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Synthesis and Characterization of Partially and Fully Saturated Menaquinone Derivatives
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Cite this: ACS Omega 2018, 3, 11, 14889–14901
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https://doi.org/10.1021/acsomega.8b02620
Published November 5, 2018

Copyright © 2018 American Chemical Society. This publication is licensed under CC-BY.

Abstract

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Menaquinones (MKs) contain both a redox active quinone moiety and a hydrophobic repeating isoprenyl side chain of varying lengths and degrees of saturation. This characteristic structure allows MKs to play a key role in the respiratory electron transport system of some prokaryotes by shuttling electrons and protons between membrane-bound protein complexes, which act as electron acceptors and donors. Hydrophobic MK molecules with partially and fully saturated isoprenyl side chains are found in a wide range of eubacteria and archaea, and the structural variations of the MK analogues are evolutionarily conserved but poorly understood. For example, Mycobacterium tuberculosis, the causative agent of tuberculosis, uses predominantly MK-9(II-H2) (saturated at the second isoprene unit) as its electron carrier and depends on the synthesis of MK-9(II-H2) for survival in host macrophages. Thus, MKs with partially saturated isoprenyl side chains may represent a novel virulence factor. Naturally occurring longer MKs are very hydrophobic, whereas MK analogues that have a truncated (i.e., one to three isoprenes) isoprenyl side chain are less hydrophobic. This improves their solubility in aqueous solutions, allowing rigorous study of their structure and biological activity. We present the synthesis and characterization of two partially saturated MK analogues, MK-2(II-H2) and MK-3(II-H2), and two novel fully saturated MK derivatives, MK-2(I,II-H4) and MK-3(I,II,III-H6).

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Introduction

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Menaquinones (or naphthoquinones, MKs) belong to the class of lipoquinones, which are a type of lipid-quinone containing isoprenoids that have a variety of biological roles. These molecules contain both a redox active quinone moiety and a hydrophobic repeating isoprenyl side chain of varying lengths and degrees of saturation (Figure 1) depending on the organism. Although the naturally occurring lipoquinones generally have longer isoprenyl side chains, these MK analogues have very low water solubility, which causes problems for biological assays; therefore, the use of truncated MK derivatives can circumvent solubility issues in aqueous assays. The 1943 Nobel prize in physiology or medicine was awarded to Henrik Dam and Edward Doisy for the discovery and characterization of vitamin K (a MK), a key cofactor in blood coagulation. (1) The interest in and the importance of MK/vitamin K, its derivatives, and vitamers (e.g., vitamins K1, K2, and K3) have remained strong. Vitamin K1, also known as phylloquinone, is found in green plants and contains four isoprene units with the terminal three saturated and functions as an electron acceptor during photosynthesis within photosystem I. (2) Vitamin K2, also known as menaquinone-4 (MK-4), has been the subject of interesting reports, demonstrating its biological roles and applications over the last 10 years. (3−6) Vitamin K3 (or menadione), the simplest 1,4-naphthoquinone derivative, which lacks the isoprenyl side chain and non-naturally occurring N-alkylated MK derivatives has also shown interesting biological properties. (7−11) In 2017, the potent cyclic peptide antibiotic, Lotilibcin, was demonstrated to be effective against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. (12) The activity of Lotilibcin was attributed to lysis of the bacterial membrane, where its membrane-disrupting effects depended on the presence of MK, which leaves the question if other MK derivatives have the same effect. (12) This report underlines the importance of understanding the relationship between the MK structure, its biological role, and its biological function.

Figure 1

Figure 1. (A) Partially saturated menaquinone-9(II-H2) [abbreviated as MK-9(II-H2)] present within M. tuberculosis, (B) partially saturated menaquinone-2(II-H2) [abbreviated as MK-2(II-H2)], (C) fully saturated menaquinone-2(I,II-H4) [abbreviated as MK-2(I,II-H4)], (D) partially saturated menaquinone-3(II-H2) [abbreviated as MK-3(II-H2)], and (E) fully saturated menaquinone-3(I,II,III-H6) [abbreviated as MK-3(I,II,III-H6)].

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MK analogues that contain partially and fully saturated isoprenyl side chains of various lengths are found in eubacteria and archaea. These characteristics are evolutionarily conserved and have long been used in taxonomic classification efforts and phenotypic organization of bacteria. (13−15) MK analogues with one or more saturated isoprene units are found in some members of Gram-positive and Gram-negative bacteria, and the systematic preparation and characterization of a few selected truncated partially and fully saturated MK derivatives are described in this manuscript. (14−17) In contrast to partial saturation, the fully saturated MK-7(14H) has been observed in archaea, which are single-celled microbes comprising part of the human microbiota. (18,19) It is thought that the full saturation of the isoprenyl side chain observed in archaea makes the cellular membrane more tolerant to extreme environments (e.g., high temperature, high salinity, and low/high pH). (18) Thus, many MK homologues that contain various degrees of saturation in their isoprenyl side chains have been isolated, but there is a limited understanding of the function of partially saturated derivatives. (16,20) Menaquinone-9(II-H2) [abbreviated as MK-9(II-H2), Figure 1A], which is saturated at the second isoprene, has been observed in a number of bacteria including Mycobacterium phlei and pathogenic Mycobacterium tuberculosis. (14,16,17,21,22) The biological significance of the partial saturation of MK-9 has remained unclear even 50 years after its first description. (20) Remarkably, the synthesis of MK-9(II-H2) was recently shown to be essential for M. tuberculosis survival in host macrophages (white blood cells of the immune system); thus, MK-9(II-H2) represents a potential novel virulence factor involved in tuberculosis (TB) disease progression. (23)
Part of our ongoing studies includes why partial saturation of MK-9 increases the virulence of pathogens such as M. tuberculosis. (23) Therefore, we need access to MK analogues containing partially and fully saturated isoprenyl side chains. However, in general, they are neither commercially available nor sold as a pure geometric isomer as in the case of vitamin K1. The potential for the formation of cis and trans MK isomers and the separation and characterization of these geometric isomers are sometimes overlooked in the literature, but it is critical for their applications in biological systems. The use of cis/trans MK mixtures in biological systems would lead to inaccurate biological activities. Recently, the separation and nuclear magnetic resonance (NMR) analysis of cis/trans mixtures of the dietary supplement menaquinone-7 (MK-7) was reported, demonstrating the importance in understanding the different chemical, biochemical, conformational, and physical properties exhibited between cis and trans MK isomers. (24,25) Truncated MK analogues (i.e., one to three isoprene units) have the advantage of being less hydrophobic, which can improve their biological activity compared to longer isoprenyl MK analogues (e.g., MK-7 and MK-9) and can be prepared using a similar methodology described in this manuscript and reports elsewhere. (26,27)
In this manuscript, we have synthesized and characterized four partially and fully saturated truncated isoprenyl MK derivatives (Figure 1B–E) as well as separated and characterized the geometric isomers formed in the reactions. We have adopted the simple naming system where MK-2 with a saturated double bond at the second isoprene unit is denoted as menaquinone-2(II-H2) and abbreviated as MK-2(II-H2), where II denotes the second isoprene unit and H2 denotes the saturation of one double bond (Figure 1B). (23,28) This naming system follows for higher degrees of saturation such as MK-2(I,II-H4), that is, saturated at isoprenes I and II and MK-3(I,II,III-H6), that is, saturated at isoprenes I, II, and III (Figure 1C,E). Although MK-2(II-H2) and menaquinone-3(II-H2) [abbreviated as MK-3(II-H2)] were known in literature reports mostly in the 1950s (29−34) and MK-2(II-H2) was considered in a computational model study, (35) there are no modern syntheses reported, and these analogues have not been extensively characterized nor have their geometric isomers been resolved and characterized in the literature. Evidence supports the trans MK isomer as the only biologically active isomer. (27) Therefore, the separation and isolation of geometric isomers of MK derivatives is critical when testing these compounds in biological assays.
The synthesis and characterization of partially and fully saturated isoprenyl MK analogues, such as the two novel fully saturated MK derivatives described in this work, are important for understanding their requirement in biological systems, as little is known about their physical properties, reactivity, or 3D-conformation within solution or cell membranes. Access to these partially and fully saturated truncated MK analogues in the pure geometric form is critical, considering the recent discovery and timeliness for understanding why partially saturated MKs [e.g., MK-9(II-H2), Figure 1A] may be a potential virulence factor against pathogenic M. tuberculosis, when currently around one-third of the world’s population is infected with latent TB and over 1.3 million people worldwide die annually from TB. (36)

Results and Discussion

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In the following, we describe the synthesis and characterization of two partially saturated MK analogues, MK-2(II-H2) and MK-3(II-H2), using modified and adapted procedures. We also describe the synthesis and characterization of two novel fully saturated MK analogues, MK-2(I,II-H4) and MK-3(I,II,III-H6), utilizing a key radical alkylation reaction. This is the first report on a preparatory scale utilizing a primary alkyl radical coupling reaction to access fully saturated MK derivatives, although in situ analysis of menaquinone-1(H2) was reported previously. (37) Importantly, a convenient analysis can be carried out by rapid detection using benzene-d6 as an NMR solvent for the evaluation of cis and trans MK mixtures (peaks coalesce in CDCl3 disguising potential isomers formed). The cis/trans isomers can then be readily separated using preparative thin-layer chromatography (TLC) and analyzed.

Synthesis and Characterization of MK-2(II-H2)

The partially saturated MK analogue, MK-2(II-H2) 3, was synthesized in a single step using Friedel–Crafts coupling between menadiol 1 and isophytol 2 (Scheme 1). The precursor menadiol was synthesized, as previously described, from menadione. (26,38) The partly hydroxylated heterogeneous Lewis–Brønsted acid catalyst, MgF2-48, was synthesized as previously described. (39−41) We chose MgF2-48 over other catalysts because it was readily prepared from inexpensive methanol and Mg0 powder as well as from commonly available 48% aqueous hydrofluoric acid. (39−41) Furthermore, the partly hydroxylated MgF2 catalyst was recently used with a biphasic n-heptane/polyene carbonate solvent system to synthesize vitamin K1 and K1-chromanol. (40) Therefore, we thought this catalyst would be an excellent choice to synthesize the partially saturated MK-2(II-H2), which has the analogous (but truncated) structure of vitamin K1 [or MK-4(II,III,IV-H6)].

