/10.1039/D4QO02235A
  15. Kristine L. Witt, Jan van Benthem, Tetyana Kobets, Guosheng Chen, Olaf Kelber, Julie Krzykwa, James T. MacGregor, Nan Mei, Constance A. Mitchell, Ivonne Rietjens, Zehra Sarigol-Kilic, Stephanie L. Smith-Roe, Helga Stopper, Yax Thakkar, Errol Zeiger, Stefan Pfuhler. A proposed screening strategy for evaluating the genotoxicity potential of botanicals and botanical extracts. Food and Chemical Toxicology 2025, 197 , 115277. https://doi.org/10.1016/j.fct.2025.115277
  16. Danni Chu, Hongkui Wang, Zhiwen Nie, Kang-li Li, Jiaqing Cao, Meijing Yang, Qin Yin, Yang Gu, Yindi Jiang. Collective biosynthesis of plant spirooxindole alkaloids through enzyme discovery and engineering. 2025https://doi.org/10.1101/2025.01.28.635216
  17. Jaewook Hwang, Jonathan Kirshner, Daniel André Ramey Deschênes, Matthew Bailey Richardson, Steven J. Fleck, Jun Guo, Jacob Owen Perley, Mohammadamin Shahsavarani, Jorge Jonathan Oswaldo Garza-Garcia, Alyssa Dawn Seveck, Savannah Sadie Doiron, Zhan Mai, Stephen Nelson Silliphant, Larry Calhoun, Di Gao, Jiazhang Lian, Ghislain Deslongchamps, Victor A. Albert, Yang Qu. Ancient gene clusters initiate monoterpenoid indole alkaloid biosynthesis and C3 stereochemistry inversion. 2025https://doi.org/10.1101/2025.01.07.631695
  18. Ihsanul Arief, Gagus Ketut Sunnardianto, Syahrul Khairi, Wahyu Dita Saputri. The potential of Mitragyna speciosa leaves as a natural source of antioxidants for disease prevention. Journal of Integrative Bioinformatics 2025, 21 (4) https://doi.org/10.1515/jib-2023-0030
  19. Allwin McDonald, Yoko Nakamura, Carsten Schotte, Kin Lau, Ryan Alam, Adriana A. Lopes, C. Robin Buell, Sarah O’Connor. Enzymatic epimerization of monoterpene indole alkaloids in Kratom. 2024https://doi.org/10.1101/2024.12.13.628308
  20. Jiang‐Ning Yu, Yue Wang, Ji‐Chen Yin, Yang Wang. Organoiodine Catalysed Intramolecular C−N Bond Oxidative Coupling for the Synthesis of 3‐Monosubstituted Oxindoles. European Journal of Organic Chemistry 2024, 27 (46) https://doi.org/10.1002/ejoc.202400822
  21. Ana C. Ramos-Valdivia, Carlos M. Cerda-García-Rojas. Biosynthesis of oxindole alkaloids: Recent advances and challenges. Current Opinion in Plant Biology 2024, 82 , 102648. https://doi.org/10.1016/j.pbi.2024.102648
  22. Teni Ernawati, Faris Hermawan, Susi Kusumaningrum. A Review on Isolation, Characterization, Biosynthesis, Synthesis, Modification, Pharmacological Activities and Toxicology of Mitragynine. Gazi University Journal of Science 2024, 37 (4) , 1654-1672. https://doi.org/10.35378/gujs.1395354
  23. Suleiman Abubakar Garba, Khozirah Shaari, Mohd Rashidi Abdul Manap, Soo Yee Lee, Isah Abdulazeez, Siti Munirah Mohd Faudzi. Quantitative analysis of selected alkaloids of Mitragyna speciosa using 1 H quantitative nuclear magnetic resonance spectroscopy. Magnetic Resonance in Chemistry 2024, 62 (11) , 803-813. https://doi.org/10.1002/mrc.5477
  24. András Dohárszky, Erika Mária Vági, Árpád Könczöl, Alexandra Simon, Erzsébet Várnagy, Miras Muratov, Kristóf István Steiger, Bianka Várnai, Szabolcs Béni, Eszter Riethmüller, Ida Fejős. Kratom Alkaloids: A Blood–Brain Barrier Specific Membrane Permeability Assay-Guided Isolation and Cyclodextrin Complexation Study. Molecules 2024, 29 (22) , 5302. https://doi.org/10.3390/molecules29225302
  25. Kirsten E. Smith, Leigh V. Panlilio, Abhisheak Sharma, Christopher R. McCurdy, Jeffrey D. Feldman, Sushobhan Mukhopadhyay, Siva Rama Raju Kanumuri, Michelle A. Kuntz, Katherine Hill, David H. Epstein. Time course of kratom effects via ecological momentary assessment, by product type, dose amount, and assayed alkaloid content. Drug and Alcohol Dependence 2024, 264 , 112460. https://doi.org/10.1016/j.drugalcdep.2024.112460
  26. Jegathiswary Ganasan, Thiruventhan Karunakaran, Yathindra Marimuthu, Nurul Najwa Rusmadi, Noor Syarafana Firouz, Janar Jenis, U. Seeta Uthaya Kumar. Chemistry and toxicity of 7-hydroxymitragynine (7-OHMG): an updated review on the oxidized derivative of mitragynine. Phytochemistry Reviews 2024, 218 https://doi.org/10.1007/s11101-024-10029-x
  27. Jorge Jonathan Oswaldo Garza-Garcia, Yang Qu. Chemical, pharmacological properties and biosynthesis of opioid mitragynine in Mitragyna speciosa (kratom). Current Opinion in Plant Biology 2024, 81 , 102600. https://doi.org/10.1016/j.pbi.2024.102600
  28. Christian P. Müller, Yuting Yang, Darshan Singh, Bernd Lenz, Elisabeth Müller. Kratom – vom natürlichen Heilmittel zur Suchtdroge und zurück. Der Nervenarzt 2024, 95 (9) , 824-829. https://doi.org/10.1007/s00115-024-01721-6
  29. Cassidy R. LoParco, Carlton Bone, Carla J. Berg, Matthew E. Rossheim, Noah C. Peeri, Kayla K. Tillett, Dong-Chul Seo. Associations Between Opioid and Kratom Use in the USA: Differences by Race/Ethnicity and Sexual Orientation. Journal of Racial and Ethnic Health Disparities 2024, 23 https://doi.org/10.1007/s40615-024-02142-6
  30. Thiruventhan Karunakaran, Jegathiswary Ganasan, Nurul Najwa Rusmadi, Rameshkumar Santhanam, Mohd Nizam Mordi. In-vitro hepatotoxic activity of mitragynine and paynantheine isolated from the leaves of Mitragyna speciosa Korth. (Kratom). Natural Product Research 2024, 17 , 1-5. https://doi.org/10.1080/14786419.2024.2375760
  31. Tanyamon Petcharat, Thanasak Sae-leaw, Soottawat Benjakul, Tran Hong Quan, Sylvia Indriani, Yuthana Phimolsiripol, Supatra Karnjanapratum. Extraction of Kratom (Mitragyna speciosa) leaf compounds by enzymatic hydrolysis-assisted process: Yield, characteristics and its in vitro cytotoxicity in cell lines. Process Biochemistry 2024, 142 , 212-222. https://doi.org/10.1016/j.procbio.2024.04.033
  32. Sanya Sureram, Nopporn Chutiwitoonchai, Tam Pooprasert, Watchara Sangsopha, Suphitcha Limjiasahapong, Narumol Jariyasopit, Yongyut Sirivatanauksorn, Sakda Khoomrung, Chulabhorn Mahidol, Somsak Ruchirawat, Prasat Kittakoop. Discovery of procyanidin condensed tannins of (−)-epicatechin from Kratom, Mitragyna speciosa, as virucidal agents against SARS-CoV-2. International Journal of Biological Macromolecules 2024, 273 , 133059. https://doi.org/10.1016/j.ijbiomac.2024.133059
  33. Jack E. Henningfield, Oliver Grundmann, Marilyn A. Huestis, Kirsten E. Smith. Kratom safety and toxicology in the public health context: research needs to better inform regulation. Frontiers in Pharmacology 2024, 15 https://doi.org/10.3389/fphar.2024.1403140
  34. Punlop Kuntiyong, Artid Buaphan, Jitnapa Sirirak, Sasipa Booranamonthol, Phongsathon Khlongkhlaeo, Kittisak Thammapichai, Sucharat Sanongkiet. Synthesis of Spiro[isoxazolidino[4,5-f]indolizidine-8,3′-oxindole], Spiro[indolizidine-1,3′-oxindoles], Indolo[2,3-a]quinolizidines and their anti-α-glucosidase activity. Tetrahedron 2024, 155 , 133907. https://doi.org/10.1016/j.tet.2024.133907
  35. Ferydoon Khamooshi, Ayobami Sunday Akinnawo, Samaneh Doraji-Bonjar, Ali Reza Modarresi-Alam. Mitragynine Chemistry: Extraction, Synthesis, and Clinical Effects. Chemistry Africa 2024, 34 https://doi.org/10.1007/s42250-024-00921-6
  36. Kirsten E. Smith, Jeffrey M. Rogers, Abhisheak Sharma, Christopher R. McCurdy, Stephanie T. Weiss, Kelly E. Dunn, Jeffrey D. Feldman, Michelle A. Kuntz, Sushobhan Mukhopadhyay, Kanumuri Siva Rama Raju, Richard C. Taylor, David H. Epstein. Responses to a “Typical” Morning Dose of Kratom in People Who Use Kratom Regularly: A Direct-Observation Study. Journal of Addiction Medicine 2024, 18 (2) , 144-152. https://doi.org/10.1097/ADM.0000000000001259
  37. Christopher R. McCurdy, Abhisheak Sharma, Kirsten E. Smith, Charles A. Veltri, Stephanie T. Weiss, Charles M. White, Oliver Grundmann. An update on the clinical pharmacology of kratom: uses, abuse potential, and future considerations. Expert Review of Clinical Pharmacology 2024, 17 (2) , 131-142. https://doi.org/10.1080/17512433.2024.2305798
  38. Moriel J Dror, Joshua Misa, Danielle A Yee, Angela M Chu, Rachel K Yu, Bradley B Chan, Lauren S Aoyama, Anjali P Chaparala, Sarah E O'Connor, Yi Tang. Engineered biosynthesis of plant heteroyohimbine and corynantheine alkaloids in Saccharomyces cerevisiae. Journal of Industrial Microbiology and Biotechnology 2024, 51 https://doi.org/10.1093/jimb/kuad047
  39. Yuting Yang, Christian P. Müller, Darshan Singh. Kratom (Mitragyna speciosa) Use and Mental Health: A Systematic Review and Multilevel Meta-Analysis. European Addiction Research 2024, 30 (4) , 252-274. https://doi.org/10.1159/000539338
  40. Anwar Salm Kalifa Kafo, Hasni Mahayidin, Nur Fatin Zalikha Zailan, Uswatun Hasanah Zaidan, Sharifah Nurfadhlin Afifah Syed Azhar, Rajesh Ramasamy, Masriana Hassan. Isolation of Phytochemical and Pharmacological Bioactive Compounds From Mitragyna speciosa (Korth.): A Scoping Review. Malaysian Journal of Medicine and Health Sciences 2023, 19 (s16) , 38-47. https://doi.org/10.47836/mjmhs.19.s16.7
  41. Rahni Hossain, Abida Sultana, Manit Nuinoon, Kunwadee Noonong, Jitbanjong Tangpong, Kazi Helal Hossain, Md Atiar Rahman. A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds. Molecules 2023, 28 (21) , 7372. https://doi.org/10.3390/molecules28217372
  42. Kyunghee Kim, Mohammadamin Shahsavarani, Jorge Jonathan Oswaldo Garza‐García, Jack Edward Carlisle, Jun Guo, Vincenzo De Luca, Yang Qu. Biosynthesis of kratom opioids. New Phytologist 2023, 240 (2) , 757-769. https://doi.org/10.1111/nph.19162
  43. Zurina Hassan, Darshan Singh, Farah Wahida Suhaimi, Nelson Jeng-Yeou Chear, Norsyifa Harun, Cheah Pike See, Gurjeet Kaur, Noorul Hamizah Mat, Siti Najmi Syuhadaa Bakar, Nur Sabrina Mohd Yusof, Vicknasingam Balasingam Kasinather, Marek C. Chawarski, Vikneswaran Murugaiyah, Surash Ramanathan. Evaluation of toxicity profile of kratom (Mitragyna speciosa Korth) decoction in rats. Regulatory Toxicology and Pharmacology 2023, 143 , 105466. https://doi.org/10.1016/j.yrtph.2023.105466
  44. Cinzia Citti, Aldo Laganà, Anna Laura Capriotti, Carmela Maria Montone, Giuseppe Cannazza. Kratom: The analytical challenge of an emerging herbal drug. Journal of Chromatography A 2023, 1703 , 464094. https://doi.org/10.1016/j.chroma.2023.464094
  45. Rakshit S. Tanna, Nadja B. Cech, Nicholas H. Oberlies, Allan E. Rettie, Kenneth E. Thummel, Mary F. Paine. Translating Kratom-Drug Interactions: From Bedside to Bench and Back. Drug Metabolism and Disposition 2023, 51 (8) , 923-935. https://doi.org/10.1124/dmd.122.001005
  46. Guido Huisman, Maximilian Menke, Oliver Grundmann, Rudy Schreiber, Natasha Mason. Examining the Psychoactive Differences between Kratom Strains. International Journal of Environmental Research and Public Health 2023, 20 (14) , 6425. https://doi.org/10.3390/ijerph20146425
  47. Rakshit S. Tanna, James T. Nguyen, Deena L. Hadi, Matthew E. Layton, John R. White, Nadja B. Cech, Nicholas H. Oberlies, Allan E. Rettie, Kenneth E. Thummel, Mary F. Paine. Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom. Clinical Pharmacology & Therapeutics 2023, 113 (6) , 1315-1325. https://doi.org/10.1002/cpt.2891
  48. Sushobhan Mukhopadhyay, Sampa Gupta, Jenny L. Wilkerson, Abhisheak Sharma, Lance R. McMahon, Christopher R. McCurdy. Receptor Selectivity and Therapeutic Potential of Kratom in Substance Use Disorders. Current Addiction Reports 2023, 10 (2) , 304-316. https://doi.org/10.1007/s40429-023-00472-9
  49. Pengpeng Zhang, Wei Wei, Xiaohai Zhang, Chaoling Wen, Chitchamai Ovatlarnporn, Opeyemi Joshua Olatunji. Antidiabetic and antioxidant activities of Mitragyna speciosa (kratom) leaf extract in type 2 diabetic rats. Biomedicine & Pharmacotherapy 2023, 162 , 114689. https://doi.org/10.1016/j.biopha.2023.114689
  50. Kristina Jenett-Siems. Mitragyna speciosa Korth., der Kratombaum. Zeitschrift für Phytotherapie 2023, 44 (03) , 139-143. https://doi.org/10.1055/a-1994-9127
  51. Angéline Kernalléguen, Nicolas Fabresse, Isabelle Etting, Islam Amine Larabi, Jean-Claude Alvarez, Anne-Laure Pélissier-Alicot. Identification et dosage de la mitragynine dans les cheveux : à propos d’un cas d’un consommateur régulier de substances psychotropes achetées sur le dark web. Toxicologie Analytique et Clinique 2023, 35 (2) , 160-164. https://doi.org/10.1016/j.toxac.2022.11.004
  52. Rubashiny Veeramohan, Arief Izzairy Zamani, Kamalrul Azlan Azizan, Hoe-Han Goh, Wan Mohd Aizat, Mohd Fauzi Abd Razak, Nur Sabrina Mohd Yusof, Sharif Mahsufi Mansor, Syarul Nataqain Baharum, Chyan Leong Ng, . Comparative metabolomics analysis reveals alkaloid repertoires in young and mature Mitragyna speciosa (Korth.) Havil. Leaves. PLOS ONE 2023, 18 (3) , e0283147. https://doi.org/10.1371/journal.pone.0283147
  53. Nelson Jeng-Yeou Chear, Tan Ai Fein Ching-Ga, Kooi-Yeong Khaw, Francisco León, Wen-Nee Tan, Siti R. Yusof, Christopher R. McCurdy, Vikneswaran Murugaiyah, Surash Ramanathan. Natural Corynanthe-Type Cholinesterase Inhibitors from Malaysian Uncaria attenuata Korth.: Isolation, Characterization, In Vitro and In Silico Studies. Metabolites 2023, 13 (3) , 390. https://doi.org/10.3390/metabo13030390
  54. Thanachon Somnarin, Pacharaporn Krawmanee, Matthew Paul Gleeson, Duangkamol Gleeson. Computational investigation of the radical‐mediated mechanism of formation of difluoro methyl oxindoles: Elucidation of the reaction selectivity and yields. Journal of Computational Chemistry 2023, 44 (5) , 670-676. https://doi.org/10.1002/jcc.27031
  55. Tuan-Anh M. Nguyen, Dagny Grzech, Khoa Chung, Zhicheng Xia, Trinh-Don Nguyen, Thu-Thuy T. Dang. Discovery of a cytochrome P450 enzyme catalyzing the formation of spirooxindole alkaloid scaffold. Frontiers in Plant Science 2023, 14 https://doi.org/10.3389/fpls.2023.1125158
  56. Melissa Hughs, Erik Kish-Trier, Aidin O’Brien, Gwendolyn A McMillin. Analysis of Mitragynine and Speciociliatine in Umbilical Cord by LC–MS-MS for Detecting Prenatal Exposure to Kratom. Journal of Analytical Toxicology 2023, 46 (9) , 957-964. https://doi.org/10.1093/jat/bkac064
  57. David Love, Nicole S. Jones. Interpol Review of Drug Analysis 2019-2022. Forensic Science International: Synergy 2023, 6 , 100299. https://doi.org/10.1016/j.fsisyn.2022.100299
  58. Maxsaya Baez Nunez, Annika Dhingra, Myra Dhingra, Rachael Kossack, Monica Dhingra. Kratom's rising role in the potential exacerbation of mental health disorders: A case report and review of the literature. Psychiatry Research Case Reports 2022, 1 (2) , 100069. https://doi.org/10.1016/j.psycr.2022.100069
  59. Blake Costine, Mengzi Zhang, Shweta Chhajed, Brian Pearson, Sixue Chen, Satya Swathi Nadakuduti. Exploring native Scutellaria species provides insight into differential accumulation of flavones with medicinal properties. Scientific Reports 2022, 12 (1) https://doi.org/10.1038/s41598-022-17586-1
  60. Syed Muhammad Umer, Mehwish Solangi, Khalid Mohammed Khan, Rahman Shah Zaib Saleem. Indole-Containing Natural Products 2019–2022: Isolations, Reappraisals, Syntheses, and Biological Activities. Molecules 2022, 27 (21) , 7586. https://doi.org/10.3390/molecules27217586
  61. Wirulda Pootakham, Thippawan Yoocha, Nukoon Jomchai, Wasitthee Kongkachana, Chaiwat Naktang, Chutima Sonthirod, Srimek Chowpongpang, Panyavut Aumpuchin, Sithichoke Tangphatsornruang. A Chromosome-Scale Genome Assembly of Mitragyna speciosa (Kratom) and the Assessment of Its Genetic Diversity in Thailand. Biology 2022, 11 (10) , 1492. https://doi.org/10.3390/biology11101492
  62. David A. Gorelick. Kratom: Substance of Abuse or Therapeutic Plant?. Psychiatric Clinics of North America 2022, 45 (3) , 415-430. https://doi.org/10.1016/j.psc.2022.04.002
  63. Preston K. Manwill, Laura Flores-Bocanegra, Manead Khin, Huzefa A. Raja, Nadja B. Cech, Nicholas H. Oberlies, Daniel A. Todd. Kratom (Mitragyna speciosa) Validation: Quantitative Analysis of Indole and Oxindole Alkaloids Reveals Chemotypes of Plants and Products. Planta Medica 2022, 88 (09/10) , 838-857. https://doi.org/10.1055/a-1795-5876
  64. Weerasak Songoen, Lothar Brecker, Thitaree Yooboon, Vasakorn Bullangpoti, Wanchai Pluempanupat, Johann Schinnerl. Ursane-type triterpenoids, steroids and phenolics from the stem bark and leaves of Nauclea orientalis (L.) L. (Rubiaceae). Biochemical Systematics and Ecology 2022, 102 , 104401. https://doi.org/10.1016/j.bse.2022.104401
  65. Neni Isnaeni, Asep Saefumillah, Antonius Herry Cahyana. Preliminary Study of Isolation and Purification Mitragynine from Kratom Leaves. Materials Science Forum 2022, 1061 , 173-179. https://doi.org/10.4028/p-74ggl5
  66. Mengzi Zhang, Abhisheak Sharma, Francisco León, Bonnie Avery, Roger Kjelgren, Christopher R. McCurdy, Brian J. Pearson, . Plant growth and phytoactive alkaloid synthesis in kratom [Mitragyna speciosa (Korth.)] in response to varying radiance. PLOS ONE 2022, 17 (4) , e0259326. https://doi.org/10.1371/journal.pone.0259326
  67. Lin Chen, Shizao Fei, Opeyemi Joshua Olatunji. LC/ESI/TOF-MS Characterization, Anxiolytic and Antidepressant-like Effects of Mitragyna speciosa Korth Extract in Diabetic Rats. Molecules 2022, 27 (7) , 2208. https://doi.org/10.3390/molecules27072208
  68. Bianka Várnai, Ferenc Zsila, Zoltán Szakács, Zsófia Garádi, Milo Malanga, Szabolcs Béni. Sulfobutylation of Beta-Cyclodextrin Enhances the Complex Formation with Mitragynine: An NMR and Chiroptical Study. International Journal of Molecular Sciences 2022, 23 (7) , 3844. https://doi.org/10.3390/ijms23073844
  69. Rakshit S. Tanna, James T. Nguyen, Deena L. Hadi, Preston K. Manwill, Laura Flores-Bocanegra, Matthew E. Layton, John R. White, Nadja B. Cech, Nicholas H. Oberlies, Allan E. Rettie, Kenneth E. Thummel, Mary F. Paine. Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants. Pharmaceutics 2022, 14 (3) , 620. https://doi.org/10.3390/pharmaceutics14030620
  70. Thiruventhan Karunakaran, Kok Zhuo Ngew, Ahmad Alif Danial Zailan, Vivien Yi Mian Jong, Mohamad Hafizi Abu Bakar. The Chemical and Pharmacological Properties of Mitragynine and Its Diastereomers: An Insight Review. Frontiers in Pharmacology 2022, 13 https://doi.org/10.3389/fphar.2022.805986
  71. Fanpeng Yang, Yina Hu, Lu Wang, Miaomiao Wu, Xiaowen Yuan, Zhigang Liu, Xiuhuan Li, Zhengshen Wang, Huaiji Zheng. Palladium‐Catalyzed Coupling Reaction of o ‐Alkenyl Chloroformylaniline with o ‐Alkynylaniline: An Approach to Indolylmethyl Oxindole. Asian Journal of Organic Chemistry 2022, 11 (2) https://doi.org/10.1002/ajoc.202100750
  72. Sarah Kerrigan, Stephanie Basiliere. Kratom: A systematic review of toxicological issues. WIREs Forensic Science 2022, 4 (1) https://doi.org/10.1002/wfs2.1420
  73. Gregory Domnic, Nelson Jeng-Yeou Chear, Siti Fairus Abdul Rahman, Surash Ramanathan, Kwok-Wai Lo, Darshan Singh, Nethia Mohana-Kumaran. Combinations of indole based alkaloids from Mitragyna speciosa (Kratom) and cisplatin inhibit cell proliferation and migration of nasopharyngeal carcinoma cell lines. Journal of Ethnopharmacology 2021, 279 , 114391. https://doi.org/10.1016/j.jep.2021.114391
  74. Thenmoly Damodaran, Nelson Jeng-Yeou Chear, Vikneswaran Murugaiyah, Mohd Nizam Mordi, Surash Ramanathan. Comparative Toxicity Assessment of Kratom Decoction, Mitragynine and Speciociliatine Versus Morphine on Zebrafish (Danio rerio) Embryos. Frontiers in Pharmacology 2021, 12 https://doi.org/10.3389/fphar.2021.714918
  75. Qianting Zhou, Xia Song, Xinying Zhang, Xuesen Fan. Synthesis of 3-spirooxindole 3 H -indoles through Rh( iii )-catalyzed [4 + 1] redox-neutral spirocyclization of N -aryl amidines with diazo oxindoles. Organic Chemistry Frontiers 2021, 8 (15) , 4131-4137. https://doi.org/10.1039/D1QO00551K
  76. Cooper S. Jamieson, Joshua Misa, Yi Tang, John M. Billingsley. Biosynthesis and synthetic biology of psychoactive natural products. Chemical Society Reviews 2021, 50 (12) , 6950-7008. https://doi.org/10.1039/D1CS00065A
  77. Zhen‐Long Yu, Rong Bai, Jun‐Jun Zhou, Hui‐Lian Huang, Wen‐Yu Zhao, Xiao‐Kui Huo, Ya‐Hui Yang, Zhi‐Lin Luan, Bao‐Jing Zhang, Cheng‐Peng Sun, Xiao‐Chi Ma. Uncarialins J—M from Uncaria rhynchophylla and Their Anti‐depression Mechanism in Unpredictable Chronic Mild Stress‐Induced Mice via Activating 5‐HT 1A Receptor. Chinese Journal of Chemistry 2021, 39 (5) , 1331-1343. https://doi.org/10.1002/cjoc.202000652
  78. Alessandro E. Vento, Simone de Persis, Sergio De Filippis, Fabrizio Schifano, Flavia Napoletano, John M. Corkery, Georgios D. Kotzalidis. Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant. Frontiers in Psychiatry 2021, 12 https://doi.org/10.3389/fpsyt.2021.640218
  79. Rakshit S. Tanna, Dan-Dan Tian, Nadja B. Cech, Nicholas H. Oberlies, Allan E. Rettie, Kenneth E. Thummel, Mary F. Paine. Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations. The Journal of Pharmacology and Experimental Therapeutics 2021, 376 (1) , 64-73. https://doi.org/10.1124/jpet.120.000270
  80. D. A. Todd, J. J. Kellogg, E. D. Wallace, M. Khin, L. Flores-Bocanegra, R. S. Tanna, S. McIntosh, H. A. Raja, T. N. Graf, S. E. Hemby, M. F. Paine, N. H. Oberlies, N. B. Cech. Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions. Scientific Reports 2020, 10 (1) https://doi.org/10.1038/s41598-020-76119-w
Download PDF
Go to Journal of Natural Products
Get e-Alerts
Get e-Alerts