Scheme 1

Scheme 1. Synthetic Scheme for the Coupling Reaction Using a MgF2-48 Catalyst To Obtain MK-2(II-H2) 3 from Menadiol 1 and Isophytol 2 (40)
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The Friedel–Crafts alkylation of 1 and 2 (Scheme 1) followed by in situ oxidation of dihydro-MK-2(II-H2) formed the desired product 3 in an 11% yield. The low yield may be attributed to the formation of the undesired C2 isomeric side product (see Scheme 1), which was readily separated using column chromatography. The inherent instability of menadiol, which is prone to auto-oxidation even when purified immediately before use may also contribute to the low yield. MK-2(II-H2) 3 was obtained as a yellow/red oil. The reaction was carried out in the dark, and the product was exposed minimally to light as previous studies have shown that interconversion to undesirable geometric isomers can occur through photo-oxidation if exposed to light. (16,42,43)
We considered other possible catalysts to carry out the transformation shown in Scheme 1. For instance, we also explored a commercially available strong Brønsted acid catalyst (Nafion perfluorinated powdered resin and Nafion perfluorinated ion-exchange resin in 10 wt % dispersion in water); however, the yields were significantly lower with the increased formation of the C2 prenylated isomeric side product (see Scheme 1). Furthermore, we were concerned about the Nafion catalyst (containing super acidic sites) dehydrating isophytol to form undesirable phytadienes, (40) which presumably contribute to it being a less desirable catalyst for this purpose.
An interesting feature of MKs is the possibility of geometric isomer formation (Figure 2A,B). The biologically active trans isomer of vitamin K1 is the natural biological form of vitamin K1. (27) Evidence also demonstrates that biological MKs have an all-trans configuration of the double bonds within the isoprenyl side chain. (27) The geometric isomers of vitamin K1, MK-7 and MK-9(II-H2) (isolated from M. phlei, Figure 1A), have been successfully separated; therefore, efforts to isolate the trans isomer of MK-2(II-H2) from its cis isomer byproduct (Figure 2B) were carried out. (16,24,27) MK-2(II-H2) 3 was initially isolated as a 2.7:1 mixture of trans/cis isomers (by NMR integration of alkene peaks in benzene-d6) after column chromatography. The trans isomer of MK-2(II-H2) 3 can be isolated using preparative TLC, similar to reports for vitamin K1 analogues (44) and MK analogues. (16)

Figure 2

Figure 2. Comparison of the 1D 1H NMR (400 MHz) spectra for the mixture of cis/trans-MK-2(II-H2) and trans-MK-2(II-H2) in C6D6 at 25 °C. (A) Structure of trans-MK-2(II-H2) with the proton labeling scheme key, (B) structure of cis-MK-2(II-H2), (C) 1D 1H NMR spectrum of the cis/trans mixture of MK-2(II-H2) in C6D6, and (D) 1D 1H NMR spectrum of trans-MK-2(II-H2) in C6D6.

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The successful separation of the trans isomer of 3 by preparative TLC allowed for characterization of a single pure geometric isomer of MK-2(II-H2), Figure 2. The structural assignment of trans-MK-2(II-H2) (Figure 2) was elucidated using two-dimensional (2D) NMR spectroscopic methods [1H–1H correlation spectroscopy (COSY) and 1H–13C heteronuclear single quantum correlation (HSQC) spectroscopy; see the Supporting Information for spectra, Figures S1–S4.1 and S7–S8.1]. Spectra obtained in benzene-d6 (C6D6) result in less overlap of the NMR signals for the cis/trans isomer mixture (Figure 2C,D), compared to CDCl3 where some of the geometric isomer peaks overlap (e.g., cis/trans alkene protons coalesce in CDCl3) and the formation of isomers is not obvious. Therefore, the use of C6D6 as a diagnostic NMR solvent for the evaluation of cis/trans mixtures for MK analogues was critical and is in line with a recently reported NMR analysis of cis/trans isomer mixtures of MK-7 (24) (see the Supporting Information for spectra in CDCl3 versus C6D6, Figure S40).

Synthesis and Characterization of MK-2(I,II-H4)

The fully saturated isoprenyl MK analogue, MK-2(I,II-H4) 7, was synthesized in three steps from commercially available 3,7-dimethyloctan-1-ol 4 (Scheme 2). The first step converted aliphatic alcohol 4 to the mesylate, which was then subjected to an SN2 reaction using NaI to yield 1-iodo-3,7-dimethyloctane 5 in 47% yield over two steps. (38) The alkyl iodide 5 was then coupled to menadione 6 via radical alkylation using benzoyl peroxide (37) as a radical initiator to yield MK-2(I,II-H4) 7 in 17% yield. The yield for the coupling reaction is close in range with that reported in the literature for other coupling reactions for the synthesis of MK analogues. (26,27,38) The unreacted alkyl iodide 5 can be recovered during column chromatography. In an effort to ensure selectivity of prenylation at C3 versus C2 (Scheme 2), the slow addition of napthoquinone 6 during the reaction was carried out so that the naphthoquinone stationary concentration in the reaction mixture is low compared to the prenyl iodide concentration. (37) MK-2(I,II-H4) 7 was obtained as a yellow oil. This is the first report of the synthesis and characterization of MK-2(I,II-H4) 7 (see the Supporting Information for the 2D NMR spectra, Figures S13–S14.1), the fully saturated analogue of MK-2.

Scheme 2

Scheme 2. Synthetic Scheme for the Three-Step Synthesis To Obtain MK-2(I,II-H4) 7a
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aThe first step forms the mesylate from 4. The second step forms aliphatic iodide 5 via a SN2 reaction. The final step couples menadione 6 and aliphatic iodide 5 using a radical alkylation initiated by benzoyl peroxide.

Synthesis and Characterization of MK-3(II-H2)

The partially saturated isoprenyl MK analogue, MK-3(II-H2) 13, was synthesized in seven steps from commercially available β-citronellol 8 (Scheme 3) via a modified adaptation of a combination of a reported synthesis of MK-4(II-H2) (38) and a less recent 1965 synthesis of MK-3(II-H2). (33) First, the hydroxyl group of β-citronellol 8 was converted into iodide 9 through methane sulfonate in 66% yield over two steps. (38) The introduction of a carbonyl group to produce citronellylacetone 10 was accomplished under basic conditions in 88% yield over two steps. (45) This was followed by a Horner–Wadsworth–Emmons reaction to give methyl ester 11 in 62% yield. (38) Reduction of 11 with the Vitride reagent produced 6,7-dihydrofarnesol 12 in 83% yield. (38,46) Finally, MK-3(II-H2) 13 was obtained from the BF3-catalyzed coupling between the partially saturated allylic alcohol 12 and menadiol 1 (prepared from menadione) (26,38) in 12% yield. (26,38) The low yield may be attributed to the formation of the undesired C2 isomeric side product (see Scheme 3), which was readily separated using column chromatography. MK-3(II-H2) 13 was obtained as a yellow oil.

Scheme 3

Scheme 3. Synthetic Scheme for the Seven-Step Synthesis To Obtain MK-3(II-H2) 13 from β-Citronellol 8 (33,38)
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Similar to MK-2(II-H2) 3, MK-3(II-H2) 13 was initially isolated as a 2.7:1 mixture (by NMR integration of alkene peaks in C6D6) of trans/cis isomers. However, the trans isomer (Figure 3A) can be isolated from the cis isomer byproduct (Figure 3B) using preparative TLC, similar to a report on cis/trans vitamin K1 analogues. (44) MK analogues can be very sensitive; for example, during purification, we observed degradation of trans-MK-3(II-H2) (Figure 3A) within a solution of dichloromethane (DCM) that was not stabilized with amylene. This was evidenced by a decreased integration value for the alkene proton at 5.19 ppm and the appearance of two extra peaks at ∼1.3 ppm and a peak at 1.12 ppm in C6D6. Amylene is a radical scavenger, and it is likely that the alkene is undergoing a radical reaction with chloride radicals present in the unstabilized DCM. Similar to MK-2(II-H2) 3, the use of benzene-d6 as a diagnostic NMR solvent for the evaluation of cis/trans mixtures of MK-3(II-H2) 13 (Figure 3C,D) was essential because the presence of the cis isomer was not well-observed in CDCl3 (see the Supporting Information for spectra in CDCl3 vs benzene-d6, Figure S40).

Figure 3

Figure 3. Comparison of the 1D 1H NMR (400 MHz) spectra for the mixture of cis/trans-MK-3(II-H2) and trans-MK-3(II-H2) in C6D6 at 25 °C. (A) Structure of trans-MK-3(II-H2) with the proton labeling scheme key, (B) structure of cis-MK-3(II-H2), (C) 1D 1H NMR spectrum of the cis/trans mixture of MK-3(II-H2) in C6D6, and (D) 1D 1H NMR spectrum of trans-MK-3(II-H2) in C6D6. Overlapping cis/trans peaks have been left unlabeled.

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The structural assignment of trans-MK-3(II-H2) (Figure 3) was elucidated using 2D NMR spectroscopic methods [1H–1H COSY, 1H–13C HSQC, and 1H–1H rotating frame Overhauser effect spectroscopy (ROESY); see the Supporting Information for spectra, Figures S23–S26.1 and S29–S31]. The assignment of the alkene proton Hh at 5.13 ppm was determined by the following: the observation of a cross peak in the COSY spectrum at 5.13 and 1.73 ppm (assignment Hw, Figure 3), the observation of a cross peak at 5.13 and 1.94 ppm (assignment Hn, Figure 3), and the lack of an observed cross peak at 5.19 and 1.73 ppm (Hw). The assignment of alkene proton Hi at 5.19 ppm was determined by the observation of a cross peak at 5.19 and 1.67 ppm and the lack of a cross peak at 5.19 and 1.73 ppm (Hw). 1H–1H 2D ROESY NMR spectroscopy (see the Supporting Information) also supported the alkene assignment by the observation of a ROE cross peak at 5.19 and 1.67 ppm (Hi–Hz interaction) and the lack of a ROE cross peak at 5.19 ppm and 1.56 ppm. The assignment of the terminal methyl groups, Hy and Hz, was also determined by 1H–1H 2D ROESY NMR spectroscopy. It is anticipated that a ROE cross peak would be observed between the alkene proton Hi and the methyl group, that is, cis to Hi, because of the close spatial proximity, and a ROE cross peak is observed, as expected, at 5.19 and 1.67 ppm (Hi–Hz interaction) (see the Supporting Information). Although Hy and Hi are within the spatial limits of an expected ROE cross peak observation, an ROE cross peak is not observed at 5.19 ppm and 1.56 ppm. This supports the structural assignment of Hy as trans to the alkene proton Hi, as Hy is further away, spatially, from Hi compared to Hz.