Journal of Natural Products

Cite this: J. Nat. Prod. 2020, 83, 7, 2165–2177
Click to copy citationCitation copied!
https://doi.org/10.1021/acs.jnatprod.0c00257
Published June 29, 2020

Copyright © 2020 American Chemical Society and American Society of Pharmacognosy. This publication is licensed under these Terms of Use.

Request reuse permissions

Article Views

37k

Altmetric

-

Citations

77
Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Decision tree for differentiating among 1–19 based on key NMR signals. As a single starting point, the 13C NMR signal for the lactam moiety is used to distinguish between oxindole (present) and indole (absent) kratom alkaloids. Once the broad structural class is determined, 1H NMR data can be used via a flowchart as a guide to elucidate the structure of these alkaloids.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. Key correlations observed in the COSY and HMBC spectra for compounds 7, 17, and 18. The latter two have the same 2D structure and thus the same correlations.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. Experimental ECD spectrum of 7 in CH3OH at 0.2 mg/mL (dashed line) and calculated ECD spectrum of (3R,15S,20S)-7 (dotted line).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. (A) Experimental ECD spectra of 17 in CH3OH at 0.2 mg/mL (dashed lines) and calculated ECD spectrum of (3R,7R,15S,20R)-17 (dotted lines). (B) Experimental ECD spectra of 18 in CH3OH at 0.2 mg/mL (dashed lines) and calculated ECD spectrum of (3R,7R,15S,20S)-18 (dotted lines).

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    This article references 82 other publications.