Synthesis and Characterization of MK-3(I,II,III-H6)

The fully saturated isoprenyl MK analogue, MK-3(I,II,III-H6) 17, was synthesized in four steps (Scheme 4) from the commercially available allylic alcohol, farnesol 14. The first step was the Pd- catalyzed transfer hydrogenation of farnesol to yield the fully saturated alcohol 15 in 88% yield. (47) Subsequent mesylation of the alcohol of product 15 followed by substitution with NaI gave aliphatic iodide 16 in 47% yield over two steps. (38,48) The final step was the radical coupling of menadione 6 and aliphatic iodide 16 using benzoyl peroxide (37) as the radical initiator to yield the desired final product, MK-3(I,II,III-H6) 17, in 15% yield. This yield is similar to that attained for the coupling reaction to obtain MK-2(I,II-H4) 7. The unreacted aliphatic iodide 16 can be recovered during purification. Similar to MK-2(I,II-H4) 7, in an attempt to ensure good selectivity of prenylation (C3 over C2, Scheme 4), slow addition of napthoquinone 6 to the prenyl iodide solution during the course of the reaction was carried out. (37) Similar to the synthesis of MK-2(I,II-H4) 7 above, this is the second report of this type of primary alkyl radical coupling reaction to access MK and the first report on a preparatory scale. MK-3(I,II,III-H6) 17 was obtained as a yellow oil. This is the first report for the synthesis and characterization of MK-3(I,II,III-H6) 17 (see the Supporting Information for 2D NMR spectra, Figures S38–S39.1), the fully saturated analogue of MK-3.

Scheme 4

Scheme 4. Synthetic Scheme for the Four-Step Synthesis To Obtain MK-3(I,II,III-H6) 17a
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aThe first step is a transfer hydrogenation to produce the fully saturated alcohol 15 from farnesol 14. The second step forms the mesylate from 15. The third step forms aliphatic iodide 16 via a SN2 reaction. The final step couples menadione 6 and aliphatic iodide 16 using a radical alkylation initiated by benzoyl peroxide.

Conclusions

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The results of these studies will allow for the synthesis of various MK analogues and give access to previously unexplored compounds with unknown biological activity. In summary, this manuscript described the synthesis and characterization of four truncated partially and fully saturated isoprenyl MK analogues as well as separated and characterized the geometric isomers formed in the reactions. The partially saturated MK-2(II-H2) was successfully synthesized in a single step from menadiol and isophytol, and the trans isomer was separated from the cis isomer byproduct by preparative TLC, followed by characterization. The novel fully saturated MK-2(I,II-H4) was successfully synthesized in three steps from 3,7-dimethyloctan-1-ol. The partially saturated MK-3(II-H2) was successfully synthesized in seven steps from β-citronellol, and the trans isomer was readily separated from the cis isomer byproduct by preparative TLC, followed by characterization. Finally, the novel fully saturated MK-3(I,II,III-H6) was successfully synthesized in four steps from farnesol. The use of benzene-d6 as a diagnostic NMR solvent for the rapid evaluation of cis/trans mixtures for MK/vitamin K analogues was essential as cis/trans peaks often coalesce in chloroform-d.
The separation and characterization of an MK analogue’s trans isomer is essential for use of these compounds in biological systems or for understanding biological systems that use MK because evidence shows that the cis isomer is not biologically active. The partially and fully saturated MK analogues synthesized in this manuscript are substrate analogues for enzymes involved in MK/vitamin K metabolism and are essential for understanding the structure–activity relationships of these biological systems. (49) They are also critical for understanding the function, reactivity, and conformation of partially saturated MK analogues as little is currently known. These MK analogues are also of interest from a therapeutic and medicinal standpoint. For instance, MK-4 (vitamin K2) was recently shown to be a potential new therapeutic strategy to treat rheumatoid arthritis; it is a proposed drug for the effective treatment of osteoporosis and has anticancer properties. Nevertheless, the synthesis of partially saturated MK analogues remains a challenge as there is currently not a suitable catalyst to selectively saturate an individual isoprene unit on an MK analogue while leaving the other double bonds unaffected. Importantly, the synthesis and characterization of these partially and fully saturated MK substrate analogues is essential for understanding why they are necessary for various organisms to survive, and most importantly, understanding the reason MK-9(II-H2) (i.e., saturated at the second isoprene unit) is a potential virulence factor for pathogenic M. tuberculosis, which is responsible for the deaths of ∼1.3 million people annually.

Experimental Section

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General Information

Menadiol 1 was synthesized as previously described (26,38) from menadione, and the MgF2-48 sol–gel catalyst was synthesized, as previously described. (39−41) For clarity, any mention of MK-2(II-H2) or MK-3(II-H2) is assumed to be the cis/trans mixture, whereas the trans isomer is specifically written as trans-MK-2(II-H2) or trans-MK-3(II-H2). We used the standard abbreviations adopted by the American Chemical Society, for example, ethyl acetate (EtOAc), methanol (MeOH), distilled-deionized water (DDI-H2O), chloroform-d (CDCl3), benzene-d6 (C6D6), equivalent (equiv), room temperature (r.t.), Rf (retention factor), high-resolution mass spectrometry (HRMS), calculated (calcd), megahertz (MHz), Hz (hertz), and so forth. See the Supporting Information for general methods and information, materials, and one-dimensional (1D) and 2D NMR spectra of synthesized compounds.

NMR Spectroscopic Studies

The synthesized compounds were dried under vacuum for ∼2–4 days (∼150–200 mTorr), unless otherwise noted, to ensure as much residual solvent from purification was removed as possible. Samples for NMR studies were prepared immediately prior to running the samples using deuterated solvents sealed under an inert atmosphere in glass ampules. The NMR sample solutions were placed under an argon atmosphere immediately and capped, and then the spectra were acquired, unless otherwise noted. NMR samples of MKs were protected from light by wrapping the samples in an aluminum foil while not in the NMR instrument because of potential degradation. 1H and 13C spectra were recorded using a Varian model MR400 or a Bruker model AVANCE Neo400 spectrometer equipped with a BBFO smart probe and an automated tuning module operating at 400 or 101 MHz, respectively. Chemical shift values (δ) are reported in ppm and referenced against the internal solvent peaks in 1H NMR (CDCl3, δ at 7.26 ppm; benzene-d6, δ at 7.16 ppm) and in 13C NMR (CDCl3, δ at 77.16 ppm; benzene-d6, δ at 128.06 ppm). All NMR spectra were recorded at either 25 or 26 °C. NMR spectra were processed using MestReNova version 10.0.1. or 12.0.2. See the Supporting Information for 1D & 2D NMR spectra and NMR experimental details.

Mass Spectrometry and Elemental Analysis

HRMS experiments were conducted either on an Agilent 6224 TOF LC/MS [O-time-of-flight (TOF)] interfaced with the Direct Analysis in Real Time (DART) source (IonSense DART-100) or on a Bruker MaXis TOF MS (Q-TOF) interfaced with the DART source (IonSense DART-SVP). A standard of Jeffamine was used as an internal standard calibration for HRMS DART experiments carried out in the positive mode. Combustion elemental analysis was carried out by ALS Environmental located in Tucson, AZ.

Preparation of MK-2(II-H2) (3)

Compound 3 was accessed from 1 and 2.

Preparation of 2-(3,7-Dimethyloct-2-en-1-yl)-3-methylnaphthalene-1,4-dione MK-2(II-H2) (3)