    1. 1
      Field, E. J. Chem. Soc., Trans. 1921, 119, 887– 891,  DOI: 10.1039/CT9211900887
      1
      Mitragynine and mitraversine, two new alkaloids from species of Mitragyne
      Field, Ellen
      Journal of the Chemical Society, Transactions (1921), 119 (), 887-91CODEN: JCHTA3; ISSN:0368-1645.
      Mitragyne speciosa, extd. with alc., the alc. residue dissolved in AcOH and dild. to ppt. resin and chlorophyll and then made alk. with NH4OH, gave an amorphous ppt., from an AcOH soln. of which picric acid ppts. mitragynine picrate, C22H31O5N.C6H3O7N3, orange-red slender needles from glacial AcOH, or MeOH, m. 223-4°. Mitragynine, amorphous crysts., b5 230-40°, m. 102-6°, contains 3 MeO groups. Hydrochloride, rhombic leaflets from alc.-Et2O, m. 243°. Acetate, slender silky needles from AcOH-Et2O, m. 142°. Trichloroacetate, C22H31O5N.CCl3CO2H, needles from Me2CO-Et2O, m. .157°. The hydrolysis product of the acetate with EtONa is a dicarboxylic acid, C17H22N(OMe)-(CO2H)2, m. 280°. Distd. with CaO, a green oil was obtained from which a red picrate was prepd., m. 218°. Mitragynine may be a deriv. of indole or at least undergoes decompn. with the formation of such a substance. M. diversifolia, treated with alc. and AcOH as above, the AcOH soln. poured into H2O, made alk., extd. with Et2O, the Et2O extd. with 10% AcOH and this ext. made alk. gave 0.27% of the wt. of the leaves of mitraversine, C22H26O4N2, m. 237°. It contains 2 MeO groups. Hydrochloride, rhombic leaflets, m. 208-10°.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaB3MXhsFejsw%253D%253D&md5=4fff795e629ece791683dc1e20fe7ba2
    2. 2
      Vermaire, D. J.; Skaer, D.; Tippets, W. A. A. Pract. 2019, 12, 103– 105,  DOI: 10.1213/XAA.0000000000000857
      2
      Kratom and General Anesthesia: A Case Report and Review of the Literature
      Vermaire Deborah J; Skaer Deborah; Tippets William
      A&A practice (2019), 12 (4), 103-105 ISSN:.
      Kratom is a botanical substance derived from the Mitragyna speciosa plant, which grows naturally in Southeast Asia. Its active compounds include alkaloids with psychoactive and opioid properties. Low doses act as a stimulant, while higher doses cause analgesia and euphoria. As a drug of abuse, there are reports of seizure, acute psychosis, and death. Both the US Food and Drug Administration and the Drug Enforcement Agency warn against the use of kratom. Here is the first reported case of an anesthetic in a patient using kratom for chronic pain.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c7is1Sltw%253D%253D&md5=c4c6358769a2681fa5d432e565ba8a24
    3. 3
      Schmuhl, K. K.; Gardner, S. M.; Cottrill, C. B.; Bonny, A. E. Subst. Abus. 2019, 1– 4,  DOI: 10.1080/08897077.2019.1671945
      3
      Home induction and outpatient treatment of kratom use disorder with buprenorphine-naloxone: A case report in a young adult
      Schmuhl Kelsey K; Schmuhl Kelsey K; Cottrill Casey B; Gardner Spencer M; Cottrill Casey B; Bonny Andrea E
      Substance abuse (2019), (), 1-4 ISSN:.
      Background: The use of the natural product, kratom, has increased significantly in recent years. The active compounds in kratom have been shown to produce both opioid and stimulant-like effects. While kratom is marketed as a safe, non-addictive method to treat pain and opioid withdrawal, there have been reports demonstrating that kratom is physiologically addictive and linked to overdose deaths. A limited number of case-reports are available describing treatment of kratom use disorder in middle-aged adults, generally in the context of chronic pain and in inpatient settings. Our case is unique in that we describe outpatient treatment of kratom use disorder in a young adult with comorbid attention deficit hyperactivity disorder (ADHD) and in the absence of chronic pain. Case: A 20-year-old college student with ADHD presented to an office-based opioid agonist treatment clinic (OBOT) for treatment of kratom use disorder. He was unable to attend inpatient or residential substance use treatment due to work and school obligations. Additionally, he had stopped taking his prescribed stimulant due to cardiac side effects. The OBOT team successfully initiated buprenorphine-naloxone (BUP/NAL) sublingual films via home induction to treat his kratom use disorder. The patient is being monitored monthly with plans to slowly taper his BUP/NAL dose as tolerated. Discussion: We present a case of a young adult male with kratom use disorder, complicated by a diagnosis of ADHD, successfully treated with BUP/NAL via home induction. The patient is currently kratom-free, reports improved mood and sleep patterns since initiating BUP/NAL, and is able to once again tolerate his ADHD stimulant medication. Healthcare providers should be aware of the use of kratom and consider utilizing BUP/NAL to treat dependence to this botanical drug.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MjgvFemtw%253D%253D&md5=eedc1ff52346299b8be5d9893014f7b0
    4. 4
      Coe, M. A.; Pillitteri, J. L.; Sembower, M. A.; Gerlach, K. K.; Henningfield, J. E. Drug Alcohol Depend. 2019, 202, 24– 32,  DOI: 10.1016/j.drugalcdep.2019.05.005
      4
      Kratom as a substitute for opioids: Results from an online survey
      Coe, Marion A.; Pillitteri, Janine L.; Sembower, Mark A.; Gerlach, Karen K.; Henningfield, Jack E.
      Drug and Alcohol Dependence (2019), 202 (), 24-32CODEN: DADEDV; ISSN:0376-8716. (Elsevier Ireland Ltd.)
      Kratom is a South Eastern Asian tree whose leaves are used to make tea-like brews or swallowed in powd. form for various health and well-being reasons including to relieve pain and opioid withdrawal. It is important to learn more about the potential public health impact of kratom in the context of the opioid epidemic. An anonymous online survey of kratom users was conducted in Sept. 2017 through the American Kratom Assocn. and assocd. social media sites. Kratom was used primarily to relieve pain (endorsed by 48% of respondents), for anxiety, PTSD, or depression (22%), to increase energy or focus (10%) and to help cut down on opioid use and/or relieve withdrawal (10%). Over 90% of respondents who used it in place of opioids indicated that it was helpful to relieve pain, reduce opioid use, and relieve withdrawal. The reported incidence of bad adverse reactions was 13%, and reactions were overwhelmingly mild and self-managed. Respondents reported using kratom for conditions which often require use of opioids, including pain and redn. of opioid use. The high self-reported efficacy and low incidence of adverse reactions assocd. with kratom use suggest that it may provide a potential alternative to opioids for some persons even though it has not been evaluated in multi-center clin. trials or approved for any therapeutic purpose. Further study of kratom, including systematic characterization of its safety and efficacy for various conditions is warranted.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlejurvN&md5=879225fc2c5d7f7e617a63b695623eb9
    5. 5
      Buresh, M. J. Addict. Med. 2018, 12, 481– 483,  DOI: 10.1097/ADM.0000000000000428
      There is no corresponding record for this reference.
    6. 6
      Corkery, J. M.; Streete, P.; Claridge, H.; Goodair, C.; Papanti, D.; Orsolini, L.; Schifano, F.; Sikka, K.; Korber, S.; Hendricks, A. J. Psychopharmacol. 2019, 33, 1102– 1123,  DOI: 10.1177/0269881119862530
      6
      Characteristics of deaths associated with kratom use
      Corkery John M; Papanti Duccio; Orsolini Laura; Schifano Fabrizio; Sikka Kanav; Streete Peter; Claridge Hugh; Goodair Christine; Korber Sophie; Hendricks Amy
      Journal of psychopharmacology (Oxford, England) (2019), 33 (9), 1102-1123 ISSN:.
      BACKGROUND: Kratom (Mitragyna speciosa Korth) use has increased in Western countries, with a rising number of associated deaths. There is growing debate about the involvement of kratom in these events. AIMS: This study details the characteristics of such fatalities and provides a 'state-of-the-art' review. METHODS: UK cases were identified from mortality registers by searching with the terms 'kratom', 'mitragynine', etc. Databases and online media were searched using these terms and 'death', 'fatal*', 'overdose', 'poisoning', etc. to identify additional cases; details were obtained from relevant officials. Case characteristics were extracted into an Excel spreadsheet, and analysed employing descriptive statistics and thematic analysis. RESULTS: Typical case characteristics (n = 156): male (80%), mean age 32.3 years, White (100%), drug abuse history (95%); reasons for use included self-medication, recreation, relaxation, bodybuilding, and avoiding positive drug tests. Mitragynine alone was identified/implicated in 23% of cases. Poly substance use was common (87%), typically controlled/recreational drugs, therapeutic drugs, and alcohol. Death cause(s) included toxic effects of kratom ± other substances; underlying health issues. CONCLUSIONS: These findings add substantially to the knowledge base on kratom-associated deaths; these need systematic, accurate recording. Kratom's safety profile remains only partially understood; toxic and fatal levels require quantification.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mvps1Gluw%253D%253D&md5=3c7117b77f7cf98ad5b17be0bf1c4c6d
    7. 7
      Murthy, P.; Clark, D. Paediatr. Child. Health. 2019, 24, 12– 14,  DOI: 10.1093/pch/pxy084
      7
      An unusual cause for neonatal abstinence syndrome
      Murthy Prashanth; Clark Deborah
      Paediatrics & child health (2019), 24 (1), 12-14 ISSN:1205-7088.
      Neonatal abstinence syndrome (NAS) secondary to maternal drug use is a well-recognized clinical entity. We present a novel case of moderately severe NAS in a term infant whose mother was self-medicating with kratom tea. The baby required oral morphine for NAS. After 12 days in neonatal intensive care unit, she was discharged on oral morphine which was discontinued after 2 months. Kratom, a psychoactive herb with opioid activity, has traditionally been used as a stimulant to boost energy, cure cough, depression, pain, sickness and a substitute for opium. Although well known in South East Asia and Africa, this drug is less familiar to physicians in North America. It is undetectable by standard urine drug screening and is being sold as a legal herbal remedy. This is the first report of a newborn developing significant NAS after maternal use of kratom tea. We believe physicians should be aware of this 'new' risk to newborns.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cfmtlSmsg%253D%253D&md5=4ebad4fae131d4bb125b95e6b0917470
    8. 8
      Mackay, L.; Abrahams, R. Can. Fam. Physician 2018, 64, 121– 122
      8
      Novel case of maternal and neonatal kratom dependence and withdrawal
      Mackay Lindsay; Abrahams Ronald
      Canadian family physician Medecin de famille canadien (2018), 64 (2), 121-122 ISSN:.
      There is no expanded citation for this reference.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MritF2rsw%253D%253D&md5=26f086b960e337d2f8aee7ad9b257491
    9. 9
      Cumpston, K. L.; Carter, M.; Wills, B. K. Am. J. Emerg. Med. 2018, 36, 166– 168,  DOI: 10.1016/j.ajem.2017.07.051
      9
      Clinical outcomes after Kratom exposures: A poison center case series
      Cumpston Kirk L; Carter Michael; Wills Brandon K
      The American journal of emergency medicine (2018), 36 (1), 166-168 ISSN:.
      There is no expanded citation for this reference.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cfhvVOnsQ%253D%253D&md5=608813d7671b9d89732389fa4ce7ddc3
    10. 10
      Castillo, A.; Payne, J. D.; Nugent, K. Proc. (Bayl. Univ. Med. Cent.) 2017, 30, 355– 357,  DOI: 10.1080/08998280.2017.11929647
      10
      Posterior reversible leukoencephalopathy syndrome after kratom ingestion
      Castillo Austin; Payne J Drew; Nugent Kenneth
      Proceedings (Baylor University. Medical Center) (2017), 30 (3), 355-357 ISSN:0899-8280.
      Posterior reversible encephalopathy syndrome has been associated with hypertension, preeclampsia, cancer chemotherapy, and drugs of abuse, such as amphetamine and methamphetamine. We report a young man who suddenly developed severe headache, disorientation, and aphasia following ingestion of kratom and Adderall. Computed tomography and magnetic resonance imaging of his head revealed foci of vasogenic edema in the posterior occipital lobes, frontal lobes, and brainstem. In addition, he had a small area of hemorrhage in the left posterior occipital lobe. Lumbar puncture revealed an increased number of red blood cells but no other abnormalities. His initial blood pressure was elevated but returned to normal during hospitalization. This case suggests that kratom can cause posterior reversible encephalopathy syndrome and needs to be considered when patients present to emergency centers with headaches, confusion, and visual disturbances.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cjjvVWnuw%253D%253D&md5=2391f9bb57ab0c0598c9020ddf9d50cd
    11. 11
      Galbis-Reig, D. Wmj. 2016, 115, 49– 52
      11
      A Case Report of Kratom Addiction and Withdrawal
      Galbis-Reig David
      WMJ : official publication of the State Medical Society of Wisconsin (2016), 115 (1), 49-52; quiz 53 ISSN:1098-1861.
      Kratom, a relatively unknown herb among physicians in the western world, is advertised on the Internet as an alternative to opioid analgesics, as a potential treatment for oploid withdrawal and as a "legal high" with minimal addiction potential. This report describes a case of kratom addiction in a 37-year-old woman with a severe oploid-like withdrawal syndrome that was managed successfully with symptom-triggered clonidine therapy and scheduled hydroxyzine. A review of other case reports of kratom toxicity, the herb's addiction potential, and the kratom withdrawal syndrome is discussed. Physicians in the United States should be aware of the growing availability and abuse of kratom and the herb's potential adverse health effects, with particular attention to kratom's toxicity, addictive potential, and associated withdrawal syndrome.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fotFahtQ%253D%253D&md5=23312a82e7b101ac8fb58acc64d5b33e
    12. 12
      Karinen, R.; Fosen, J. T.; Rogde, S.; Vindenes, V. Forensic Sci. Int. 2014, 245, e29-e32  DOI: 10.1016/j.forsciint.2014.10.025
      There is no corresponding record for this reference.
    13. 13
      Forrester, M. B. J. Addict. Dis. 2013, 32, 396– 400,  DOI: 10.1080/10550887.2013.854153
      13
      Kratom exposures reported to Texas poison centers
      Forrester Mathias B
      Journal of addictive diseases (2013), 32 (4), 396-400 ISSN:.
      Kratom use is a growing problem in the United States. Kratom exposures reported to Texas poison centers between January 1998 and September 2013 were identified. No kratom exposures were reported from 1998 to 2008 and 14 exposures were reported from 2009 to September 2013. Eleven patients were male, and 11 patients were in their 20s. The kratom was ingested in 12 patients, inhaled in 1, and both ingested and inhaled in 1. Twelve patients were managed at a healthcare facility and the remaining 2 were managed at home.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3lsVChsg%253D%253D&md5=804dd16635e981eb82f7bb1b5befaa9d
    14. 14
      Holler, J. M.; Vorce, S. P.; McDonough-Bender, P. C.; Magluilo, J., Jr.; Solomon, C. J.; Levine, B. J. Anal. Toxicol. 2011, 35, 54– 9,  DOI: 10.1093/anatox/35.1.54
      14
      A Drug Toxicity Death Involving Propylhexedrine and Mitragynine
      Holler, Justin M.; Vorce, Shawn P.; McDonough-Bender, Pamela C.; Magluilo, Joseph, Jr.; Solomon, Carol J.; Levine, Barry
      Journal of Analytical Toxicology (2011), 35 (1), 54-59CODEN: JATOD3; ISSN:0146-4760. (Preston Publications)
      A death involving abuse of propylhexedrine and mitragynine is reported. Propylhexedrine is a potent α-adrenergic sympathomimetic amine found in nasal decongestant inhalers. The decedent was found dead in his living quarters with no signs of phys. trauma. Anal. of his computer showed information on kratom, a plant that contains mitragynine, which produces opiumlike effects at high doses and stimulant effects at low doses, and a procedure to conc. propylhexedrine from over-the-counter inhalers. Toxicol. results revealed the presence of 1.7 mg/L propylhexedrine and 0.39 mg/L mitragynine in his blood. Both drugs, as well as acetaminophen, morphine, and promethazine, were detected in the urine. Quant. results were achieved by gas chromatog.-mass spectrometry monitoring selected ions for the propylhexedrine heptafluorobutyryl deriv. Liq. chromatog.-tandem mass spectrometry in multiple reactions monitoring mode was used to obtain quant. results for mitragynine. The cause of death was ruled propylhexedrine toxicity, and the manner of death was ruled accidental. Mitragynine may have contributed as well, but as there are no published data for drug concns., the medical examiner did not include mitragynine toxicity in the cause of death. This is the first known publication of a case report involving propylhexedrine and mitragynine. (c) 2011 Preston Publications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1yktr0%253D&md5=f3b49903ef9a8ae4c3d8256321326707
    15. 15
      McWhirter, L.; Morris, S. Eur. Addict. Res. 2010, 16, 229– 31,  DOI: 10.1159/000320288