To a dry 150 mL round-bottom thick-walled pressure flask was added a dry stir bar, dry heptane (21 mL), and polyene carbonate (21 mL). The solution was bubbled with argon for several min. Then, menadiol 1 (1.22 g, 7.00 mmol) was added and stirred until dissolution occurred under argon bubbling. Then, isophytol 2 (1.09 g, 7.00 mmol) was added, followed by MgF2-48 (350 mg). The biphasic reaction mixture was bubbled with argon for ∼1 min and then sealed tightly with a Teflon screw cap. The sealed reaction mixture was covered in an aluminum foil to minimize light exposure and was stirred for 5 h at 100 °C under an argon atmosphere. The yellow biphasic suspension was then cooled to an ambient temperature. The 1H NMR spectrum of the crude product confirmed product formation by the presence of a doublet at 3.37 ppm (CDCl3). The layers were separated, and the polyene carbonate layer (bottom layer) was extracted with n-pentane (3 × 100 mL). The combined yellow organic extracts were washed with DDI H2O (100 mL), washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure at an ambient temperature. The crude oil was dried overnight under reduced pressure to yield 1.31 g of crude red oil. The crude red oil was purified by flash column chromatography (300 mL of 230–400 mesh SiO2, 20:1 n-pentane/EtOAc, 40 mm column) to yield 0.235 g (0.757 mmol, 10.8% yield) as a yellow/red oil after drying under vacuum (200 mTorr). The C2 isomeric side product was readily separated by flash column chromatography eluting after the C3 desired product. The product was obtained as a mixture of trans/cis isomers (ratio of trans/cis = 2.7:1 by NMR integration of alkene peaks), as has similarly been reported for vitamin K1 analogues (44) and various MK analogues. (27)1H NMR (400 MHz, C6D6): δ 8.00–8.06 (m, 2H), 7.0–7.06 (m, 2H), 5.12 (t, J = 7.0 Hz, 1H, trans isomer), 5.06 (t, J = 7.0 Hz, 1H, cis isomer), 3.28 (d, J = 7.7 Hz, 2H, cis isomer), 3.26 (d, J = 7.1 Hz, 2H, trans isomer), 2.19 (t, J = 7.8 Hz, 2H, cis isomer), 1.98 (s, 3H), 1.92 (t, J = 7.5 Hz, 2H, trans isomer), 1.72 (s, 3H, trans isomer), 1.63 (s, 3H, cis isomer), 1.50–1.58 (m, 1H, cis isomer),1.40–1.49 (m, 1H, trans isomer), 1.40–1.48 (m, 2H, cis isomer), 1.31–1.39 (m, 2H, trans isomer), 1.21–1.27 (q, 2H, cis isomer), 1.06–1.11 (q, 2H, trans isomer), 0.93 (d, J = 6.6 Hz, 6H, cis isomer), 0.83 (d, J = 6.6 Hz, 6H, trans isomer). 13C NMR (101 MHz, C6D6): δ 184.99, 184.97, 184.24, 184.16, 145.97, 145.95, 143.21, 143.18, 137.93, 137.62, 133.09, 133.06, 132.68, 132.66, 126.31, 126.22, 120.31, 119.82, 40.36, 39.34, 38.95, 32.56, 28.35, 28.20, 26.25, 26.15, 26.08, 25.98, 23.54, 22.87, 22.81, 16.32, 12.62, 12.58. HRMS (DART, Q-TOF): calcd for C21H27O2 [(M + H)+], 311.2006; found, 311.2018.
A sample for analytical characterization of trans-MK-2(II-H2) was purified by normal phase preparative TLC (see experimental below) on silica gel using (30:1) n-pentane/EtOAc as the eluting solvent; Rf cis: 0.37, Rf trans: 0.32; ratio of trans/cis before separation was 2.7:1 (the ratio was measured from the NMR integration of alkene peaks). Although we isolated the pure trans isomer, the cis isomer coeluted with the trans isomer, and efforts to obtain a sample of the pure cis isomer were not successful. The cis and the trans isomers have different NMR spectra in C6D6 for the protons and carbons within the isoprenyl side chain. Data for trans-MK-2(II-H2): 1H NMR (400 MHz, C6D6): δ 8.00–8.07 (m, 2H), 7.00–7.05 (m, 2H), 5.12 (t, J = 7.0 Hz, 1H), 3.26 (d, J = 7.0 Hz, 2H), 1.98 (s, 3H), 1.92 (t, J = 7.5 Hz, 2H), 1.72 (s, 3H), 1.40–1.49 (m, 1H), 1.31–1.39 (m, 2H), 1.06–1.11 (q, 2H), 0.83 (d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, C6D6): δ 184.98, 184.24, 145.97, 143.21, 137.62, 133.09, 133.05, 132.69, 132.66, 126.31, 126.22, 119.82, 40.36, 38.95, 28.20, 26.25, 26.08, 22.81, 16.32, 12.58. HRMS (DART, Q-TOF): calcd for C21H27O2 [(M + H)+], 311.2006; found, 311.1991. NMR data for the cis isomer (obtained from spectra with both cis and trans isomers present): 1H NMR (400 MHz, C6D6): δ 8.00–8.06 (m, 2H), 7.00–7.06 (m, 2H), 5.06 (t, J = 7.0 Hz, 1H), 3.28 (d, J = 7.7 Hz, 2H), 2.19 (t, J = 7.8 Hz, 2H), 1.98 (s, 3H), 1.63 (s, 3H), 1.50–1.58 (m, 1H), 1.40–1.48 (m, 2H), 1.21–1.27 (q, 2H), 0.93 (d, J = 6.6 Hz, 6H).
A sample for analytical characterization of trans-MK-2(II-H2) was prepared by using normal phase preparative TLC. First, 8.0 mg of cis/trans-MK-2(II-H2) (dissolved in a minimal amount of DCM) was loaded onto a preparative TLC plate via a capillary tube and then eluted once using 30:1 n-pentane/EtOAc and an elution time of 45 min. The TLC plate was briefly air-dried and then eluted a second time under the same conditions. The yellow band was illuminated under ultraviolet light, and while illuminated, the band was divided into a top two-third and a bottom one-third. The bottom one-third was carefully removed with a razor blade, extracted with DCM, filtered through a disposable Pasteur pipette filled with glass wool (prerinsed with DCM), concentrated under reduced pressure at an ambient temperature, and dried for 4 days at reduced pressure (200 mTorr) to provide 2.5 mg of trans-MK-2(II-H2) as a yellow oil (31.3% recovery).

Preparation of MK-2(I,II-H4) (7)

Compound 7 was accessed through compound 5 from commercially available compound 4.

1-Iodo-3,7-dimethyloctane (5)

To a dry 250 mL round-bottom Schlenk flask was added a dry stir bar, 3,7-dimethyl-1-octanol 4 (8.61 g, 54.4 mmol), and dry DCM (100 mL), which was then purged/evacuated with argon repeatedly. The solution was cooled to 0 °C in an ice–H2O bath. Then, methanesulfonyl chloride (2.16 mL, 3.20 g, 27.9 mmol, 1.2 equiv) was added under an argon atmosphere followed by dropwise addition of dry triethylamine (11.39 mL, 8.26 g, 81.6 mmol, 1.5 equiv) over 5 min at 0 °C. The resulting solution was stirred at an ambient temperature for 1.5 h under argon. The reaction was quenched with sat. NaHCO3 (100 mL), and then the phases were separated. The aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure at an ambient temperature (residual triethylamine can be removed by vacuum pumping for ∼1 h) to yield 9.65 g of crude yellow oil. The crude mesylate was dissolved in dry and degassed acetone (100 mL, dried over anhydrous K2CO3 immediately prior for ∼10 min) in a dry 250 mL round-bottom Schlenk flask. Then, NaI (16.50 g, 110.0 mmol, 2.0 equiv) was added, and the solution was refluxed for 2 h under argon. The white reaction mixture was diluted with ice–DDI H2O (100 mL) and diethyl ether (100 mL), and then the phases were separated. The aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure at an ambient temperature to yield 9.83 g of crude clear and yellow oil. The crude product was purified by flash column chromatography (800 mL of 230–400 mesh SiO2, 10:1 n-pentane/EtOAc, 70 mm column) to yield 6.91 g (25.8 mmol, 47.4% yield) as a clear and colorless oil after drying under vacuum (150 mTorr). 1H NMR (400 MHz, CDCl3): δ 3.14–3.28 (m, 2H), 1.83–1.92 (m, 1H), 1.60–1.69 (m, 1H), 1.48–1.58 (m, 2H), 1.21–1.35 (m, 3H), 1.06–1.21 (m, 3H), 0.87 (d, J = 6.6 Hz, 9H). 13C NMR (101 MHz, CDCl3): δ 41.13, 39.33, 34.04, 28.10, 24.68, 22.85, 22.75, 18.89, 5.58. Anal. Calcd for C10H21I: C, 44.79; H, 7.89. Found: C, 44.81; H, 7.72.

2-(3,7-Dimethyloctyl)-3-methylnaphthalene-1,4-dione MK-2(I,II-H4) (7)

To a dry 100 mL round-bottom Schlenk flask was added a dry stir bar and dry and degassed benzene (30 mL) followed by 1-iodo-3,7-dimethyloctane 5 (2.68 g, 10.0 mmol, 1 equiv). To a dry 20 mL vial was added dry and degassed benzene (15 mL) followed by menadione 6 (1.72 g, 10.0 mmol) and benzoyl peroxide (2.42 g, 10.0 mmol, 1 equiv) and then sonicated until dissolution occurred under argon. The naphthoquinone–benzoyl peroxide solution was added dropwise for over 2 h 15 min to the refluxing prenyl iodide solution, which was under an argon atmosphere during the reaction. After the addition was complete, the solution was refluxed for an additional 1 h. The solution was diluted with sat. NaHCO3 (100 mL) and diethyl ether (100 mL), and then the phases were separated. The aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure at an ambient temperature to yield a crude yellow powder. The crude powder was purified by flash column chromatography (10:1.5 n-pentane/EtOAc) to yield 0.539 g (1.73 mmol, 17.3% yield) after drying under vacuum (150 mTorr) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.05–8.09 (m, 2H), 7.66–7.70 (m, 2H), 2.55–2.68 (m, 2H), 2.18 (s, 3H), 1.12–1.58 (m, 10H), 0.98 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 185.51, 184.81, 148.13, 143.02, 133.44, 133.40, 132.40, 132.34, 126.38, 126.32, 39.45, 37.08, 35.90, 33.58, 28.11. HRMS (DART, O-TOF): calcd for C21H29O2 [(M + H)+], 313.2162; found, 313.2158.

Preparation of MK-3(II-H2) (13)

Compound 13 was accessed through compounds 9, 10, 11, and 12 starting from commercially available compound 8.

8-Iodo-2,6-dimethyloct-2-ene (9)

To a dry 500 mL round-bottom Schlenk flask was added a dry stir bar, (±)β-citronellol 8 (17.00 g, 108.8 mmol), dry DCM (200 mL), and dry trimethylamine (22.8 mL, 16.52 g, 163.2 mmol, 1.5 equiv), which was then purged/evacuated with argon repeatedly. Then, methanesulfonyl chloride (10.4 mL, 15.33 g, 133.8 mmol, 1.23 equiv) was added dropwise for over 5 min at 0 °C under argon. The resulting solution was stirred at an ambient temperature for 1.5 h under argon. The reaction was quenched with sat. NaHCO3 (200 mL), and then the phases were separated. The aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure at an ambient temperature (residual triethylamine can be removed by vacuum pumping for ∼1 h) to yield a crude orange oil. The crude mesylate was dissolved in dry acetone (200 mL) in a dry 500 mL round-bottom Schlenk flask. Then, NaI (33.00 g, 220.2 mmol, 2.02 equiv) was added, and the solution was refluxed for 3 h under argon. The resulting white reaction mixture was diluted with ice–DDI H2O (200 mL) and diethyl ether (100 mL), and then the phases were separated. The aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure at an ambient temperature to yield 22.56 g of crude yellow oil. The crude yellow oil was purified by flash column chromatography (800 mL of 230–400 mesh SiO2, 10:1 n-pentane/EtOAc, 70 mm column) to yield 19.10 g (71.8 mmol, 66.0% yield) after vacuum pumping (150 mTorr) overnight as a clear and colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.09 (t, J = 7.0 Hz, 1H), 3.13–3.28 (m, 2H), 1.92–2.02 (m, 2H), 1.84–1.92 (m, 1H), 1.69 (s, 3H), 1.62–1.67 (m, 1H), 1.61 (s, 3H), 1.51–1.59 (m, 1H), 1.29–1.39 (m, 1H), 1.13–1.22 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 131.63, 124.60, 41.06, 36.47, 33.73, 25.87, 25.47, 18.81, 17.84, 5.32. HRMS (DART, Q-TOF): calcd for C10H20I [(M + H)+], 267.0604; found: 267.0613.

6,10-Dimethylundec-9-en-2-one (10)

To a dry 250 mL round-bottom Schlenk flask was added a dry stir bar and dry tert-butanol (60 mL, dried over activated 3 Å molecular sieves 10 g sieves/100 mL solvent) followed by t-BuOK (4.92 g, 40.3 mmol, 1.2 equiv), and the solution was refluxed for 30 min under argon to dissolve t-BuOK and then cooled to 60 °C. Then, ethyl acetoacetate (4.81 g, 36.9 mmol, 1.1 equiv) was added dropwise, and the reaction mixture was stirred for 30 min at 60 °C under argon. Then, 8-iodo-2,6-dimethyloct-2-ene 9 (8.94 g, 33.6 mmol) was added dropwise. The reaction mixture was refluxed for 25 h under argon. The reaction mixture was then vacuum-filtered and washed with diethyl ether (50 mL). The filtrate solvent was removed under reduced pressure at an ambient temperature. To the crude residue was added 2 N KOH (128 mL), and the reaction mixture was stirred for 3 h at 80 °C under argon. The reaction mixture was cooled to ambient temperature, and then the alkaline solution was acidified with acetic acid (20 mL). The acidified solution was extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure at an ambient temperature to yield 6.37 g of crude clear and colorless oil. The crude oil was purified by vacuum distillation (bp: 108–111 °C/4 mmHg) (45) to yield 5.82 g (29.6 mmol, 88.1% yield) as a clear and colorless oil after drying under vacuum (150 mTorr). 1H NMR (400 MHz, CDCl3): δ 5.09 (t, J = 7.2 Hz, 1H), 2.40 (t, J = 7.5 Hz, 2H), 2.13 (s, 3H), 1.87–2.03 (m, 2H), 1.68 (s, 3H), 1.60 (s, 3H), 1.49–1.63 (m, 2H), 1.34–1.43 (m, 1H), 1.23–1.34 (m, 2H), 1.05–1.17 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 209.43, 131.26, 125.00, 44.26, 37.09, 36.58, 32.42, 30.01, 25.87, 25.66, 21.54, 19.58, 17.79. HRMS (DART, O-TOF): calcd for C13H25O [(M + H)+], 197.1905; found, 197.1894.

Methyl 3,7,11-Trimethyldodeca-2,10-dienoate (11)

To a 50 mL dry round-bottom Schlenk flask that was purged/evacuated with argon was added NaOMe (4.87 g, 90.2 mmol, 1.36 equiv to triethyl phosphonoacetate) followed by MeOH (12.51 g), and this solution was stirred for 5 min under argon. To this solution was added triethyl phosphonoacetate (14.86 g, 66.3 mmol, 1.54 equiv) dropwise and allowed to stir at an ambient temperature for 30 min under argon. To a dry 250 mL round-bottom Schlenk flask was added dry pentane (80 mL, dried by passing through an activated neutral alumina column under argon immediately prior) followed by 6,10-dimethylundec-9-en-2-one 10 (8.45 g, 43.0 mmol). Then, the phosphonium ylide solution was added dropwise over 10 min under argon. The reaction mixture was stirred for 4 h at an ambient temperature under argon. Then, DDI H2O (100 mL) was added to terminate the reaction. The reaction mixture was extracted with pentane (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with DDI H2O (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure at an ambient temperature to yield 9.60 g of crude oil after vacuum pumping overnight. The crude oil was purified by flash column chromatography (95:5 n-pentane/EtOAc) to yield 6.71 g (26.6 mmol, 61.9% yield) as a clear and colorless oil after drying under vacuum (150 mTorr). 1H NMR (400 MHz, CDCl3): δ 5.66 (s, 1H), 5.09 (t, J = 7.1 Hz, 1H), 3.68 (s, 3H), 2.15 (s, 3H), 2.11 (t, J = 7.6 Hz, 2H), 1.90–2.00 (m, 2H), 1.68 (s, 3H), 1.60 (s, 3H), 1.37–1.57 (m, 3H), 1.24–1.33 (m, 2H), 1.08–1.17 (m, 2H), 0.87 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 167.44, 160.87, 131.27, 125.01, 115.16, 50.91, 41.37, 37.14, 36.57, 32.38, 25.87, 25.68, 24.97, 19.64, 18.88, 17.78. HRMS (DART, O-TOF): calcd for C15H32NO [(M + NH4)+], 242.2478; found, 242.2484.

3,7,11-Trimethyldodeca-2,10-dien-1-ol (12)

To a dry 250 mL round-bottom Schlenk flask was added a dry stir bar, dry pentane (85 mL, dried over an activated alumina column under argon immediately prior), and methyl 3,7,11-trimethyldodeca-2,10-dienoate 11 (8.31 g, 32.9 mmol). The flask was purged/evacuated with argon repeatedly. Then, Vitride reagent (Red-Al sodium bis(2-methoxyethoxy)aluminum hydride solution, 32.1 mL of ≥60 wt % solution in toluene, 98.7 mmol, 3.0 equiv) was added dropwise via a dry glass syringe. The reaction mixture turned milky white upon addition of the Vitride reagent. The reaction mixture was stirred for 1.75 h at an ambient temperature under argon and was completed by TLC analysis (10:1 n-pentane/EtOAc, stain with KMnO4 to visualize) and by 1H NMR analysis. A Fieser method quench was used as follows. (46) The reaction solution was cooled to −78 °C (dry ice/acetone), and then DDI H2O (20 mL) was slowly added (dropwise) under argon purge to quench the reaction. The reaction solution was removed from the −78 °C (dry ice/acetone) bath, and then 15% aq NaOH (20 mL) was added slowly followed by DDI H2O (60 mL) and n-pentane (100 mL). The solution was stirred at an ambient temperature for 30 min. The solution was filtered through a pad of Celite and washed with n-pentane (200 mL), and then the phases were separated. The aqueous layer was extracted with n-pentane (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with DDI H2O (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure at an ambient temperature. The crude oil was vacuum-pumped over night to yield 6.34 g as a crude opaque colorless oil. The crude oil was purified via flash column chromatography (1000 mL of 230–400 mesh SiO2, 5:1 n-pentane/EtOAc, 70 mm column) to yield 6.09 g (27.2 mmol, 82.7% yield) as an opaque colorless oil after drying under vacuum (150 mTorr). 1H NMR (400 MHz, CDCl3): δ 5.41 (t, J = 7.5 Hz, 1H), 5.10 (t, J = 7.1 Hz, 1H), 4.15 (d, J = 7.0 Hz, 2H), 1.90–2.07 (m, 4H), 1.73 (s, 3H, cis isomer*), 1.68 (s, 3H), 1.67 (s, 3H, trans isomer*), 1.60 (s, 3H), 1.33–1.47 (m, 3H), 1.23–1.32 (m, 2H), 1.06–1.17 (m, 2H), 0.87 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 140.40, 131.18, 125.14, 123.28, 59.58, 40.01, 37.23, 36.74, 32.47, 25.87, 25.70, 25.25, 19.72, 17.78, 16.33. HRMS (DART, Q-TOF): calcd for C15H32NO [(M + NH4)+], 242.2478; found, 242.2473. *Determined from the 1H–13C 2D HSQC and 1H–1H 2D COSY NMR spectra (data not shown).

2-Methyl-3-(3,7,11-trimethyldodeca-2,10-dien-1-yl)naphthalene-1,4-dione MK-3(II-H2) (13)