      15
      A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence
      McWhirter Laura; Morris Siobhan
      European addiction research (2010), 16 (4), 229-31 ISSN:.
      Kratom (Mitragyna speciosa) has been used for medicinal and recreational purposes. It has reported analgesic, euphoric and antitussive effects via its action as an agonist at opioid receptors. It is illegal in many countries including Thailand, Malaysia, Myanmar, South Korea and Australia; however, it remains legal or uncontrolled in the UK and USA, where it is easily available over the Internet. We describe a case of kratom dependence in a 44-year-old man with a history of alcohol dependence and anxiety disorder. He demonstrated dependence on kratom with withdrawal symptoms consisting of anxiety, restlessness, tremor, sweating and cravings for the substance. A reducing regime of dihydrocodeine and lofexidine proved effective in treating subjective and objective measures of opioid-like withdrawal phenomena, and withdrawal was relatively short and benign. There are only few reports in the literature of supervised detoxification and drug treatment for kratom dependence. Our observations support the idea that kratom dependence syndrome is due to short-acting opioid receptor agonist activity, and suggest that dihydrocodeine and lofexidine are effective in supporting detoxification.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cfivFensQ%253D%253D&md5=45fce464c0d99e13ca326f39a47a61b6
    16. 16
      The New York Times. April 17, 2019. https://www.nytimes.com/2019/04/17/us/kratom-overdose-deaths.html (accessed October 25, 2019).
      There is no corresponding record for this reference.
    17. 17
      U.S. Food & Drug Administration. February 21, 2018 https://www.fda.gov/news-events/press-announcements/fda-oversees-destruction-and-recall-kratom-products-and-reiterates-its-concerns-risks-associated (accessed October 25, 2019).
      There is no corresponding record for this reference.
    18. 18
      United States Drug Enforcement Administration. August 30, 2016. https://www.dea.gov/press-releases/2016/08/30/dea-announces-intent-schedule-kratom (accessed October 25, 2019).
      There is no corresponding record for this reference.
    19. 19
      Forbes. October 13, 2016. https://www.forbes.com/sites/davidkroll/2016/08/30/dea-to-place-kratom-mitragynine-on-schedule-i-premature-move-may-compromise-research-benefits/#679fe47d2b8f (accessed October 25, 2019).
      There is no corresponding record for this reference.
    20. 20
      Johnson, E. J.; González-Peréz, V.; Tian, D.-D.; Lin, Y. S.; Unadkat, J. D.; Rettie, A. E.; Shen, D. D.; McCune, J. S.; Paine, M. F. Drug Metab. Dispos. 2018, 46, 1046– 1052,  DOI: 10.1124/dmd.118.081273
      20
      review Selection of priority natural products for evaluation as potential precipitants of natural product-drug interactions: a NaPDI center recommended approach
      Johnson, Emily J.; Gonzalez-Perez, Vanessa; Tian, Dan-Dan; Lin, Yvonne S.; Unadkat, Jashvant D.; Rettie, Allan E.; Shen, Danny D.; McCune, Jeannine S.; Paine, Mary F.
      Drug Metabolism & Disposition (2018), 46 (7), 1046-1052CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)
      A review. Pharmacokinetic interactions between natural products (NPs) and conventional medications (prescription and nonprescription) are a long-standing but understudied problem in contemporary pharmacotherapy. Consequently, there are no established methods for selecting and prioritizing com. available NPs to evaluate as precipitants of NP-drug interactions (NPDIs). As such, NPDI discovery remains largely a retrospective, bedside-to-bench process. This Recommended Approach, developed by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), describes a systematic method for selecting NPs to evaluate as precipitants of potential clin. significant pharmacokinetic NPDIs. Guided information-gathering tools were used to score, rank, and triage NPs from an initial list of 47 candidates. Triaging was based on the presence and/or absence of an NPDI identified in a clin. study (=20% or <20% change in the object drug area under the concn. vs. time curve, resp.), as well as mechanistic and descriptive in vitro and clin. data. A qual. decision-making tool, termed the fulcrum model, was developed and applied to 11 high-priority NPs for rigorous study of NPDI risk. Application of this approach produced a final list of five high-priority NPs, four of which are currently under investigation by the NaPDI Center.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFSgurrJ&md5=3f77ddff421bd6c0141faf5889f39e5e
    21. 21
      Tian, D.-D.; Kellogg, J. J.; Okut, N.; Oberlies, N. H.; Cech, N. B.; Shen, D. D.; McCune, J. S.; Paine, M. F. Drug Metab. Dispos. 2018, 46, 552,  DOI: 10.1124/dmd.117.079491
      21
      Identification of intestinal UDP-glucuronosyltransferase inhibitors in green tea (Camellia sinensis) using a biochemometric approach: application to raloxifene as a test drug via in vitro to in vivo extrapolation
      Tian, Dan-Dan; Kellogg, Joshua J.; Okut, Nese; Oberlies, Nicholas H.; Cech, Nadja B.; Shen, Danny D.; McCune, Jeannine S.; Paine, Mary F.
      Drug Metabolism & Disposition (2018), 46 (5), 552-560CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)
      Green tea (Camellia sinensis) is a popular beverage worldwide, raising concern for adverse interactions when co-consumed with conventional drugs. Like many botanical natural products, green tea contains numerous polyphenolic constituents that undergo extensive glucuronidation. As such, the UDP-glucuronosyltransferases (UGTs), particularly intestinal UGTs, represent potential first-pass targets for green tea-drug interactions. Candidate intestinal UGT inhibitors were identified using a biochemometrics approach, which combines bioassay and chemometric data. Exts. and fractions prepd. from four widely consumed teas were screened (20-180 mg/mL) as inhibitors of UGT activity (4-methylumbelliferone glucuronidation) in human intestinal microsomes; all demonstrated concn.-dependent inhibition. A biochemometrics-identified fraction rich in UGT inhibitors from a representative tea was purified further and subjected to second-stage biochemometric anal. Five catechins were identified as major constituents in the bioactive subfractions and prioritized for further evaluation. Of these catechins, (-)epicatechin gallate and (-)-epigallocatechin gallate showed concn.-dependent inhibition, with IC50 values (105 and 59 μ M, resp.) near or below concns. measured in a cup (240 mL) of tea (66 and 240 μ M, resp.). Using the clin. intestinal UGT substrate raloxifene, the Ki values were ∼1.0 and 2.0 μ M, resp. Using estd. intestinal lumen and enterocyte inhibitor concns., a mechanistic static model predicted green tea to increase the raloxifene plasma area under the curve up to 6.1- and 1.3-fold, resp. Application of this novel approach, which combines biochemometrics with in vitro-in vivo extrapolation, to other natural product-drug combinations will refine these procedures, informing the need for further evaluation via dynamic modeling and clin. testing.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOjsLjN&md5=0cb38e0a92e89525d97c360e3ed8a239
    22. 22
      Gufford, B. T.; Chen, G.; Lazarus, P.; Graf, T. N.; Oberlies, N. H.; Paine, M. F. Drug Metab. Dispos. 2014, 42, 1675– 1683,  DOI: 10.1124/dmd.114.059451
      22
      Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation
      Gufford, Brandon T.; Chen, Gang; Lazarus, Philip; Graf, Tyler N.; Oberlies, Nicholas H.; Paine, Mary F.
      Drug Metabolism & Disposition (2014), 42 (10), 1675-1683, 9 pp.CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)
      Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying dietary substance-drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/exts. (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize addnl. perpetrators of dietary substance-drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/exts. inhibited UGT activity by >50% in at least one enzyme source, prompting IC50 detn. The IC50 values of 13 constituents/exts. (≤10 mM with at least one enzyme source) were well below intestinal tissue concns. or concns. in relevant juices, suggesting that these diet derived substances can inhibit intestinal UGTs at clin. achievable concns. Evaluation of the effect of inhibitor depletion on IC50 detn. demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify dietary substance-drug interactions that warrant advanced modeling and simulation to inform clin. assessment.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1yqur3K&md5=9616e20dd42c3ff1177b99d967987428
    23. 23
      Kellogg, J. J.; Paine, M. F.; McCune, J. S.; Oberlies, N. H.; Cech, N. B. Nat. Prod. Rep. 2019, 36, 1196– 1221,  DOI: 10.1039/C8NP00065D
      23
      Selection and characterization of botanical natural products for research studies: a NaPDI center recommended approach
      Kellogg, Joshua J.; Paine, Mary F.; McCune, Jeannine S.; Oberlies, Nicholas H.; Cech, Nadja B.
      Natural Product Reports (2019), 36 (8), 1196-1221CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
      A review. Covering: up to the end of 2018 Dietary supplements, which include botanical (plant-based) natural products, constitute a multi-billion-dollar industry in the US. While there is general agreement that rigorous scientific studies are needed to evaluate the safety and efficacy of botanical natural products used by consumers, researchers conducting such studies face a unique set of challenges. Botanical natural products are inherently complex mixts., with compn. that differs depending on myriad factors including variability in genetics, cultivation conditions, and processing methods. Unfortunately, many studies of botanical natural products are carried out with poorly characterized study material, such that the results are irreproducible and difficult to interpret. This review provides recommended approaches for addressing the crit. questions that researchers must address prior to in vitro or in vivo (including clin.) evaluation of botanical natural products. We describe selection and authentication of botanical material and identification of key biol. active compds., and compare state-of-the-art methodologies such as untargeted metabolomics with more traditional targeted methods of characterization. The topics are chosen to be of maximal relevance to researchers, and are reviewed critically with commentary as to which approaches are most practical and useful and what common pitfalls should be avoided.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFKmurg%253D&md5=cb245ca58f01bfc4979389687a8b6451
    24. 24
      Brantley, S. J.; Gufford, B. T.; Dua, R.; Fediuk, D. J.; Graf, T. N.; Scarlett, Y. V.; Frederick, K. S.; Fisher, M. B.; Oberlies, N. H.; Paine, M. F. CPT: Pharmacometrics Syst. Pharmacol. 2014, 3, 107,  DOI: 10.1038/psp.2013.69
      24
      Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb-Drug Interaction
      Brantley, S. J.; Gufford, B. T.; Dua, R.; Fediuk, D. J.; Graf, T. N.; Scarlett, Y. V.; Frederick, K. S.; Fisher, M. B.; Oberlies, N. H.; Paine, M. F.
      CPT: Pharmacometrics & Systems Pharmacology (2014), 3 (March), e107CODEN: CPSPBR; ISSN:2163-8306. (Nature Publishing Group)
      Herb-drug interaction predictions remain challenging. Physiol. based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb-drug interactions using the semipurified milk thistle prepn., silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and ([ital: null])-warfarin AUC by 5% and 4%, resp. A proof-of-concept clin. study confirmed minimal interaction between high-dose silibinin and both midazolam and ([ital: null])-warfarin (9 and 13% increase in AUC, resp.). Unexpectedly, ([ital: null])-warfarin AUC decreased (by 15%), but this is unlikely to be clin. important. Application of this PBPK modeling framework to other herb-drug interactions could facilitate development of guidelines for quant. prediction of clin. relevant interactions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Whtr7N&md5=e6e01ffb3c177cc872746270a174ee33
    25. 25
      Beckett, A. H.; Shellard, E. J.; Tackie, A. N. Planta Med. 1965, 13, 241– 246,  DOI: 10.1055/s-0028-1100118
      25
      Mitragyna species of Asia. IV. Alkaloids of leaves of Mitragyna speciosa. Isolation of mitragynine and speciofoline
      Beckett, Arnold H.; Shellard, Edward J.; Tackie, A. N.
      Planta Medica (1965), 13 (), 241-6CODEN: PLMEAA; ISSN:0032-0943.
      CA 66: 11091s. The alkaloids mitragynine and speciofoline (described for the first time) are isolated from the ethanol ext. of dry leaves of M. speciosa by column chromatog. using Al2O3 and eluting with ether and CHCl3 and various salts of mitragynine are prepd. Mitragynine, C23H30N2O4.EtOH, m. 97-8°, [α]20D -127° (c 2, CHCl3), gives a blue color when treated with vanillin and HCl; picrate m. 224.5° (MeOH); HCl salt m. 246-8° (ether/alc.); perchlorate m. 245-6° (glacial HOAc); HI salt m. 232-3° (ether/alc.); trichloroacetate m. 157° (acetone/ether); oxalate m. 219-20° (60% alc.); acetate m. 172° (Ac2O-ether); HBr salt m. 246-7° (ether/alc.); trinitrobenzene deriv. m. 146-7° (MeOH); cinnamate m. 155-6° (MeCOEt). Speciofoline, C22H28N2O5, m. 235-6°, [α]22D -102.9° (c 2, CHCl3), gives a light orange color when treated with vanillin and HCl; HBr salt m. 219-21° (alc.).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXksVequr4%253D&md5=550a1dedbab6932827d627b2d4d7ea9f
    26. 26
      Beckett, A.; Shellard, E.; Phillipson, J.; Lee, C. M. Planta Med. 1966, 14, 277– 288,  DOI: 10.1055/s-0028-1100055
      26
      Mitragyna species of Asia. VII. Indole alkaloids from the leaves of Mitragyna speciosa Korth
      Beckett, Arnold H.; Shellard, Edward J.; Phillipson, John D.; Lee, Calvin M.
      Planta Medica (1966), 14 (3), 277-88CODEN: PLMEAA; ISSN:0032-0943.
      cf. preceding abstr. Five addnl. alkaloids have been isolated from M. speciosa. Previously known and described are ajmalicine and corynantheidine; new are speciogynine, paynantheine, and speciociliatine. They are all derived from I, and their distinguishing features are tabulated. [TABLE OMITTED]
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXhtFSqsw%253D%253D&md5=15e5817323b9378d7bbae019b9493987
    27. 27
      Zacharias, D.; Rosenstein, R.; Jeffrey, G. Acta Crystallogr. 1965, 18, 1039– 1043,  DOI: 10.1107/S0365110X65002499
      27
      The structure of mitragynine hydroiodide
      Zacharias, David E.; Rosenstein, R. D.; Jeffrey, G. A.
      Acta Crystallographica (1965), 18 (6), 1039-43CODEN: ACCRA9; ISSN:0365-110X.
      C23H30N2O4, is an alkaloid contg. the indolo[2,3-a]quinolizine ring system substituted with methoxyl, ethyl, and methyl β-methoxyacryloyl groups. The structure was unknown at the beginning of this investigation, but was subsequently reported from a chem. study (Joshi, et al., CA 59, 3974f). This x-ray analysis confirms the conclusions of the chem. work and also shows that the methoxycarbonyl and methoxyl groups have a trans configuration about the double bond in the acrylyl moiety. The x-ray analysis was carried out on crystals of the hydroiodide which are orthorhombic with a 11.51, b 7.87, c 26.69 A.; space group is P212121. The heavy-atom method was used with 3-dimensional Fourier syntheses and structure factors computed 1st on an IBM 1620 and subsequently on an IBM 7070 computer. Two successive refinements with progressive addn. of the light atoms gave the complete structure. Subsequent refinement with isotropic temp. factors on all atoms gave an R index of 0.12.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXkt1Wjsbg%253D&md5=cd58e800e3ee1971902f8986af70d1fa
    28. 28
      Beckett, A. H.; Shellard, E. J.; Phillipson, J. D.; Lee, C. M. Planta Med. 1966, 14, 277– 288,  DOI: 10.1055/s-0028-1100055
      28
      Mitragyna species of Asia. VII. Indole alkaloids from the leaves of Mitragyna speciosa Korth
      Beckett, Arnold H.; Shellard, Edward J.; Phillipson, John D.; Lee, Calvin M.
      Planta Medica (1966), 14 (3), 277-88CODEN: PLMEAA; ISSN:0032-0943.
      cf. preceding abstr. Five addnl. alkaloids have been isolated from M. speciosa. Previously known and described are ajmalicine and corynantheidine; new are speciogynine, paynantheine, and speciociliatine. They are all derived from I, and their distinguishing features are tabulated. [TABLE OMITTED]
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXhtFSqsw%253D%253D&md5=15e5817323b9378d7bbae019b9493987
    29. 29
      Shellard, E.; Houghton, P.; Resha, M. Planta Med. 1978, 34, 253– 263,  DOI: 10.1055/s-0028-1097448
      29
      The mitragyna species of Asia. Part XXXII. The distribution of alkaloids in young plants of Mitragyna speciosa Korth grown from seed obtained from Thailand
      Shellard, E. J.; Houghton, P. J.; Resha, Masechaba
      Planta Medica (1978), 34 (3), 253-63CODEN: PLMEAA; ISSN:0032-0943.
      The major indole alkaloids, in young plants of M. speciosa, as distinct from those in the mature plants, are those possessing C-3Hβ with isocorynantheidine, isopaynantheine, and mitraciliatine (found for the first time in M. speciosa) being the dominant ones although speciogynine, a C-3Hα alkaloid, occurred in the major quantities. The oxindole alkaloids rhynchociline and ciliaphylline were also found in M. speciosa for the first time, although not in the leaves, while specionoxeine and isospecionoxeine were found for the first time in this species obtained from Thailand.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXmvFSquw%253D%253D&md5=e1990f35860b03f28211a44318e778c0