To a 100 mL round-bottom Schlenk flask was added a stir bar, EtOAc (16 mL), and 1,4 dioxane (16 mL), and then the flask was purged/evacuated with argon repeatedly. Then, menadiol 1 (2.50 g, 11.5 mmol, 4:1 menadiol/menadione by NMR integration in CDCl3, menadiol is unstable in CDCl3) and 3,7,11-trimethyldodeca-2,10-dien-1-ol 12 (2.81 g, 12.5 mmol, 1.09 equiv) were added followed by dropwise addition of distilled BF3 etherate (0.8 mL, fresh bottle) under argon. The reaction mixture refluxed at 70 °C for 3 h under argon. The reaction mixture turned dark orange and was quenched with ice–DDI H2O (100 mL) and then extracted with diethyl ether (3 × 100 mL). The combined yellow organic extracts were washed with sat. NaHCO3 (100 mL), washed with DDI H2O (100 mL), washed with brine (100 mL), dried with anhydrous Na2SO4, and then concentrated under reduced pressure at an ambient temperature to yield 5.06 g of the crude red solid. The crude solid was purified by flash column chromatography (1000 mL of 230–400 mesh SiO2, 20:1 n-pentane/EtOAc) to yield 1.28 g (yield at this stage = 29.4%, 3.38 mmol) as a red oil, but further purification was needed as evidenced by 1H NMR analysis. The C2 isomeric side product was readily separated by flash column chromatography eluting after the C3 desired product. The red oil was subjected to a second column chromatography purification using the same conditions as the first purification, and then the material was dried under reduced pressure (150 mTorr) overnight to yield 0.501 g (1.32 mmol, 11.5% yield) as a yellow oil. Similar to vitamin K1 analogues, (44) various MK analogues (27) and MK-2(II-H2) 3, the product was obtained as a mixture of trans/cis isomers (ratio of trans/cis = 2.7:1 by NMR integration of alkene peaks). 1H NMR (400 MHz, C6D6): δ 8.00–8.07 (m, 2H), 7.01–7.06 (m, 2H), 5.27 (t, J = 7.1 Hz, 1H, cis isomer), 5.19 (t, J = 7.1 Hz, 1H, trans isomer), 5.13 (t, J = 7.0 Hz, 1H, trans isomer), 5.07 (t, J = 7.0 Hz, 1H, cis isomer), 3.29 (d, J = 7.2 Hz, 2H, cis isomer), 3.26 (d, J = 7.1 Hz, 2H, trans isomer), 2.21 (t, J = 7.5 Hz, 2H, cis isomer), 1.98 (s, 3H), 1.94 (t, J = 7.5 Hz, 2H, trans isomer), 1.73 (s, 3H, trans isomer), 1.71 (s, 3H, cis isomer), 1.67 (s, 3H, trans isomer), 1.64 (s, 3H, cis isomer), 1.61 (s, 3H, cis isomer), 1.56 (s, 3H, trans isomer), 1.01–1.51 (m, 9H), 0.95 (d, J = 6.6 Hz, 3H, cis isomer), 0.86 (d, J = 6.5 Hz, 3H, trans isomer). 13C NMR (101 MHz, C6D6): δ 184.99, 184.96, 184.23, 184.15, 145.96, 143.20, 143.18, 137.93, 137.59, 133.08, 133.05, 132.68, 132.66, 130.97, 130.89, 126.31, 126.22, 125.58, 125.51, 120.32, 119.87, 40.40, 37.60, 37.58, 37.39, 36.92, 32.80, 32.66, 32.60, 26.27, 26.12, 26.06, 25.99, 25.95, 25.91, 25.80, 25.67, 23.55, 19.86, 19.81, 17.79, 17.73, 16.33, 12.63, 12.59. HRMS (DART, Q-TOF): calcd for C26H35O2 [(M + H)+], 379.2632; found, 379.2643.
A sample for analytical characterization of trans-MK-3(II-H2) was prepared similarly as described (see experimental below) for trans-MK-2(II-H2) above by normal phase preparative TLC on silica gel using (30:1) n-pentane/EtOAc as the eluting solvent; Rf cis: 0.35, Rf trans: 0.30; ratio of trans/cis before separation was 2.7:1 (ratio by NMR integration of alkene peaks). Importantly, the bottom one-half of the band was isolated, instead of the bottom one-third of the band as was done to obtain trans-MK-2(II-H2). This purification provided 3.7 mg of trans-MK-3(II-H2) as a yellow oil (43.5% recovery) from the initial 8.5 mg cis/trans mixture loaded onto the TLC plate after drying under vacuum (200 mTorr) for 4 days. Similar to MK-2(II-H2) 3, we isolated the pure trans isomer; however, the cis isomer coeluted with the trans isomer, and efforts to obtain a sample of the pure cis isomer were not successful. Similar to MK-2(II-H2) 3, the cis and trans isomers of MK-3(II-H2) have different NMR spectra in C6D6 for the protons and carbons that belong to the isoprenyl side chain. Data for trans-MK-3(II-H2): 1H NMR (400 MHz, C6D6): δ 8.00–8.07 (m, 2H), 7.00–7.06 (m, 2H), 5.19 (t, J = 7.1 Hz, 1H), 5.13 (t, J = 7.0 Hz, 1H), 3.27 (d, J = 7.1 Hz, 2H), 1.98 (s, 3H), 1.94 (t, J = 7.5 Hz, 2H), 1.73 (s, 3H), 1.67 (s, 3H), 1.56 (s, 3H), 1.01–1.47 (m, 9H), 0.86 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, C6D6): δ 184.97, 184.24, 145.96, 143.21, 137.59, 133.08, 133.05, 132.69, 132.67, 130.89, 126.31, 126.22, 125.51, 119.87, 40.40, 37.58, 36.91, 32.60, 26.27, 26.06, 25.91, 25.67, 19.81, 17.73, 16.33, 12.59. HRMS (DART, Q-TOF): calcd for C26H35O2 [(M + H)+], 379.2632; found, 379.2639. NMR data for the cis isomer (obtained from spectra with both cis and trans isomers present): 1H NMR (400 MHz, C6D6): δ 8.00–8.06 (m, 2H), 7.01–7.06 (m, 2H), 5.27 (t, J = 7.1 Hz, 1H), 5.07 (t, J = 7.0 Hz, 1H), 3.29 (d, J = 7.2 Hz, 2H), 2.21 (t, J = 7.5 Hz, 2H), 1.98 (s, 3H), 1.71 (s, 3H), 1.64 (s, 3H), 1.61 (s, 3H), 1.01–1.51 (m, 9H), 0.95 (d, J = 6.6 Hz, 3H).

Preparation of MK-3(I,II,III-H6) (17)

Compound 17 was accessed through compounds 15 and 16 starting from commercially available compound 14.

3,7,11-Trimethyldodecan-1-ol (15)

To a dry 500 mL round-bottom Schlenk flask was added a dry stir bar, dry methanol (200 mL), ammonium formate (29.15 g, 462.3 mmol, 9.28 equiv), and farnesol 14 (11.08 g, 49.83 mmol), followed by careful addition of the palladium catalyst by a funnel (2.14 g, 20.1 mmol, 0.4 equiv). The reaction mixture was stirred at an ambient temperature for 5 days under positive pressure from an argon balloon, and 1H NMR analysis showed only residual alkene present. The reaction mixture was filtered through a pad of Celite and washed with MeOH (600 mL). MeOH was removed under reduced pressure at an ambient temperature. The crude product was then filtered through a silica plug (4:1 n-pentane/EtOAc, 500 mL eluent) and washed with EtOAc (300 mL). The organic filtrate was concentrated under reduced pressure at an ambient temperature to yield a crude clear and colorless oil. The crude oil was suspended in diethyl ether (200 mL), washed with sat. NaHCO3 (200 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure at an ambient temperature to yield a crude clear and colorless oil. The crude oil was purified by flash column chromatography (1000 mL of 230–400 mesh SiO2, 4:1 n-pentane/EtOAc, 70 mm column) to yield 9.99 g (43.7 mmol, 87.8% yield) as a clear and colorless oil after drying under vacuum (150 mTorr). 1H NMR (400 MHz, CDCl3): δ 3.63–3.73 (m, 2H), 1.49–1.63 (m, 3H), 1.01–1.42 (m, 14H), 0.89 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.6 Hz, 6H), 0.84 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 61.43, 40.21, 40.12, 39.51, 37.64, 37.60, 37.51, 37.47, 37.41, 32.94, 29.67, 29.65, 28.13, 24.97, 24.94, 24.52, 22.87, 22.78, 19.89, 19.84, 19.82, 19.77. HRMS (DART, Q-TOF): calcd for C15H36NO [(M + NH4)+], 246.2791; found, 246.2796.

1-Iodo-3,7,11-trimethyldodecane (16)

To a dry 250 mL round-bottom Schlenk flask was added a dry stir bar, 3,7,11-trimethyldodecan-1-ol 15 (9.41 g, 41.2 mmol), and dry DCM (125 mL). The flask was purged/evacuated with argon repeatedly. The solution was cooled to 0 °C in an ice–H2O bath. Then, dry triethylamine (8.61 mL, 6.25 g, 61.8 mmol, 1.5 equiv) was added to the flask followed by dropwise addition of methanesulfonyl chloride (3.82 mL, 5.66 g, 49.4 mmol, 1.2 equiv) at 0 °C for over 5 min while stirring under argon. The reaction mixture was stirred at an ambient temperature for 40 min under argon. The off-white reaction mixture was quenched with sat. NaHCO3 (100 mL), and then the phases were separated. The aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous MgSO4, vacuum-filtered, and then concentrated under reduced pressure at an ambient temperature (residual triethylamine can be removed by vacuum pumping for ∼1 h) to yield 12.98 g of crude clear and light-yellow oil. To another dry 250 mL round-bottom Schlenk flask was added dry and degassed acetone (100 mL, dried over anhydrous K2CO3 for ∼10 min immediately prior) and crude mesylate followed by NaI (15.44 g, 103.0 mmol, 2.5 equiv). The reaction mixture turned bright yellow upon addition of NaI and was refluxed for 1 h and 40 min under argon. The yellow reaction mixture was diluted with diethyl ether (100 mL) and DDI H2O (100 mL), and then the phases were separated. The aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous MgSO4, vacuum-filtered, and then concentrated under reduced pressure at an ambient temperature to yield a crude yellow murky oil. To remove the salt impurities, the crude oil was suspended in n-pentane (100 mL) and washed with DDI H2O (100 mL), and then the phases were separated. The aqueous layer was extracted with n-pentane (3 × 100 mL). The combined organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous MgSO4, vacuum-filtered, and then concentrated under reduced pressure at an ambient temperature to yield 13.19 g of crude clear and light-yellow oil. The crude oil was purified by flash column chromatography (1000 mL of 230–400 mesh SiO2, 100% n-pentane, Rf = 0.71, 70 mm column) to yield 6.52 g (19.3 mmol, 46.8% yield) after drying under vacuum (200 mTorr) as a clear and colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.14–3.28 (m, 2H), 1.83–1.92 (m, 1H), 1.60–1.69 (m, 1H), 1.47–1.57 (m, 2H), 1.01–1.41 (m, 13H), 0.84–0.88 (m, 12H). 13C NMR (101 MHz, CDCl3): δ 41.19, 41.12, 39.52, 37.52, 37.46, 37.42, 37.40, 36.76, 36.70, 34.07, 34.04, 32.93, 32.91, 28.15, 24.98, 24.96, 24.38, 24.37, 22.89, 22.79, 19.90, 19.83, 18.95, 18.89, 5.55. Anal. Calcd for C15H31I: C, 53.25; H, 9.24. Found: C, 53.78; H, 9.38.