    30. 30
      Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi, N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto, L. T.; Watanabe, K.; Murayama, T.; Horie, S. J. Med. Chem. 2002, 45, 1949– 1956,  DOI: 10.1021/jm010576e
      30
      Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands
      Takayama, Hiromitsu; Ishikawa, Hayato; Kurihara, Mika; Kitajima, Mariko; Aimi, Norio; Ponglux, Dhavadee; Koyama, Fumi; Matsumoto, Kenjiro; Moriyama, Tomoyuki; Yamamoto, Leonard T.; Watanabe, Kazuo; Murayama, Toshihiko; Horie, Syunji
      Journal of Medicinal Chemistry (2002), 45 (9), 1949-1956CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Mitragynine is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compd., synthesis of some derivs., evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compds. for μ-, δ-, and κ-receptors were detd. in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivs. of mitragynine, i.e., mitragynine pseudoindoxyl (I) and 7-hydroxymitragynine, were found as opioid agonists with higher potency than morphine in the expt. with guinea pig ileum. In addn., I induced an analgesic activity in the tail flick test in mice.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitVOjur0%253D&md5=df2bbc1f913e4d8404a9e27375b3c993
    31. 31
      Takayama, H. Chem. Pharm. Bull. 2004, 52, 916– 928,  DOI: 10.1248/cpb.52.916
      31
      Chemistry and pharmacology of analgesic indole alkaloids from the Rubiaceous plant, Mitragyna speciosa
      Takayama, Hiromitsu
      Chemical & Pharmaceutical Bulletin (2004), 52 (8), 916-928CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)
      A review. The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochem. studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compds. were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of mitragynine, the major constituent of this plant, and its analogs were found in in vitro and in vivo expts. and the mechanisms underlying the analgesic activity were clarified. The essential structural features of mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacol. evaluation of the natural and synthetic derivs. Among the mitragynine derivs., 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvVKktbk%253D&md5=7f8c2d9978db7f60516f517988d3e014
    32. 32
      Takayama, H.; Kitajima, M.; Kogure, N. Curr. Org. Chem. 2005, 9, 1445– 1464,  DOI: 10.2174/138527205774370559
      32
      Chemistry of indole alkaloids related to the corynanthe-type from Uncaria, Nauclea and Mitragyna plants
      Takayama, Hiromitsu; Kitajima, Mariko; Kogure, Noriyuki
      Current Organic Chemistry (2005), 9 (15), 1445-1464CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
      A review. A no. of monoterpenoid indole and oxindole alkaloids were isolated from botanical sources, and many of them were found to possess significant pharmacol. activities and are utilized as key lead compds. in new drug development. In this review, the recent results of our phytochem. and synthetic studies of indole alkaloids having the Corynanthe-type related skeleton from genera Uncaria, Nauclea, and Mitragyna, which are classified under tribe Cinchoneae, family Rubiaceae, are described.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVakt7rO&md5=e6e271e70a1a641f97cd4fbe4690b33e
    33. 33
      Marston, A.; Hostettmann, K. Nat. Prod. Rep. 1991, 8, 391– 413,  DOI: 10.1039/np9910800391
      33
      Modern separation methods
      Marston, A.; Hostettmann, K.
      Natural Product Reports (1991), 8 (4), 391-413CODEN: NPRRDF; ISSN:0265-0568.
      A review with 269 refs. on chromatog. methods used for the isolation of natural products.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlslygt7w%253D&md5=e319628376d8d5bcef662c9e0b82e210
    34. 34
      Stead, P. Isolation by Preparative HPLC. In Natural Products Isolation; Cannell, R. J. P., Ed.; Humana Press: Totowa, NJ, 1998; pp 165– 208.
      There is no corresponding record for this reference.
    35. 35
      Betz, J. M.; Brown, P. N.; Roman, M. C. Fitoterapia 2011, 82, 44– 52,  DOI: 10.1016/j.fitote.2010.09.011
      35
      Accuracy, precision, and reliability of chemical measurements in natural products research
      Betz, Joseph M.; Brown, Paula N.; Roman, Mark C.
      Fitoterapia (2011), 82 (1), 44-52CODEN: FTRPAE; ISSN:0367-326X. (Elsevier B.V.)
      A review. Natural products chem. is the discipline that lies at the heart of modern pharmacognosy. The field encompasses qual. and quant. anal. tools that range from spectroscopy and spectrometry to chromatog. Among other things, modern research on crude botanicals is engaged in the discovery of the phytochem. constituents necessary for therapeutic efficacy, including the synergistic effects of components of complex mixts. in the botanical matrix. In the phytomedicine field, these botanicals and their contained mixts. are considered the active pharmaceutical ingredient (API), and pharmacognosists are increasingly called upon to supplement their mol. discovery work by assisting in the development and utilization of anal. tools for assessing the quality and safety of these products. Unlike single-chem. entity APIs, botanical raw materials and their derived products are highly variable because their chem. and morphol. depend on the genotypic and phenotypic variation, geog. origin and weather exposure, harvesting practices, and processing conditions of the source material. Unless controlled, this inherent variability in the raw material stream can result in inconsistent finished products that are under-potent, over-potent, and/or contaminated. Over the decades, natural product chemists have routinely developed quant. anal. methods for phytochems. of interest. Quant. methods for the detn. of product quality bear the wt. of regulatory scrutiny. These methods must be accurate, precise, and reproducible. Accordingly, this review discusses the principles of accuracy (relationship between exptl. and true value), precision (distribution of data values), and reliability in the quantitation of phytochems. in natural products.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVKls70%253D&md5=d785954b667d5111d972b6db8229af3f
    36. 36
      Li, S.; Yuan, W.; Deng, G.; Wang, P.; Yang, P.; Aggarwal, B. Pharm. Crops 2011, 2, 28– 54,  DOI: 10.2174/2210290601102010028
      36
      Chemical composition and product quality control of turmeric (Curcuma longa L.)
      Li, Shiyou; Yuan, Wei; Deng, Guangrui; Wang, Ping; Yang, Peiying; Aggarwal, Bharat B.
      Pharmaceutical Crops (2011), 2 (), 28-54CODEN: PCHRBU; ISSN:2210-2906. (Bentham Science Publishers Ltd.)
      A review. Chem. constituents of various tissues of turmeric (Curcuma longa L.) have been extensively investigated. To date, at least 235 compds., primarily phenolic compds. and terpenoids have been identified from the species, including 22 diarylheptanoids and diarylpentanoids, eight phenylpropene and other phenolic compds., 68 monoterpenes, 109 sesquiterpenes, five diterpenes, three triterpenoids, four sterols, two alkaloids, and 14 other compds. Curcuminoids (diarylheptanoids) and essential oils are major bioactive ingredients showing various bioactivities in in vitro and in vivo bioassays. Curcuminoids in turmeric are primarily accumulated in rhizomes. The essential oils from leaves and flowers are usually dominated by monoterpenes while those from roots and rhizomes primarily contained sesquiterpenes. The contents of curcuminoids in turmeric rhizomes vary often with varieties, locations, sources, and cultivation conditions, while there are significant variations in compn. of essential oils of turmeric rhizomes with varieties and geog. locations. Further, both curcuminoids and essential oils vary in contents with different extn. methods and are unstable with extn. and storage processes. As a result, the quality of com. turmeric products can be markedly varied. While curcumin (1), demethoxycurcumin (2), and bisdemethoxycurcumin (5) have been used as marker compds. for the quality control of rhizomes, powders, and ext. ("curcumin") products, Ar-turmerone (99), α-turmerone (100), and β-turmerone (101) may be used to control the product quality of turmeric oil and oleoresin products. Authentication of turmeric products can be achieved by chromatog. and NMR techniques, DNA markers, with morphol. and anat. data as well as GAP and other information available.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1GjtbfO&md5=c80633c79db31449ddb1511f394084fa
    37. 37
      Napolitano, J. G.; Lankin, D. C.; Chen, S. N.; Pauli, G. F. Magn. Reson. Chem. 2012, 50, 569– 575,  DOI: 10.1002/mrc.3829
      37
      Complete 1H NMR spectral analysis of ten chemical markers of Ginkgo biloba
      Napolitano, Jose G.; Lankin, David C.; Chen, Shao-Nong; Pauli, Guido F.
      Magnetic Resonance in Chemistry (2012), 50 (8), 569-575CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      The complete and unambiguous 1H NMR assignments of ten marker constituents of Ginkgo biloba are described. The comprehensive 1H NMR profiles (fingerprints) of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, bilobalide, quercetin, kaempferol, isorhamnetin, isoquercetin, and rutin in DMSO-d6 were obtained through the examn. of 1D 1H NMR and 2D 1H,1H-COSY data, in combination with 1H iterative full spin anal. (HiFSA). The computational anal. of discrete spin systems allowed a detailed characterization of all the 1H NMR signals in terms of chem. shifts (δH) and spin-spin coupling consts. (JHH), regardless of signal overlap and higher order coupling effects. The capability of the HiFSA-generated 1H fingerprints to reproduce exptl. 1H NMR spectra at different field strengths was also evaluated. As a result of this anal., a revised set of 1H NMR parameters for all ten phyto-constituents was assembled. Furthermore, precise 1H NMR assignments of the sugar moieties of isoquercetin and rutin are reported for the first time. Copyright © 2012 John Wiley & Sons, Ltd.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XovFWktrc%253D&md5=cc60c88c73582ede4354478fdb0bd4c6
    38. 38
      Niemitz, M.; Laatikainen, R.; Chen, S. N.; Kleps, R.; Kozikowski, A. P.; Pauli, G. F. Magn. Reson. Chem. 2007, 45, 878– 882,  DOI: 10.1002/mrc.2061
      38
      Complete 1H NMR spectral fingerprint of huperzine A
      Niemitz, Matthias; Laatikainen, Reino; Chen, Shao-Nong; Kleps, Robert; Kozikowski, Alan P.; Pauli, Guido F.
      Magnetic Resonance in Chemistry (2007), 45 (10), 878-882CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      Complete anal. of the 1H NMR spectrum of huperzine A, 1-amino-13-ethylidene-11-methyl-6-aza-tricyclo[7.3.1.02,7]trideca-2 (7),3,10-trien-5-one, a Lycopodium alkaloid and anti-Alzheimer drug lead contg. an ABCD(E)(MN)(OP)X3Y3-type system of 15 nonexchangeable protein spins, is reported for the 1st time, and earlier assignments are cor. The complete 1H parameter set of 11 chem. shifts clarifies the diastereotopism of both methylgene groups, and provides a total of 38 obsd. H,H-couplings including 31 long-range (4-6J) connectivities. The NMR data is consistent with the comparatively rigid alicyclic backbone predicted by mol. mechanics calcns., and forms the basis for 1H NMR fingerprint anal. for the purpose of dereplication, purity anal., and elucidation of structural analogs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFOnu7jI&md5=10ad38b5be5ec06b1aa23d157a80b1d9
    39. 39
      Seebacher, W.; Simic, N.; Weis, R.; Saf, R.; Kunert, O. Magn. Reson. Chem. 2003, 41, 636– 638,  DOI: 10.1002/mrc.1214
      39
      Complete assignments of 1H and 13C NMR resonances of oleanolic acid, 18α-oleanolic acid, ursolic acid and their 11-oxo derivatives
      Seebacher, Werner; Simic, Nebojsa; Weis, Robert; Saf, Robert; Kunert, Olaf
      Magnetic Resonance in Chemistry (2003), 41 (8), 636-638CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      Complete assignments of 1H and 13C NMR chem. shifts for oleanolic acid, 18α-oleanolic acid, ursolic acid and their 11-oxo derivs. based on 1H, 13C, 2-dimensional DQF-COSY, NOESY, HSQC, HMBC and HSQC-TOCSY expts. were achieved.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlvFSiur8%253D&md5=051177f19ad71ea06339ab6508322618
    40. 40
      Sy-Cordero, A. A.; Pearce, C. J.; Oberlies, N. H. J. Antibiot. 2012, 65, 541– 9,  DOI: 10.1038/ja.2012.71
      40
      Revisiting the enniatins: a review of their isolation, biosynthesis, structure determination and biological activities
      Sy-Cordero, Arlene A.; Pearce, Cedric J.; Oberlies, Nicholas H.
      Journal of Antibiotics (2012), 65 (11), 541-549CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)
      A review. Enniatins are cyclohexadepsipeptides isolated largely from Fusarium species of fungi, although they have been isolated from other genera, such as Verticillium and Halosarpheia. They were first described over 60 years ago, and their range of biol. activities, including antiinsectan, antifungal, antibiotic and cytotoxic, drives contemporary interest. To date, 29 enniatins have been isolated and characterized, either as a single compd. or mixts. of inseparable homologs. Structurally, these depsipeptides are biosynthesized by a multifunctional enzyme, termed enniatin synthetase, and are composed of six residues that alternate between N-Me amino acids and hydroxy acids. Their structure elucidation can be challenging, particularly for enniatins isolated as inseparable homologs; however, several strategies and tools have been utilized to solve these problems. Currently, there is one drug that has been developed from a mixt. of enniatins, fusafungine, which is used as a topical treatment of upper respiratory tract infections by oral and/or nasal inhalation. Given the range of biol. activities obsd. for this class of compds., research on enniatins will likely continue. This review strives to digest the past studies, as well as, describe tools and techniques that can be utilized to overcome the challenges assocd. with the structure elucidation of mixts. of enniatin homologs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslagsLrE&md5=13828a23868b277d1460b1f71b83ee73
    41. 41
      Kao, D.; Flores-Bocanegra, L.; Raja, H. A.; Darveaux, B. A.; Pearce, C. J.; Oberlies, N. H. Phytochemistry 2020, 172, 112238,  DOI: 10.1016/j.phytochem.2019.112238
      41
      New tricks for old dogs: Two new macrocyclic trichothecene epimers and absolute configuration of 16-hydroxyverrucarin B
      Kao, Diana; Flores-Bocanegra, Laura; Raja, Huzefa A.; Darveaux, Blaise A.; Pearce, Cedric J.; Oberlies, Nicholas H.
      Phytochemistry (Elsevier) (2020), 172 (), 112238CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Ltd.)
      Two new compds., 3'-epi-16-hydroxyverrucarin A and 3'-epiverrucarin X, have been isolated and identified, and the characterization data of a series of known trichothecenes have been refined. The interesting structure and potent biol. activities of macrocyclic trichothecenes have been of interest to the scientific community for several decades. However, some of the characterization data for the older analogs of this class are not well documented, either because of a lack of abs. configuration or a lack of clarity in the NMR data, largely due to technol. limitations at the time they were discovered. NMR techniques, application of Mosher's esters anal., and electronic CD were used here both to refine the characterization of known trichothecenes, as well as to uncover new structures. These studies demonstrate strategies that can be used to interrogate the characterization data of well-known secondary metabolites, thereby gaining greater insight into methods that can be used to refine previous literature.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFCit74%253D&md5=aa2d8e50cc193e861824af06d896d93b
    42. 42
      https://www.fda.gov/news-events/public-health-focus/fda-and-kratom (accessed January 20, 2020).
      There is no corresponding record for this reference.
    43. 43
      Hollingsworth, M. L.; Andra Clark, A.; Forrest, L. L.; Richardson, J.; Pennington, R. T.; Long, D. G.; Cowan, R.; Chase, M. W.; Gaudeul, M.; Hollingsworth, P. M. Mol. Ecol. Resour. 2009, 9, 439– 457,  DOI: 10.1111/j.1755-0998.2008.02439.x
      43
      Selecting barcoding loci for plants: evaluation of seven candidate loci with species-level sampling in three divergent groups of land plants
      Hollingsworth, Michelle L.; Clark, Alex Andra; Forrest, Laura L.; Richardson, James; Pennington, R. Toby; Long, David G.; Cowan, Robyn; Chase, Mark W.; Gaudeul, Myriam; Hollingsworth, Peter M.
      Molecular Ecology Resources (2009), 9 (2), 439-457CODEN: MEROCJ; ISSN:1755-098X. (Wiley-Blackwell)
      There has been considerable debate, but little consensus regarding locus choice for DNA barcoding land plants. This is partly attributable to a shortage of comparable data from all proposed candidate loci on a common set of samples. In this study, we evaluated the seven main candidate plastid regions (rpoC1, rpoB, rbcL, matK, trnH-psbA, atpF-atpH, psbK-psbI) in three divergent groups of land plants [Inga (angiosperm); Araucaria (gymnosperm); Asterella s.l. (liverwort)]. Across these groups, no single locus showed high levels of universality and resolvability. Interspecific sharing of sequences from individual loci was common. However, when multiple loci were combined, fewer barcodes were shared among species. Evaluation of the performance of previously published suggestions of particular multilocus barcode combinations showed broadly equiv. performance. Minor improvements on these were obtained by various new three-locus combinations involving rpoC1, rbcL, matK and trnH-psbA, but no single combination clearly outperformed all others. In terms of abs. discriminatory power, promising results occurred in liverworts (e.g. c. 90% species discrimination based on rbcL alone). However, Inga (rapid radiation) and Araucaria (slow rates of substitution) represent challenging groups for DNA barcoding, and their corresponding levels of species discrimination reflect this (upper est. of species discrimination = 69% in Inga and only 32% in Araucaria; mean = 60% averaging all three groups). DNA sequence and amino acid sequences of these seven candidate plastid loci from various plants are deposited in GenBank/EMBL/DDBJ under various accession nos., including ACCNs in range AM919789-AM919982, ACCNs in range AM919986-AM920060, ACCNs in range AM920063-AM920083, AM920086-AM920111, AM920113-AM920150, AM920152-AM920192, AM920194-AM920223, ACCNs in range AM920226-AM920247, AM920249-AM920308, AM920310, ACCNs in range AM921997-AM922019, AM922021-AM922096, FJ173458-FJ173802 and FJ205612-FJ205615.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjvVKgtbs%253D&md5=b887641922b574f4e665757fdc086583
    44. 44
      Kress, W. J.; Wurdack, K. J.; Zimmer, E. A.; Weigt, L. A.; Janzen, D. H. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 8369– 8374,  DOI: 10.1073/pnas.0503123102
      44
      Use of DNA barcodes to identify flowering plants
      Kress, W. John; Wurdack, Kenneth J.; Zimmer, Elizabeth A.; Weigt, Lee A.; Janzen, Daniel H.
      Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (23), 8369-8374CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Methods for identifying species by using short orthologous DNA sequences, known as "DNA barcodes," have been proposed and initiated to facilitate biodiversity studies, identify juveniles, assoc. sexes, and enhance forensic analyses. The cytochrome c oxidase 1 sequence, which has been found to be widely applicable in animal barcoding, is not appropriate for most species of plants because of a much slower rate of cytochrome c oxidase 1 gene evolution in higher plants than in animals. We therefore propose the nuclear internal transcribed spacer region and the plastid trnH-psbA intergenic spacer as potentially usable DNA regions for applying barcoding to flowering plants. The internal transcribed spacer is the most commonly sequenced locus used in plant phylogenetic investigations at the species level and shows high levels of interspecific divergence. The trnH-psbA spacer, although short (≈450-bp), is the most variable plastid region in angiosperms and is easily amplified across a broad range of land plants. Comparison of the total plastid genomes of tobacco and deadly nightshade enhanced with trials on widely divergent angiosperm taxa, including closely related species in seven plant families and a group of species sampled from a local flora encompassing 50 plant families (for a total of 99 species, 80 genera, and 53 families), suggest that the sequences in this pair of loci have the potential to discriminate among the largest no. of plant species for barcoding purposes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlsV2mtbY%253D&md5=4cb6c3928c04e884cfad4636b8f550f5
    45. 45
      Kress, W. J.; Erickson, D. L. PLoS One 2007, 2, e508  DOI: 10.1371/journal.pone.0000508
      There is no corresponding record for this reference.
    46. 46
      Li, X.; Yang, Y.; Henry, R. J.; Rossetto, M.; Wang, Y.; Chen, S. Biol. Rev. 2015, 90, 157– 166,  DOI: 10.1111/brv.12104
      46
      Plant DNA barcoding: from gene to genome
      Li Xiwen; Yang Yang; Henry Robert J; Rossetto Maurizio; Wang Yitao; Chen Shilin
      Biological reviews of the Cambridge Philosophical Society (2015), 90 (1), 157-66 ISSN:.
      DNA barcoding is currently a widely used and effective tool that enables rapid and accurate identification of plant species; however, none of the available loci work across all species. Because single-locus DNA barcodes lack adequate variations in closely related taxa, recent barcoding studies have placed high emphasis on the use of whole-chloroplast genome sequences which are now more readily available as a consequence of improving sequencing technologies. While chloroplast genome sequencing can already deliver a reliable barcode for accurate plant identification it is not yet resource-effective and does not yet offer the speed of analysis provided by single-locus barcodes to unspecialized laboratory facilities. Here, we review the development of candidate barcodes and discuss the feasibility of using the chloroplast genome as a super-barcode. We advocate a new approach for DNA barcoding that, for selected groups of taxa, combines the best use of single-locus barcodes and super-barcodes for efficient plant identification. Specific barcodes might enhance our ability to distinguish closely related plants at the species and population levels.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crnsFygsA%253D%253D&md5=850019e10c4794b3f62af11a7116b6a5
    47. 47
      Ebihara, A.; Nitta, J. H.; Ito, M. PLoS One 2010, 5, e15136  DOI: 10.1371/journal.pone.0015136
      There is no corresponding record for this reference.
    48. 48
      Brown, P. N.; Lund, J. A.; Murch, S. J. J. Ethnopharmacol. 2017, 202, 302– 325,  DOI: 10.1016/j.jep.2017.03.020
      48
      A botanical, phytochemical and ethnomedicinal review of the genus Mitragyna korth: Implications for products sold as kratom
      Brown, Paula N.; Lund, Jensen A.; Murch, Susan J.
      Journal of Ethnopharmacology (2017), 202 (), 302-325CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
      The genus Mitragyna (Rubiacaeae) has been traditionally used in parts of Africa, Asia and Oceania. In recent years, there has been increased interest in species of Mitragyna with the introduction of products to western markets and regulatory uncertainty. This paper reviewed the traditional ethnomedicinal uses of leaves for species belonging to the genus Mitragyna with ref. to the botany and known chem. in order to highlight areas of interest for products currently being sold as kratom. A literature search was conducted using Web of Science, Google Scholar, the Royal Museum for Central Africa, Internet Archive, Hathi Trust, and Biodiversity Heritage Library search engines in the spring of 2015, fall of 2016 and winter of 2017 to document uses of bark, leaf and root material.Leaves of M. speciosa (kratom) had the most common documented ethnomedicinal uses as an opium substitute or remedy for addiction. Other species of Mitragyna were reportedly used for treating pain, however the mode of prepn. was most often cited as topical application. Other uses of Mitragyna included treatment of fever, skin infections, and as a mild anxiolytic. Mitragyna species have been used medicinally in various parts of the world and that there is significant traditional evidence of use. Modern products that include formulations as topical application of liniments, balms or tinctures may provide effective alternatives for treatment of certain types of pains. Future research is required to establish safety and toxicol. limits, medicinal chem. parameters and the potential for different physiol. responses among varying genetic populations to support regulatory requirements for Mitragyna spp.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvFensLo%253D&md5=c9df1fd21f5ec044209f79747a9c83fc
    49. 49
      Raffa, R. B. Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-opium Source; CRC Press, 2014.
      There is no corresponding record for this reference.
    50. 50
      Takayama, H.; Kurihara, M.; Kitajima, M.; Said, I. M.; Aimi, N. Tetrahedron 1998, 54, 8433– 8440,  DOI: 10.1016/S0040-4020(98)00464-5
      50
      New indole alkaloids from the leaves of Malaysian Mitragyna speciosa
      Takayama, Hiromitsu; Kurihara, Mika; Kitajima, Mariko; Said, Ikram M.; Aimi, Norio
      Tetrahedron (1998), 54 (29), 8433-8440CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
      Three new monoterpenoid indole alkaloids; 3,4,5,6-tetradehydromitragynine, mitralactonal, and mitrasulgynine which contain a sulfonate function were isolated, in addn. to seven known compds., from the leaves of the Malaysian Mitragyna speciosa.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXksFCqsL0%253D&md5=205189645b9873bf89413b306820c16f
    51. 51
      León, F.; Habib, E.; Adkins, J. E.; Furr, E. B.; McCurdy, C. R.; Cutler, S. J. Nat. Prod. Commun. 2009, 4, 907– 910,  DOI: 10.1177/1934578X0900400705
      51
      Phytochemical characterization of the leaves of Mitragyna speciosa grown in USA
      Leon, Francisco; Habib, Eman; Adkins, Jessica E.; Furr, Edward B.; McCurdy, Christopher R.; Cutler, Stephen J.
      Natural Product Communications (2009), 4 (7), 907-910CODEN: NPCACO; ISSN:1934-578X. (Natural Product Inc.)
      Mitragyna speciosa (Rubiaceae) has traditionally been used in the tropical regions of Asia, Africa and Indonesia as a substitute for opium. Indole alkaloids are the most common compds. that have been isolated. We investigated the constituents of the leaves of M. speciosa that was grown at the University of Mississippi. Several alkaloids were isolated, including ajmalicine, corynantheidine, isomitraphylline, mitraphylline, paynantheine, isocorynantheidine, 7-hydroxymitragynine and mitragynine, but their percentages were lower than those in a com. Thai sample of "kratom". In addn., we isolated the flavonoid epicatechin, a saponin daucosterol, the triterpenoid saponins quinovic acid 3-O-β-D-quinovopyranoside, quinovic acid 3-O-β-D-glucopyranoside, as well as several glycoside derivs. including 1-O-feruloyl-β-D-glucopyranoside, benzyl-β-D-glucopyranoside, 3-oxo-α-ionyl-O-β-D-glucopyranoside, roseoside, vogeloside, and epivogeloside. This is the first report of the last group of compds. having been isolated from a Mitragyna species. Biol. studies are currently underway to test these compds. for opioid activity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptlemsr0%253D&md5=d2f6822e5eb7f95e581203e8fe408398
    52. 52
      Beckett, A.; Shellard, E.; Phillipson, J.; Lee, C. M. J. Pharm. Pharmacol. 1965, 17, 753– 755,  DOI: 10.1111/j.2042-7158.1965.tb07599.x
      52
      Alkaloids from Mitragyna speciosa
      Beckett, A. H.; Shellard, E. J.; Phillipson, J. D.; Lee, Calvin M.
      Journal of Pharmacy and Pharmacology (1965), 17 (11), 753-5CODEN: JPPMAB; ISSN:0022-3573.
      Alkaloids were isolated from a MeOH ext. of the leaves of M. speciosa. The picrates gave mitragynine, corynantheidine, isomitraphylline, and speciophylline (I). The picrate mother liquors gave ajmalicine, speciogynine (II), and psynantheine (III). I is an oxoindole alkaloid with a structure similar to mitraphylline. The N.M.R. spectrum placed the ester methoxy group at 6.62 τ. II and III were found to be indoles. The structure of II is similar to mitragynine. A methoxy group in the 9-position of II and III is suggested. Ir bands were found for II and III between 2700 and 2800 cm.-1 There was no C3H multiplet in the N.M.R. above 6.0 τ. III had no 3-proton triplet for the C-CH3 in the 9.1 τ region. III had multiplets for 3 protons in the olefinic region 5.2-4.2 τ. III is a 9-methoxy deriv. of corynantheine-type structure.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XhtFKmsQ%253D%253D&md5=e9f443eff29e09974983bd10a8cc2756
    53. 53
      Shellard, E. J.; Hougton, P. J.; Resha, M. Planta Med. 1978, 33, 223– 227,  DOI: 10.1055/s-0028-1097379
      53
      The Mitragyna species of Asia. Part XXX: Oxidation products of mitragynine and speciociliatine
      Shellard, E. J.; Houghton, P. J.; Resha, M.
      Planta Medica (1978), 33 (3), 223-7CODEN: PLMEAA; ISSN:0032-0943.
      Oxidn. of mitragynine and speciociliatine with Me3COCl gave a mixt. of mitragynine oxindole A, mitragynine oxindole B, and speciociliatine oxindole B (I). Oxidn. of mitragynine with m-ClC6H4C(O)OOH gave the oxidn. products II and III.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXls1ersLc%253D&md5=5e3c3af680b5bb4a384778ae9b10bf9d
    54. 54
      Cao, X.-F.; Wang, J.-S.; Wang, X.-B.; Luo, J.; Wang, H.-Y.; Kong, L.-Y. Phytochemistry 2013, 96, 389– 396,  DOI: 10.1016/j.phytochem.2013.10.002
      54
      Monoterpene indole alkaloids from the stem bark of Mitragyna diversifolia and their acetylcholine esterase inhibitory effects
      Cao, Xing-Fen; Wang, Jun-Song; Wang, Xiao-Bing; Luo, Jun; Wang, Hong-Ying; Kong, Ling-Yi
      Phytochemistry (Elsevier) (2013), 96 (), 389-396CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Ltd.)
      Five monoterpene indole alkaloids, mitradiversifoline, with a unique rearranged skeleton, specionoxeine-N(4)-oxide, 7-hydroxyisopaynantheine, 3-dehydropaynantheine, and 3-isopaynantheine-N(4)-oxide, and 10 known ones, were isolated from Mitragyna diversifolia. All the isolates were evaluated for their inhibition of acetylcholinesterase activities, and four showed moderate activities, with IC50 values of 4.1, 5.2, 10.2, and 10.3 μM, resp.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs12lurnF&md5=1eb77ffabd69d63823cfa445da76acc6
    55. 55
      Beckett, A. H.; Lee, C. M.; Tackie, A. N. Tetrahedron Lett. 1963, 4, 1709– 1714,  DOI: 10.1016/S0040-4039(01)90899-8
      There is no corresponding record for this reference.
    56. 56
      Hemingway, S. R.; Houghton, P. J.; Phillipson, J. D.; Shellard, E. J. Phytochemistry 1975, 14, 557– 563,  DOI: 10.1016/0031-9422(75)85128-4
      56
      9-Hydroxyrhynchophylline-type oxindole alkaloids
      Hemingway, Sarah R.; Houghton, Peter J.; Phillipson, J. David; Shellard, Edward J.
      Phytochemistry (Elsevier) (1975), 14 (2), 557-63CODEN: PYTCAS; ISSN:0031-9422.
      Speciofoline (I) was assigned the epiallo B configuration on the basis of isomerization studies, NMR and CD spectra, and 3 new speciofoline isomers, mitrafoline (II) (allo A), isomitrafoline (III) (allo B) and isospeciofoline (epiallo A) (IV) were isolated from Mitragyna speciosa. Rotundifoleine (V) and isorotundifoleine (VI), were sepd. as minor products from crystalline samples of rotundifoline and isorotundifoline (VII) resp., previously isolated from M. parvifolia. A transient product observed during the isomerization of (VII) was identifed as the pseudo B isomer, 3-epiisorotundifoline (VIII).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXktFSmtrc%253D&md5=053167f5f15d8ece4688363437e3edba
    57. 57
      Ali, Z.; Demiray, H.; Khan, I. A. Tetrahedron Lett. 2014, 55, 369– 372,  DOI: 10.1016/j.tetlet.2013.11.031
      57
      Isolation, characterization, and NMR spectroscopic data of indole and oxindole alkaloids from Mitragyna speciosa
      Ali, Zulfiqar; Demiray, Hatice; Khan, Ikhlas A.
      Tetrahedron Letters (2014), 55 (2), 369-372CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      A new indole alkaloid, 7β-hydroxy-7H-mitraciliatine (I) and a new oxindole alkaloid, isospeciofoleine (II) together with 4 known alkaloids were isolated from Mitragyna speciosa and characterized by NMR, CD, and MS spectroscopic data analyses. The 1H and 13C NMR spectroscopic data of isospeciofoline (3), isorotundifoline (4), paynantheine (5), and 3-isopaynantheine (6) were also reported for the first time.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOmt77P&md5=2aa62ffa9ab5bcbb32d389c2ec59bd32
    58. 58
      Cu, N. Bull. Soc. Chim. Fr. 1957, 1292– 1294
      58
      Alkaloids of Pseudocinchona africana. Corynoxeine and corynoxine, two new oxindole alkaloids. Identity of rhynchophylline and dihydrocornyoxeine
      Cu, Nguyen An; Goutarel, Robert; Janot, Maurice-Marie
      Bulletin de la Societe Chimique de France (1957), (), 1292-4CODEN: BSCFAS; ISSN:0037-8968.