2-Methyl-3-(3,7,11-trimethyldodecyl)naphthalene-1,4-dione MK-3(I,II,III,H6) (17)

To a dry 100 mL round-bottom Schlenk flask was added under argon, a dry stir bar, dry and degassed benzene (30 mL), and 1-iodo-3,7,11-trimethyldodecane 16 (3.38 g, 10.0 mmol, 1.00 equiv). To a dry 20 mL vial was added benzene (15 mL), which was degassed via argon needle purge, followed by menadione 6 (1.72 g, 10.0 mmol, 1.00 equiv) and benzoyl peroxide (2.42 g, 10.0 mmol, 1.00 equiv) and then sonicated until dissolution occurred under argon. The naphthoquinone–benzoyl peroxide solution was added dropwise to the refluxing prenyl iodide solution for over 2 h and 15 min while the reaction mixture was refluxing under argon. The solution was then refluxed for an additional 1 h. The reaction mixture was diluted with sat. NaHCO3 (100 mL) and DDI H2O (100 mL), and then the phases were separated. The aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined yellow organic extracts were washed with sat. NaHCO3 (100 mL), washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure at an ambient temperature to yield 6.63 g of crude yellow powder. The crude product was purified by flash column chromatography (1000 mL of 230–400 mesh SiO2, 10:1 n-pentane/EtOAc, 70 mm column) to yield 0.555 g (1.45 mmol, 14.5% yield) after drying under vacuum (200 mTorr) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.05–8.09 (m, 2H), 7.66–7.70 (m, 2H), 2.55–2.68 (m, 2H), 2.18 (s, 3H), 1.02–1.57 (m, 17H), 0.98 (d, J = 6.6 Hz, 3H), 0.84–0.87 (m, 9H). 13C NMR (101 MHz, CDCl3): δ 185.53, 184.82, 148.14, 143.03, 133.45, 133.42, 132.41, 132.34, 126.40, 126.33, 39.52, 37.55, 37.52, 37.44, 37.20, 37.17, 35.95, 35.86, 33.59, 32.94, 28.14, 24.98, 24.95, 24.57, 22.88, 22.79, 19.90, 19.85, 19.69, 19.62, 12.65. HRMS (DART, Q-TOF): calcd for C26H39O2 [(M + H)+], 383.2945; found, 383.2935.

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Author Information

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  • Corresponding Author
  • Authors
    • Jordan T. Koehn - Chemistry Department, , and , Colorado State University, Fort Collins, Colorado 80523, United States;  Orcidhttp://orcid.org/0000-0003-3008-6303
    • Dean C. Crick - Cell and Molecular Biology Program  and  Microbiology, Immunology, and Pathology Department, , and , Colorado State University, Fort Collins, Colorado 80523, United States;  Orcidhttp://orcid.org/0000-0001-9281-7058
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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Drs. Crans and Crick thank NIH for funding (grant #AI119567) and NSF for funding (grant #CHE-1709564). Dr. Crans also thanks the Arthur Cope Foundation administered by the American Chemical Society for the partial support. We also thank Colorado State University Libraries Open Access Research and Scholarship Fund for partial funding of open access option. We also thank Thomas J. Olson for early contributions to the MK-3(I,II,III-H6) synthesis.