      The residual alkaloidal material after sepn. of corynanthine, corynanthidine, corynantheine, dihydrocorynantheine, and corynantheidine from the bark of P. africana was chromatographed on Al2O3 to give β-yohimbine and 2 new alkaloids, corynoxeine (I), C22H26N2O4, m. 210°, [α]D 23° (c 1.0, C5H5N), -21.5 ± 2° (c 1.0, CHCl3), [α]Hg -31.5 ± 1° (CHCl3), and corynoxine (II), C22H28N2O4, m. 166-8°, [α]D -14 ± 3° (c 1.0, C5H5N), [α]D -3° (c 1.75, CHCl3). I had 2 MeO groups and an active H atom but no N-Me or C-Me groups and was reduced with Pd to dihydrocorynoxeine (Ia), C22H28N2O4, m. 210°, [α]D -17 ± 2° (CHCl3), [α]Hg -15.5° (c 0.92, CHCl3), contg. a C-Me group (Kuhn-Roth), and oxidized by CrO3 to EtCO2H, showing the presence of an HC:CH2 group in I. I and Ia had superimposable UV spectra characterized by a band at 2-5 mμ (log ε 4.28) not displaced by the bathochromic shift in alk. media in the region 260-300 mμ. The UV absorption spectrum is formed by the summation of 2 nonconjugated chromaphores, MeO2CC:CHOMe, absorbing at 245 mμ, and a 3,3'-disubstituted oxindole. Confirmation was provided by the IR spectrum of I characterized by 4 strong bands at 5.8, 5.9, 6.1, 6.2 μ, and a band at 11 μ not present in the spectrum of Ia. Ia hydrolyzed by 2N KOH in MeOH gave an amphoteric acid with the grouping HO2CC:CHOMe, hydrolyzed with 2N H2SO4 to a β-aldehydic acid, decarboxylated in the course of the reaction to an amorphous aldehyde "dihydrocorynoxeinal," C19H24N2O2, [α]D 22 ± 2° (CHCl3), not contg. an MeO group and with a typical oxindole spectrum, reduced according to Wolff-Kischner to dihydrocorynoxeinane, C19H26N2O, m. 70°, [α]D 24 ± 2° (CHCl3), with a typical oxindole spectrum. II had a C-Me and 2 MeO groups and an active H atom but no N-Me group, and was not reduced by Pd, showing the presence of a CH2CH2 chain. The UV spectrum was superimposable on that of I and showed the same bathochromic shift in alk. media. The IR spectrum had the same characteristics as that of I in the region 6 μ though the 2 CO bands were united in a broad band at 5.9 μ. The same degrdn. sequence as given for Ia converted II to corynoxinal (IIa), C19H24N2O2, [α]D -16 ± 2° (CHCl3), [α]Hg -15 ± 1° (c 2.0, CHCl3), and corynoxinane (IIb), C19H26N2O, m. 70°, [α]D -25 ± 2° (c 1.0, CHCl3), [α]Hg -27 ± 2° (c 1.13, CHCl3). IIa and IIb had no MeO groups and gave oxindole UV absorption spectra. The IR spectrum of IIa was identical with that of dihydrocorynoxeinal in which the 2 CO groups formed a broad band at 5.9 μ, the 6.1 μ band disappeared, but the 6.2 μ dihydroindole band was conserved. Similarly, the IR spectra of IIb and dihydrocorynoxeinane were identical. Rhynchophylline, isolated from Adina rubrostipulata (cf. Kates and Marion, C.A. 45, 6646b), m. 210°, [α]D -18 ± 2° (CHCl3), IR spectrum superimposable on that of Ia, and is apparently identical with Ia. Structures are proposed for I and II which should lead to the further elucidation of the typically oxindolic alkaloid, gelsemine.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG1cXltVOjtQ%253D%253D&md5=2eb62b9270e0f36241e58623521e7e48
    59. 59
      Shellard, E. Planta Med. 1978, 34, 26– 36,  DOI: 10.1055/s-0028-1097410
      59
      The Mitragyna species of Asia. Part XXXI. The alkaloids of Mitragyna speciosa Korth from Thailand
      Shellard, E. J.; Houghton, P. J.; Resha, Masechaba
      Planta Medica (1978), 34 (1), 26-36CODEN: PLMEAA; ISSN:0032-0943.
      In addn. to the previously reported alkaloids from M. speciosa a no. of addnl. oxindole alkaloids were isolated, 3 of which are new. These have been named mitrafoline, isomitrafoline,and isospeciofoline. Mitragynine oxindoles A and B were found for the first time in plant material while corynoxeine and the corynoxines were found for the first time in the genus Mitragyna. Examn. of 13 monthly samples of leaves showed that mitragynine and paynantheine remained the dominant indole alkaloids of the mature plant throughout the entire period of collection.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXmtFWqtb8%253D&md5=1553e6db0fd95665c839d7c7270e51cd
    60. 60
      Kitajima, M.; Misawa, K.; Kogure, N.; Said, I. M.; Horie, S.; Hatori, Y.; Murayama, T.; Takayama, H. J. Nat. Med. 2006, 60, 28– 35,  DOI: 10.1007/s11418-005-0001-7
      60
      A new indole alkaloid, 7-hydroxyspeciociliatine, from the fruits of Malaysian Mitragyna speciosa and its opioid agonistic activity
      Kitajima, Mariko; Misawa, Kaori; Kogure, Noriyuki; Said, Ikram M.; Horie, Syunji; Hatori, Yoshio; Murayama, Toshihiko; Takayama, Hiromitsu
      Journal of Natural Medicines (2006), 60 (1), 28-35CODEN: JNMOBN ISSN:. (Springer Tokyo)
      A new indole alkaloid, 7-hydroxyspeciociliatine (1), was isolated from the fruits of Malaysian Mitragyna speciosa Korth., together with 11 known indole and oxindole alkaloids (3-13). The structure of the new compd. was detd. by spectroscopic anal. and chem. conversion. The opioid agonistic activity of the new alkaloid was investigated in guinea-pig ileum expts. The compd. was found to have a weak stimulatory effect on μ-opioid receptors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitlGrur8%253D&md5=3f631d44d1b13ec103b955169bbd42f4
    61. 61
      Lee, C. M.; Trager, W. F.; Beckett, A. H. Tetrahedron 1967, 23, 375– 385,  DOI: 10.1016/S0040-4020(01)83323-8
      61
      Corynantheidine-type alkaloids. II. Absolute configuration of mitragynine, speciociliatine, mitraciliatine and speciogynine
      Lee, Calvin M.; Trager, William F.; Beckett, Arnold H.
      Tetrahedron (1967), 23 (1), 375-85CODEN: TETRAB; ISSN:0040-4020.
      cf. preceeding abstr. The abs. configuration of mitragynine (allo), speciociliatine (I) (epiallo), mitraciliatine (pseudo), and speciogynine (normal) was detd. from ir, N.M.R., O.R.D., and circular dichroism data; all have the C-15 hydrogen α. Moreover, the preferred conformation of each configuration was established. The abs. configuration of any ring substituted or unsubstituted corynantheidine-type alkaloid of unknown configuration can be detd. by use of the phys. criteria presented. 25 references.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXjvVWjsQ%253D%253D&md5=99b353d6b9c7a5ad8f8b7aeacda25441
    62. 62
      1H NMR Properties of Piperidine Derivatives. In Studies in Organic Chemistry; Rubiralta, M.; Giralt, E.; Diez, A., Eds.; Elsevier, 1991; Vol. 43, pp 34– 87.
      There is no corresponding record for this reference.
    63. 63
      Alkorta, I.; Elguero, J. Magn. Reson. Chem. 2004, 42, 955– 961,  DOI: 10.1002/mrc.1460
      63
      A GIAO/DFT study of 1H, 13C and 15N shieldings in amines and its relevance in conformational analysis
      Alkorta, Ibon; Elguero, Jose
      Magnetic Resonance in Chemistry (2004), 42 (11), 955-961CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      The 1H, 13C and 15N abs. shieldings of 13 amines were calcd. at the GIAO/B3LYP/6-311++G** level. For some compds. (ethylamine, piperidine and 1-methylpiperidine) two conformations were calcd. The 13C and 15N data could be correctly correlated with exptl. chem. shifts, allowing the conformation of 1-methylpiperidine to be established. The 1H NMR abs. shieldings, although less well correlated with δ values, were used to account for the anisotropy effects of the N lone pair.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpvVygsrc%253D&md5=12282fdb9c6636e09056b621597a0fd7
    64. 64
      Trager, W.; Lee, C. M.; Phillipson, J.; Haddock, R.; Dwuma-Badu, D.; Beckett, A. Tetrahedron 1968, 24, 523– 543,  DOI: 10.1016/0040-4020(68)88002-0
      64
      Configurational analysis of rhynchophylline-type oxindole alkaloids. Absolute configuration of ciliaphylline, rhynchociline, specionoxeine, isospecionoxeine, rotundifoline and isorotundifoline
      Trager, William F.; Lee, Calvin M.; Phillipson, John D.; Haddock, R. E.; Dwuma-Badu, D.; Beckett, Arnold H.
      Tetrahedron (1968), 24 (2), 523-43CODEN: TETRAB; ISSN:0040-4020.
      From a general configurational and conformational anal. of rhynchophyllinoid alkaloids, unique phys. criteria are developed that differentiate between the 8 possible configurational types. The criteria are applied to 6 rhynchophylline-type alkaloids of unknown configurations and show that ciliaphylline I (R = OMe, R' = Et), specionoxeine I (R = OMe, R' = CH:CH2), and isorotundifoline I (R = OH, R' = Et) have the normal B configuration while rhynchociline I (R = OMe, R' = Et), isospecionoxeine I (R = OMe, R' = CH:CH2), and rotundifoline I (R = OH, R' = Et) have the normal A configuration. All 6 alkaloids have the C-15 Hα abs. stereochemistry.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXjvFyrsw%253D%253D&md5=d61a4f4e0c73af38c7aa4487b125374c
    65. 65
      Xu, J.; Shao, L.-D.; Li, D.; Deng, X.; Liu, Y.-C.; Zhao, Q.-S.; Xia, C. J. Am. Chem. Soc. 2014, 136, 17962– 17965,  DOI: 10.1021/ja5121343
      65
      Construction of Tetracyclic 3-Spirooxindole through Cross-Dehydrogenation of Pyridinium: Applications in Facile Synthesis of (±)-Corynoxine and (±)-Corynoxine B
      Xu, Jun; Shao, Li-Dong; Li, Dashan; Deng, Xu; Liu, Yu-Chen; Zhao, Qin-Shi; Xia, Chengfeng
      Journal of the American Chemical Society (2014), 136 (52), 17962-17965CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A facile and straightforward method was developed to construct the fused tetracyclic 3-spirooxindole skeleton, which exists widely in natural products. The formation of the tetracyclic 3-spirooxindole structure was achieved through a transition-metal-free intramol. cross-dehydrogenative coupling of pyridinium, which were formed in situ by the condensation of 3-(2-bromoethyl)indolin-2-one derivs. with 3-substituted pyridines. As examples of the application of this new methodol., two potentially medicinal natural products, (±)-corynoxine (I) and (±)-corynoxine B, were efficiently synthesized in five scalable steps.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOgsL%252FP&md5=9b0366aabeba2e1ec21590d3528f3733
    66. 66
      Berner, M.; Tolvanen, A.; Jokela, R. Acid-catalysed Epimerization of Bioactive Indole Alkaloids and Their Derivatives. In Studies in Natural Products Chemistry; Atta ur Raman, Ed.; Elsevier, 2001; Vol. 25, pp 3– 42.
      There is no corresponding record for this reference.
    67. 67
      Laus, G.; Wurst, K. Helv. Chim. Acta 2003, 86, 181– 187,  DOI: 10.1002/hlca.200390009
      67
      X-ray crystal structure analysis of oxindole alkaloids
      Laus, Gerhard; Wurst, Klaus
      Helvetica Chimica Acta (2003), 86 (1), 181-187CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
      The single-crystal X-ray structures of speciophylline, mitraphylline, and rhynchophylline, oxindole alkaloids from the Peruvian climbing vine Uncaria tomentosa (Rubiaceae), were detd. The three compds. show N ···H-N hydrogen bonding, which has not been obsd. in the crystal structures of the related alkaloids pteropodine and isopteropodine. In the tetracyclic alkaloid rhynchophylline, the side chain is rotated out of the ring plane into a position perpendicular to it. This is in contrast to the situation of the pentacyclic analog mitraphylline, which possesses a conformationally rigid tricyclic core. This conformational difference possibly causes the competitive antagonism of these two types of alkaloids.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXht1OjtLs%253D&md5=b452333e36ae340e374488d4af001ebd
    68. 68
      Wanner, M. J.; Ingemann, S.; van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2013, 2013, 1100– 1106,  DOI: 10.1002/ejoc.201201505
      68
      Total Synthesis of the Spirocyclic Oxindole Alkaloids Corynoxine, Corynoxine B, Corynoxeine, and Rhynchophylline
      Wanner, Martin J.; Ingemann, Steen; van Maarseveen, Jan H.; Hiemstra, Henk
      European Journal of Organic Chemistry (2013), 2013 (6), 1100-1106CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Racemic total syntheses of four spirocyclic oxindole alkaloids are reported. The general starting material was an N-2-butenylated 2-hydroxytryptamine, which underwent a base-mediated Mannich spirocyclization with a functionalized aldehyde to generate the C-ring. The second key step was a Pd-catalyzed cyclization of an α-keto ester enolate (in the original aldehyde) onto an allylic carbonate (in the N-substituent) to form the D-ring. The stereoselectivities of the key steps were moderate, but the isomers were readily purified, so that the natural products could be conveniently prepd., three of them for the first time.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkvFKrsQ%253D%253D&md5=3f2a4d0ec2a87db3d274f51d91d9edc6
    69. 69
      Reinhardt, J. K.; Klemd, A. M.; Danton, O.; De Mieri, M.; Smieško, M.; Huber, R.; Bürgi, T.; Gründemann, C.; Hamburger, M. J. Nat. Prod. 2019, 82, 1424– 1433,  DOI: 10.1021/acs.jnatprod.8b00791
      69
      Sesquiterpene lactones from Artemisia argyi: Absolute configuration and immunosuppressant activity
      Reinhardt, Jakob K.; Klemd, Amy M.; Danton, Ombeline; De Mieri, Maria; Smiesko, Martin; Huber, Roman; Burgi, Thomas; Grundemann, Carsten; Hamburger, Matthias
      Journal of Natural Products (2019), 82 (6), 1424-1433CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      A library of exts. from plants used in Chinese Traditional Medicine was screened for inhibition of T lymphocyte proliferation. An Et acetate ext. from aerial parts of Artemisia argyi showed promising activity and was submitted to HPLC-based activity profiling to track the active compds. From the most active time window, three guaianolides (1, 2, and 5) and two seco-tanapartholides (3 and 4) were identified and, in a less active time window, five new sesquiterpene lactones (8-11, 17), along with six known sesquiterpene lactones and two known flavonoids. The abs. configurations of compds. 1, 2, 5-10, 13-15, 17, and 18 were established by comparison of exptl. with calcd. electronic CD (ECD) spectra. For seco-tanapartholides B (3) and A (4), ECD yielded ambiguous results, and their abs. configurations were detd. by comparing exptl. and calcd. vibrational CD (VCD) spectra. Compds. 1-5 showed significant, noncytotoxic inhibition of T lymphocyte proliferation, with IC50 values between 1.0 and 3.7 μM.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFWgtLnN&md5=e20016f1a8dcfaf2b6d839d23b6052d4
    70. 70
      Bustos-Brito, C.; Joseph-Nathan, P.; Burgueño-Tapia, E.; Martínez-Otero, D.; Nieto-Camacho, A.; Calzada, F.; Yépez-Mulia, L.; Esquivel, B.; Quijano, L. J. Nat. Prod. 2019, 82, 1207– 1216,  DOI: 10.1021/acs.jnatprod.8b00952
      70
      Structure and absolute configuration of abietane diterpenoids from Salvia clinopodioides: Antioxidant, antiprotozoal, and antipropulsive activities
      Bustos-Brito, Celia; Joseph-Nathan, Pedro; Burgueno-Tapia, Eleuterio; Martinez-Otero, Diego; Nieto-Camacho, Antonio; Calzada, Fernando; Yepez-Mulia, Lilian; Esquivel, Baldomero; Quijano, Leovigildo
      Journal of Natural Products (2019), 82 (5), 1207-1216CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      The aerial parts of Salvia clinopodioides afforded abietanes 1a, 2a, and 3 (clinopodiolides A-C), two of which possess an unusual lactol moiety at C-19-C-20, together with an icetexane named clinopodiolide D (4a). Their structures were established by spectroscopic means, mainly 1H and 13C NMR, including 1D and 2D homo- and heteronuclear expts. The antioxidant, antiprotozoal, and antidiarrheal effects of the isolates were evaluated. Compds. 2a and 3 showed better effects than α-tocopherol in the inhibition of lipid peroxidn. with IC50 (μM) = 5.9 ± 0.1 and 2.7 ± 0.2, resp., and moderate activity in the DPPH assay. All tested compds. showed moderate antiamoebic and antigiardial activity, as well as a good antipropulsive effect.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXovVyrtrk%253D&md5=7eaa3667d58910da0e9d9bcbc430dd12
    71. 71
      El-Kashef, D. H.; Daletos, G.; Plenker, M.; Hartmann, R.; Mándi, A.; Kurtán, T.; Weber, H.; Lin, W.; Ancheeva, E.; Proksch, P. J. Nat. Prod. 2019, 82, 2460– 2469,  DOI: 10.1021/acs.jnatprod.9b00125
      71
      Polyketides and a Dihydroquinolone Alkaloid from a Marine-Derived Strain of the Fungus Metarhizium marquandii
      El-Kashef, Dina H.; Daletos, Georgios; Plenker, Malte; Hartmann, Rudolf; Mandi, Attila; Kurtan, Tibor; Weber, Horst; Lin, Wenhan; Ancheeva, Elena; Proksch, Peter
      Journal of Natural Products (2019), 82 (9), 2460-2469CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      Three new natural products, including 2 butenolide derivs. and 1 dihydroquinolone deriv., together with 9 known natural products were isolated from a marine-derived strain of the fungus Metarhizium marquandii. The structures of the new compds. were unambiguously deduced by spectroscopic means including HRESIMS and 1D/2D NMR spectroscopy, ECD, VCD, OR measurements and calcns. The abs. configuration of marqualide (I) was detd. by a combination of modified Mosher's method with TDDFT-ECD calcns. at different levels, which revealed the importance of intramol. hydrogen-bonding in detg. the ECD features. The (3R,4R) abs. configuration of aflaquinolone I (II), detd. by OR, ECD, and VCD calcns., was opposite to the (3S,4S) abs. configuration of the related aflaquinolones A-G suggesting that the fungus Metarhizium marquandii produces aflaquinolone I with a different configuration (chiral switching). The abs. configuration of the known natural product, terrestric acid hydrate, was likewise detd. for the 1st time. TDDFT-ECD calcns. allowed detn. of the abs. configuration of its chirality center remote from the stereogenic unsatd. γ-lactone chromophore. ECD calcns. aided by solvent models revealed the importance of intramol. hydrogen bond networks in stabilizing conformers and detg. relations between ECD transitions and abs. configurations.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1Shsb7E&md5=5dccd962459d630ad8bf6e75e7e05558
    72. 72
      Cao, F.; Meng, Z.-H.; Mu, X.; Yue, Y.-F.; Zhu, H.-J. J. Nat. Prod. 2019, 82, 386– 392,  DOI: 10.1021/acs.jnatprod.8b01030
      72
      Absolute Configuration of Bioactive Azaphilones from the Marine-Derived Fungus Pleosporales sp. CF09-1
      Cao, Fei; Meng, Zhi-Hui; Mu, Xing; Yue, Yu-Fei; Zhu, Hua-Jie
      Journal of Natural Products (2019), 82 (2), 386-392CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      Investigation of the marine-derived fungus Pleosporales sp. CF09-1 cultured in modified PDB medium led to the isolation of 6 new azaphilone derivs., pleosporalones B and C (I ad II) and plosporalones E-H, and 1 known analog pleosporalone D. The abs. configurations of C-2' and C-3' in pleosporalone D were assigned by a vibrational CD method. The C-11 relative configurations for the pair of C-11 epimers (pleosporalones E and F) were established by comparing the magnitude of the computed 13C NMR chem. shifts (Δδcalcd) with the exptl. 13C NMR values (Δδexp) for the epimers. Antiphytopathogenic and anti-Vibrio activities were evaluated. I exhibited potent antifungal activities against the fungi Alternaria brassicicola and Fusarium oxysporum with the same MIC value of 1.6 μg/mL, which were stronger than the pos. control ketoconazole among these compds. Addnl., I displayed significant activity against the fungus Botryosphaeria dothidea (MIC, 3.1 μg/mL). Pleosporalone G and F displayed moderate anti-Vibrio activities against Vibrio anguillarum and Vibrio parahemolyticus, with MIC values of 13 and 6.3 μg/mL for pleosporalone G and 6.3 and 25 μg/mL for pleosporalone F, resp.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisValtbo%253D&md5=2dacc6f58de96fdcf98afd98a29e96ce
    73. 73
      Arreaga-González, H. M.; Rodríguez-García, G.; del Río, R. E.; Ferreira-Sereno, J. A.; García-Gutiérrez, H. A.; Cerda-García-Rojas, C. M.; Joseph-Nathan, P.; Gómez-Hurtado, M. A. J. Nat. Prod. 2019, 82, 3394– 3400,  DOI: 10.1021/acs.jnatprod.9b00734
      73
      Configurational Variation of a Natural Compound within Its Source Species. The Unprecedented Case of Areolal in Piptothrix areolare
      Arreaga-Gonzalez, Hector M.; Rodriguez-Garcia, Gabriela; del Rio, Rosa E.; Ferreira-Sereno, Jose A.; Garcia-Gutierrez, Hugo A.; Cerda-Garcia-Rojas, Carlos M.; Joseph-Nathan, Pedro; Gomez-Hurtado, Mario A.
      Journal of Natural Products (2019), 82 (12), 3394-3400CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      The exceptional case of a natural compd. that shows drastic abs. configuration variations within the same species was examd. Sequential samples of areolal (1) isolated from Piptothrix areolare showed dextrorotatory (ee 32%), almost racemic (ee 4%), levorotatory (ee 82%), and again dextrorotatory (ee 10%) values. Enantiomeric compns. of this epoxythymol deriv. were detd. from individual plant specimens collected from the same geog. location over a 46-day period, which were processed using the same extn. and isolation methods. Detection of this unusual phenomenon was possible by anal. of NMR data recorded in the presence of BINOL as a chiral solvating agent. The abs. configuration of (-)-(8S)-areolal followed from vibrational CD data of an enantiomerically enriched sample, while single-crystal X-ray diffraction and supramol. analyses revealed interactions that diminish the crystal entropy in rac-1. These results might be related with environmental factors and biochem. processes, suggesting the need of strict evaluations of enantiomeric compn. of natural products that could be considered for human applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFyqtrvI&md5=859eb605770ad2114e636e1f0b443a27
    74. 74
      Raja, H. A.; Baker, T. R.; Little, J. G.; Oberlies, N. H. Food Chem. 2017, 214, 383– 392,  DOI: 10.1016/j.foodchem.2016.07.052
      74
      DNA barcoding for identification of consumer-relevant mushrooms: A partial solution for product certification?
      Raja, Huzefa A.; Baker, Timothy R.; Little, Jason G.; Oberlies, Nicholas H.
      Food Chemistry (2017), 214 (), 383-392CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
      One challenge in the dietary supplement industry is confirmation of species identity for processed raw materials, i.e. those modified by milling, drying, or extn., which move through a multilevel supply chain before reaching the finished product. This is particularly difficult for samples contg. fungal mycelia, where processing removes morphol. characteristics, such that they do not present sufficient variation to differentiate species by traditional techniques. To address this issue, we have demonstrated the utility of DNA barcoding to verify the taxonomic identity of fungi found commonly in the food and dietary supplement industry; such data are crit. for protecting consumer health, by assuring both safety and quality. By using DNA barcoding of nuclear ribosomal internal transcribed spacer (ITS) of the rRNA gene with fungal specific ITS primers, ITS barcodes were generated for 33 representative fungal samples, all of which could be used by consumers for food and/or dietary supplement purposes. In the majority of cases, we were able to sequence the ITS region from powd. mycelium samples, grocery store mushrooms, and capsules from com. dietary supplements. After generating ITS barcodes utilizing std. procedures accepted by the Consortium for the Barcode of Life, we tested their utility by performing a BLAST search against authenticate published ITS sequences in GenBank. In some cases, we also downloaded published, homologous sequences of the ITS region of fungi inspected in this study and examd. the phylogenetic relationships of barcoded fungal species in light of modern taxonomic and phylogenetic studies. We anticipate that these data will motivate discussions on DNA barcoding based species identification as applied to the verification/certification of mushroom-contg. dietary supplements.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtF2hurnP&md5=c0b2f3c4a4f86f9fdc38532010a1207c
    75. 75
      Dunning, L. T.; Savolainen, V. Bot. J. Linn. Soc. 2010, 164, 1– 9,  DOI: 10.1111/j.1095-8339.2010.01071.x
      There is no corresponding record for this reference.
    76. 76
      Ford, C. S.; Ayres, K. L.; Toomey, N.; Haider, N.; Van Alphen Stahl, J.; Kelly, L. J.; Wikström, N.; Hollingsworth, P. M.; Duff, R. J.; Hoot, S. B. Bot. J. Linn. Soc. 2009, 159, 1– 11,  DOI: 10.1111/j.1095-8339.2008.00938.x
      There is no corresponding record for this reference.
    77. 77
      Pawar, R. S.; Handy, S. M.; Cheng, R.; Shyong, N.; Grundel, E. Planta Med. 2017, 83, 921– 936,  DOI: 10.1055/s-0043-107881
      77
      Assessment of the Authenticity of Herbal Dietary Supplements: Comparison of Chemical and DNA Barcoding Methods
      Pawar, Rahul S.; Handy, Sara M.; Cheng, Raymond; Shyong, Nicole; Grundel, Erich
      Planta Medica (2017), 83 (11), 921-936CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
      About 7 % of the U. S. population reports using botanical dietary supplements. Increased use of such supplements has led to discussions related to their authenticity and quality. Reports of adulteration with substandard materials or pharmaceuticals are of concern because such substitutions, whether inadvertent or deliberate, may reduce the efficacy of specific botanicals or lead to adverse events. Methods for verifying the identity of botanicals include macroscopic and microscopic examns., chem. anal., and DNA-based methods including DNA barcoding. Macroscopic and microscopic examns. may fail when a supplement consists of botanicals that have been processed beyond the ability to provide morphol. characterizations. Chem. anal. of specific marker compds. encounters problems when these compds. are not distinct to a given species or when purified ref. stds. are not available. Recent investigations describing DNA barcoding anal. of botanical dietary supplements have raised concerns about the authenticity of the supplements themselves as well as the appropriateness of using DNA barcoding techniques with finished botanical products. We collected 112 market samples of frequently consumed botanical dietary supplements of ginkgo, soy, valerian, yohimbe, and St. John's wort and analyzed each for specific chem. markers (i.e., flavonol glycosides, total isoflavones, total valerenic acids, yohimbine, and hypericins, resp.). We used traditional DNA barcoding techniques targeting the nuclear ITS2 gene and the chloroplast gene psbA-trnH on the same samples to det. the presence of DNA of the labeled ingredient. We compared the results obtained by both methods to assess the contribution of each in detg. the identity of the samples.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVCqu7Y%253D&md5=db2e07475b5fccc221b191802bcc6e2e
    78. 78
      Cheng, T.; Xu, C.; Lei, L.; Li, C.; Zhang, Y.; Zhou, S. Mol. Ecol. Resour. 2016, 16, 138– 149,  DOI: 10.1111/1755-0998.12438
      78
      Barcoding the kingdom plantae: new PCR primers for ITS regions of plants with improved universality and specificity
      Cheng, Tao; Xu, Chao; Lei, Li; Li, Changhao; Zhang, Yu; Zhou, Shiliang
      Molecular Ecology Resources (2016), 16 (1), 138-149CODEN: MEROCJ; ISSN:1755-098X. (Wiley-Blackwell)
      The internal transcribed spacer (ITS) of nuclear ribosomal DNA is one of the most commonly used DNA markers in plant phylogenetic and DNA barcoding analyses, and it has been recommended as a core plant DNA barcode. Despite this popularity, the universality and specificity of PCR primers for the ITS region are not satisfactory, resulting in amplification and sequencing difficulties. By thoroughly surveying and analyzing the 18S, 5.8S and 26S sequences of Plantae and Fungi from GenBank, we designed new universal and plant-specific PCR primers for amplifying the whole ITS region and a part of it (ITS1 or ITS2) of plants. In silico analyses of the new and the existing ITS primers based on these highly representative data sets indicated that (i) the newly designed universal primers are suitable for over 95% of plants in most groups; and (ii) the plant-specific primers are suitable for over 85% of plants in most groups without amplification of fungi. A total of 335 samples from 219 angiosperm families, 11 gymnosperm families, 24 fern and lycophyte families, 16 moss families and 17 fungus families were used to test the performances of these primers. In vitro PCR produced similar results to those from the in silico analyses. Our new primer pairs gave PCR improvements up to 30% compared with common-used ones. The new universal ITS primers will find wide application in both plant and fungal biol., and the new plant-specific ITS primers will, by eliminating PCR amplification of nonplant templates, significantly improve the quality of ITS sequence information collections in plant mol. systematics and DNA barcoding.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitV2jsbbL&md5=690069c351bb33c712638c8d5ec07bc0
    79. 79
      Löfstrand, S. D.; Krüger, Å.; Razafimandimbison, S. G.; Bremer, B. Syst. Bot. 2014, 39, 304– 315,  DOI: 10.1600/036364414X678116
      There is no corresponding record for this reference.
    80. 80
      Razafimandimbison, S. G.; Bremer, B. Am. J. Bot. 2002, 89, 1027– 1041,  DOI: 10.3732/ajb.89.7.1027
      80
      Phylogeny and classification of Naucleeae S.L. (Rubiaceae) inferred from molecular (ITS, rBCL, and tRNT-F) and morphological data
      Razafimandimbison, Sylvain G.; Bremer, Birgitta
      American Journal of Botany (2002), 89 (7), 1027-1041CODEN: AJBOAA; ISSN:0002-9122. (Botanical Society of America)
      Parsimony analyses of the tribe Naucleeae sensu lato (s.l.) using the noncoding internal transcribed spacer (ITS) regions of nuclear rDNA, the protein-coding rbcL and noncoding trnT-F regions of chloroplast DNA, and morphol. data were performed to construct new intratribal classification, test the monophyly of previous subtribal circumscriptions, and evaluate the generic status of Naucleeae s.l. Fifty-two ITS, 45 rbcL, and 55 trnT-F new sequences are published here. Our study supports the monophyly of the subtribes Anthocephalidae, Mitragynae, Uncariae all sensu Haviland and Naucleinae sensu Ridsdale. There was no support for Cephalanthidae sensu Haviland and Adininae sensu Ridsdale. Naucleeae can be subdivided into six highly supported and morphol. distinct subtribes. Breoniinae, Cephalanthinae, Corynantheinae, Naucleinae, and Mitragyninae, Uncarinae, plus one, Adininae, which is poorly supported. The relationships among these subtribes were largely unresolved. We maintain the following 22 genera: Adina, Adinauclea, Breonadia, Breonia, Burttdavya, Cephalanthus, Gyrostipula, Haldina, Janotia, Ludekia, Metadina, Mitragyna, Myrmeconauclea, Nauclea, Neolamarckia, Neonauclea, Ochreinauclea, Pausinystalia, Pertusadina, Sarcocephalus, Sinoadina, and Uncaria. Pseudocinchona is reestablished. Corynanthe is restricted to C. paniculata and Hallea is reincluded in Mitragyna. Our results were inconclusive for assessing the relationships among Adina, Adinauclea, Metadina, and Pertusadina due to lack of resoln.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislejtg%253D%253D&md5=dc6e3d53a33203c56391d5ec5e4cce17
    81. 81
      Tnah, L.; Lee, S.; Tan, A.; Lee, C.; Ng, K.; Ng, C.; Farhanah, Z. N. Food Control 2019, 95, 318– 326,  DOI: 10.1016/j.foodcont.2018.08.022
      81
      DNA barcode database of common herbal plants in the tropics: a resource for herbal product authentication
      Tnah, L. H.; Lee, S. L.; Tan, A. L.; Lee, C. T.; Ng, K. K. S.; Ng, C. H.; Nurul Farhanah, Z.
      Food Control (2019), 95 (), 318-326CODEN: FOOCEV; ISSN:0956-7135. (Elsevier Ltd.)
      Ensuring the authenticity of raw materials used in herbal manufg. is a key step prior to material processing. As species authentication is fundamental in the confirmation of herbal product quality, DNA barcoding techniques represent an efficient method for detecting plant-based adulterants in traded herbal products. Through this study, we established a DNA barcoding authentication system for 112 common herbal plant species in the tropics, which can be used for species identification and authentication. The DNA barcode ref. database for the authentication system was generated using rbcL for primary differentiation, and trnH-psbA for secondary differentiation. The performance of the barcodes in resolving species was evaluated using similarity BLAST, phylogenetic tree reconstruction and by estg. the barcoding gap. In this study, the multigene tiered approach for DNA barcoding is proven robust with high species-level resoln. (96.4%). Upon completion of the DNA barcoding authentication system, 30 herbal products from the local market were tested for their authenticity using this approach. Recovery of DNA barcodes from the herbal products was 73.4%, of which 56.7% of the products tested were authentic, whereas 10% of the herbal products were substituted with other plant taxa and 6.7% were contaminated. To this end, authentication of herbal products is challenging, but with the establishment of a new DNA barcoding authentication system for common herbal plants in the tropics, the existing quality assurance and adulteration screening programs employed by regulatory agencies could be significantly strengthened.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsF2mu7fF&md5=9216e652ad786af7bed161b0391c30bc
    82. 82
      Raja, H. A.; Miller, A. N.; Pearce, C. J.; Oberlies, N. H. J. Nat. Prod. 2017, 80, 756– 770,  DOI: 10.1021/acs.jnatprod.6b01085
      82
      Fungal Identification Using Molecular Tools: A Primer for the Natural Products Research Community
      Raja, Huzefa A.; Miller, Andrew N.; Pearce, Cedric J.; Oberlies, Nicholas H.
      Journal of Natural Products (2017), 80 (3), 756-770CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      A review. Fungi are morphol., ecol., metabolically, and phylogenetically diverse. They are known to produce numerous bioactive mols., which makes them very useful for natural products researchers in their pursuit of discovering new chem. diversity with agricultural, industrial, and pharmaceutical applications. Despite their importance in natural products chem., identification of fungi remains a daunting task for chemists, esp. those who do not work with a trained mycologist. The purpose of this review is to update natural products researchers about the tools available for mol. identification of fungi. In particular, we discuss (1) problems of using morphol. alone in the identification of fungi to the species level; (2) the three nuclear ribosomal genes most commonly used in fungal identification and the potential advantages and limitations of the ITS region, which is the official DNA barcoding marker for species-level identification of fungi; (3) how to use NCBI-BLAST search for DNA barcoding, with a cautionary note regarding its limitations; (4) the numerous curated mol. databases contg. fungal sequences; (5) the various protein-coding genes used to augment or supplant ITS in species-level identification of certain fungal groups; and (6) methods used in the construction of phylogenetic trees from DNA sequences to facilitate fungal species identification. We recommend that, whenever possible, both morphol. and mol. data be used for fungal identification. Our goal is that this review will provide a set of standardized procedures for the mol. identification of fungi that can be utilized by the natural products research community.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis1agtr8%253D&md5=5da43eae011fd414b20212e0f6d57072

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00257.

    • 1H NMR, 13C NMR, and HRESIMS data for compounds 1–19; 2D NMR data (COSY, HSQC, and HMBC) for new compounds 7, 11, 17, and 18; ECD data for compounds 1–14 and 16–19 (PDF)


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.