References

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    Epilepsy is a debilitating disease affecting 1-2% of the world's population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by current medication suggesting a crit. need for new anti-epileptic drugs (AEDs). In an effort to discover new therapeutics for the management of epilepsy, we began our study by screening drugs that, like some currently used AEDs, inhibit histone deacetylases (HDACs) using a well-established larval zebrafish model. In this model, 7-day post fertilization (dpf) larvae are treated with the widely used seizure-inducing compd. pentylenetetrazol (PTZ) which stimulates a rapid increase in swimming behavior previously detd. to be a measurable manifestation of seizures. In our first screen, we tested a no. of different HDAC inhibitors and found that one, 2-benzamido-1 4-naphthoquinone (NQN1), significantly decreased swim activity to levels equal to that of valproic acid, 2-n-propylpentanoic acid (VPA). We continued to screen structurally related compds. including Vitamin K3 (VK3) and a no. of novel Vitamin K (VK) analogs. We found that VK3 was a robust inhibitor of the PTZ-induced swim activity, as were several of our novel compds. Three of these compds. were subsequently tested on mouse seizure models at the National Institute of Neurol. Disorders and Stroke (NINDS) Anticonvulsant Screening Program. Compd. 2h reduced seizures particularly well in the minimal clonic seizure (6 Hz) and corneal-kindled mouse models of epilepsy, with no observable toxicity. As VK3 affects mitochondrial function, we tested the effects of our compds. on mitochondrial respiration and ATP prodn. in a mouse hippocampal cell line. We demonstrate that these compds. affect ATP metab. and increase total cellular ATP. Our data indicate the potential utility of these and other VK analogs for the prevention of seizures and suggest the potential mechanism for this protection may lie in the ability of these compds. to affect energy prodn.
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  10. 10
    Chadar, D.; Camilles, M.; Patil, R.; Khan, A.; Weyhermüller, T.; Salunke-Gawali, S. Synthesis and Characterization of n-alkylamino Derivatives of Vitamin K3: Molecular Structure of 2-propylamino-3-methyl-1,4-naphthoquinone and Antibacterial Activities. J. Mol. Struct. 2015, 1086, 179– 189,  DOI: 10.1016/j.molstruc.2015.01.029
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    Kathawate, L.; Joshi, P. V.; Dash, T. K.; Pal, S.; Nikalje, M.; Weyhermüller, T.; Puranik, V. G.; Konkimalla, V. B.; Salunke-Gawali, S. Reaction Between Lawsone and Aminophenol Derivatives: Synthesis, Characterization, Molecular Structures and Antiproliferative Activity. J. Mol. Struct. 2014, 1075, 397– 405,  DOI: 10.1016/j.molstruc.2014.07.007
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    Itoh, H.; Tokumoto, K.; Kaji, T.; Paudel, A.; Panthee, S.; Hamamoto, H.; Sekimizu, K.; Inoue, M. Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic. J. Org. Chem. 2018, 83, 6924– 6935,  DOI: 10.1021/acs.joc.7b02318
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    12
    Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic
    Itoh, Hiroaki; Tokumoto, Kotaro; Kaji, Takuya; Paudel, Atmika; Panthee, Suresh; Hamamoto, Hiroshi; Sekimizu, Kazuhisa; Inoue, Masayuki
    Journal of Organic Chemistry (2018), 83 (13), 6924-6935CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    WAP-8294A2 (lotilibcin) is a potent antibiotic with superior in vivo efficacy to vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). Despite the great medical importance, its mol. mode of action remains unknown. Here we report the total synthesis of complex macrocyclic peptide lotilibcin comprised of 12 amino acids with a β-hydroxy fatty-acid chain, and its deoxy analog. A full solid-phase synthesis of WAP-8294A2 and its deoxy analog enabled their rapid assembly and the first detailed investigation of their functions. Lotilibcin and deoxy analog were equipotent against various strains of Gram-pos. bacteria including MRSA. We present evidence that the antimicrobial activities of WAP-8294A2 and analog are due to lysis of the bacterial membrane, and their membrane-disrupting effects depend on the presence of menaquinone, an essential factor for the bacterial respiratory chain. The established synthetic routes and the menaquinone-targeting mechanisms provide valuable information for designing and developing new antibiotics based on their structures.
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  13. 13
    Thomson, R. H. Naturally Occurring Quinones; Academic Press Inc., 1971.
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    Collins, M. D.; Jones, D. Distribution of Isoprenoid Quinone Structural Types in Bacteria and Their Taxonomic Implications. Microbiol. Rev. 1981, 45, 316– 354
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    14
    Distribution of isoprenoid quinone structural types in bacteria and their taxonomic implication
    Collins M D; Jones D
    Microbiological reviews (1981), 45 (2), 316-54 ISSN:0146-0749.
    There is no expanded citation for this reference.
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  15. 15
    Collins, M. D.; Shah, H. N.; Minnikin, D. E. A Note on the Separation of Natural Mixtures of Bacterial Menaquinones using Reverse Phase Thin-layer Chromatography. J. Appl. Bacteriol. 1980, 48, 277– 282,  DOI: 10.1111/j.1365-2672.1980.tb01227.x
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    15
    A note on the separation of natural mixtures of bacterial menaquinones using reverse phase thin-layer chromatography
    Collins, M. D.; Shah, H. N.; Minnikin, D. E.
    Journal of Applied Bacteriology (1980), 48 (2), 277-82CODEN: JABAA4; ISSN:0021-8847.
    Natural mixts. of bacterial menaquinones were sepd. according to the length and degree of satn. of the polyisoprenyl side-chain with Merck RP-18F254 reverse-phase, thin-layer chromatog. plates. This system affords a simple and rapid means of menaquinone characterization.
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  16. 16
    Dunphy, P. J.; Brodie, A. F. The Structure and Function of Quinones in Respiratory Metabolism. Methods in Enzymology; Academic Press, 1971; Vol. 18, pp 407– 461.
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    Dunphy, P. J.; Gutnick, D. L.; Phillips, P. G.; Brodie, A. F. A New Natural Naphthoquinone in Mycobacterium phlei. Cis-dihydromenaquinone-9, Structure and Function. J. Biol. Chem. 1968, 243, 398– 407
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    New natural naphthoquinone in Mycobacterium phlei. cis-Dihydromenaquinone-9, structure and function
    Dunphy, Patrick J.; Gutnick, David L.; Phillips, Philip G.; Brodie, Arnold F.
    Journal of Biological Chemistry (1968), 243 (2), 398-407CODEN: JBCHA3; ISSN:0021-9258.
    The natural quinone, II-dihydromenaquinone-9 [MK9(II-H)] (I), from M. phlei has been resolved into 2 components by adsorption thin-layer chromatog. Chem. anal. of the sepd. products indicated that they were both 1,4-naphthoquinones of I type, differing only in the geometry of the double bond in the ring-terminal isoprene unit. By N.M.R. spectroscopy it was possible to show that the major component was all-trans form of I, while the minor product was the 3'-methyl-cis-MK9(2H) isomer. This new quinone appeared to be biol. active, since T was incorporated into the cis isomer. In contrast, very little incorporation of T was found in the trans isomer. The incorporation into the cis isomer was phosphate-dependent. 37 references.
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  18. 18
    Ogawa, T.; Isobe, K.; Mori, T.; Asakawa, S.; Yoshimura, T.; Hemmi, H. A novel geranylgeranyl reductase from the methanogenic archaeon Methanosarcina acetivorans displays unique regiospecificity. FEBS J. 2014, 281, 3165– 3176,  DOI: 10.1111/febs.12851
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    Bang, C.; Schmitz, R. A. Archaea Associated with Human Surfaces: Not To Be Underestimated. FEMS Microbiol. Rev. 2015, 39, 631– 648,  DOI: 10.1093/femsre/fuv010
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    Gale, P. H.; Arison, B. H.; Trenner, N. R.; Page, A. C.; Folkers, K.; Brodie, A. F. Characterization of Vitamin K9(H) from Mycobacterium phlei. Biochemistry 1963, 2, 200– 203,  DOI: 10.1021/bi00901a038
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    Characterization of vitamin K9(H) from Mycobacterium phlei
    Gale, P. H.; Arison, B. H.; Trenner, N. R.; Page, A. C., Jr.; Folkers, K.; Brodie, A. F.
    Biochemistry (1963), 2 (1), 200-3CODEN: BICHAW; ISSN:0006-2960.
    A newly characterized naphthoquinone has been isolated from M. phlei. Spectral data and chromatographic results revealed that it is closely related structurally to vitamin K2(45), but differs in that one of the side-chain isoprenoid units is reduced. Nuclear magnetic resonance data also show that the satd. isoprenoid unit is not located at either end of the side-chain. This compd. is designated vitamin K5(H) by the same nomenclature used for the new coenzyme Q10(H-10).
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  21. 21
    Azerad, R.; Cyrot, M.-O.; Lederer, E. Structure of the Dihydromenaquinone-9 of Mycobacterium phlei. Biochem. Biophys. Res. Commun. 1967, 27, 249– 252,  DOI: 10.1016/s0006-291x(67)80069-x
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    Azerad, R.; Cyrot-Pelletier, M.-O. Structure and Configuration of the Polyprenoid Side Chain of Dihydromenaquinones from Myco- and Corynebacteria. Biochimie 1973, 55, 591– 603,  DOI: 10.1016/s0300-9084(73)80421-3
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    Upadhyay, A.; Fontes, F. L.; Gonzalez-Juarrero, M.; McNeil, M. R.; Crans, D. C.; Jackson, M.; Crick, D. C. Partial Saturation of Menaquinone in Mycobacterium tuberculosis: Function and Essentiality of a Novel Reductase, MenJ. ACS Cent. Sci. 2015, 1, 292– 302,  DOI: 10.1021/acscentsci.5b00212
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    23
    Partial Saturation of Menaquinone in Mycobacterium tuberculosis: Function and Essentiality of a Novel Reductase, MenJ
    Upadhyay, Ashutosh; Fontes, Fabio L.; Gonzalez-Juarrero, Mercedes; McNeil, Michael R.; Crans, Debbie C.; Jackson, Mary; Crick, Dean C.
    ACS Central Science (2015), 1 (6), 292-302CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    Menaquinone (MK) with partially satd. isoprenyl moieties is found in a wide range of eubacteria and Archaea. In many Gram-pos. organisms, including mycobacteria, it is the double bond found in the β-isoprene unit that is reduced. Mass spectral characterization of menaquinone from mycobacterial knockout strains and heterologous expression hosts demonstrates that Rv0561c (designated menJ) encodes an enzyme which reduces the β-isoprene unit of menaquinone in Mycobacterium tuberculosis, forming the predominant form of menaquinone found in mycobacteria. MenJ is highly conserved in mycobacteria species but is not required for growth in culture. Disruption of menJ reduces mycobacterial electron transport efficiency by 3-fold, but mycobacteria are able to maintain ATP levels by increasing the levels of the total menaquinone in the membrane; however, MenJ is required for M. tuberculosis survival in host macrophages. Thus, MK with partially hydrogenated isoprenyl moieties represents a novel virulence factor and MenJ is a contextually essential enzyme and a potential drug target in pathogenic mycobacteria and other Gram-pos. pathogens.
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  24. 24
    Sitkowski, J.; Bocian, W.; Szterk, A. The application of multidimensional NMR analysis to cis/trans isomers study of menaquinone-7 (vitamine K2MK-7), identification of the (E,Z3,E2,ω)-menaquinone-7 isomer in dietary supplements. J. Mol. Struct. 2018, 1171, 449– 457,  DOI: 10.1016/j.molstruc.2018.06.029
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    Szterk, A.; Zmysłowski, A.; Bus, K. Identification of cis/trans isomers of menaquinone-7 in food as exemplified by dietary supplements. Food Chem. 2018, 243, 403– 409,  DOI: 10.1016/j.foodchem.2017.10.001
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    Koehn, J. T.; Magallanes, E. S.; Peters, B. J.; Beuning, C. N.; Haase, A. A.; Zhu, M. J.; Rithner, C. D.; Crick, D. C.; Crans, D. C. A Synthetic Isoprenoid Lipoquinone, Menaquinone-2, Adopts a Folded Conformation in Solution and at a Model Membrane Interface. J. Org. Chem. 2018, 83, 275– 288,  DOI: 10.1021/acs.joc.7b02649
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    26
    A Synthetic Isoprenoid Lipoquinone, Menaquinone-2, Adopts a Folded Conformation in Solution and at a Model Membrane Interface
    Koehn, Jordan T.; Magallanes, Estela S.; Peters, Benjamin J.; Beuning, Cheryle N.; Haase, Allison A.; Zhu, Michelle J.; Rithner, Christopher D.; Crick, Dean C.; Crans, Debbie C.
    Journal of Organic Chemistry (2018), 83 (1), 275-288CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Menaquinones (naphthoquinones, MK) are isoprenoids that play key roles in the respiratory electron transport system of some prokaryotes by shuttling electrons between membrane-bound protein complexes acting as electron acceptors and donors. Menaquinone-2 (MK-2), a truncated MK, was synthesized and the studies presented here characterize the conformational and chem. properties of the hydrophobic MK-2 mol. Using 2D NMR spectroscopy, we established for the 1st time that MK-2 has a folded conformation defined by the isoprenyl side-chain folding back over the naphthoquinone in a U-shape, which depends on the specific environmental conditions found in different solvents. We used mol. mechanics to illustrate conformations found by the NMR expts. The measured redox potentials of MK-2 differed in 3 org. solvents, where MK-2 was most easily reduced in DMSO, which may suggest a combination of solvent effect (presumably in part because of differences in dielec. consts.) and/or conformational differences of MK-2 in different org. solvents. Furthermore, MK-2 was found to assoc. with the interface of model membranes represented by Langmuir phospholipid monolayers and reverse micelles. MK-2 adopted a slightly different U-shaped conformation within reverse micelles compared to within soln., which was in sharp contrast to the extended conformations illustrated in literature for MKs.
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    Daines, A. M.; Payne, R. J.; Humphries, M. E.; Abell, A. D. The Synthesis of Naturally Occurring Vitamin K and Vitamin K Analogues. Curr. Org. Chem. 2003, 7, 1625– 1634,  DOI: 10.2174/1385272033486279
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    The synthesis of naturally occurring vitamin K and vitamin K analogues
    Daines, Alison M.; Payne, Richard J.; Humphries, Mark E.; Abell, Andrew D.
    Current Organic Chemistry (2003), 7 (16), 1625-1634CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
    A review. The synthesis of vitamin K and its analogs has been an important goal since the biochem. roles of the K vitamins were elucidated. This review presents a detailed account of syntheses of natural K vitamins and analogs that contain side chain functionality.
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    IUPAC-IUB Nomenclature of Quinones with Isoprenoid Side-Chains. Pure Appl. Chem. 1974, 38, 439– 447
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    Phoenix, J.; Edwards, R. H. T.; Jackson, M. J. The effect of vitamin E analogues and long hydrocarbon chain compounds on calcium-induced muscle damage. A novel role for α-tocopherol?. Biochim. Biophys. Acta, Mol. Basis Dis. 1991, 1097, 212– 218,  DOI: 10.1016/0925-4439(91)90037-a
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    29
    The effect of vitamin E analogs and long hydrocarbon chain compounds on calcium-induced muscle damage. A novel role for α-tocopherol?
    Phoenix, Joanne; Edwards, Richard H. T.; Jackson, Malcolm J.
    Biochimica et Biophysica Acta, Molecular Basis of Disease (1991), 1097 (3), 212-18CODEN: BBADEX; ISSN:0925-4439.
    Previous studies have demonstrated that supplemental α-tocopherol inhibited calcium-induced cytosolic enzyme efflux from normal rat skeletal muscles incubated in vitro and suggested that the protective action was mediated by the phytyl chain of α-tocopherol. In order to investigate this further a no. of hydrocarbon chain analogs of tocopherol (7,8-di-Me tocol, 5,7-di-Me tocol, tocol, α-tocotrienol, α-tocopherol [10], vitamin K1, vitamin K1 [10], vitamin K1 diacetate, vitamin K2 [20], phytyl ubiquinone and retinol) were tested for any ability to inhibit calcium ionophore, A23187, induced creatine kinase (CK) enzyme efflux. Some compds. were very effective inhibitors and comparison of their structures and ability to inhibit thiobarbituric acid-reactive substances prodn. in muscle homogenates revealed that the effects did not appear related to antioxidant capacity or chromanol Me groups, but rather the length and structure of the hydrocarbon chain was the important mediator of the effects seen.
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    Wiss, O.; Weber, F.; Rüegg, R.; Isler, O. The Biological Activity of Vitamins K1 and K2 and their Isoprenologs. Hoppe-Seyler’s Z. Physiol. Chem. 1959, 314, 245– 249,  DOI: 10.1515/bchm2.1959.314.1.245
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    30
    The biological activity of vitamins K1 and K2 and their isoprenologs
    Wiss, O.; Weber, F.; Ruegg, R.; Isler, O.
    Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie (1959), 314 (), 245-9CODEN: HSZPAZ; ISSN:0018-4888.
    The biol. activities of vitamin K1 and its homologs with 5, 10, 15, 25, and 30 C atoms as well as those of vitamin K2 and its homologs with 10, 15, 20, 25, and 35 C atoms in the side chain were tested on vitamin K depleted chickens. Normalization of blood clotting, measured by detg. prothrombin time, served as criterion. The length of the side chain was shown to greatly affect activity. The natural form of vitamin K1 was more effective than any of its homologs. In the vitamin K2 series the homolog with a side chain of 25 C atoms was superior to all the others, including vitamin K1. This compd. has not been found in nature as yet.
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    Noll, H. Physicochemical Characterization of Vitamin K Homologs. I. Identification by a Novel Method of Quantitative Infrared Spectrophotometry. J. Biol. Chem. 1960, 235, 2207– 2216
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    Isler, O.; Rüegg, R.; Studer, A.; Jürgens, R. Specificity of the Vitamin K1 Constitution and its Analogs Toward Coumarin Linkages. Hoppe-Seyler’s Z. Physiol. Chem. 1953, 295, 290– 309,  DOI: 10.1515/bchm2.1953.295.1.290
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    32
    Specificity of the vitamin K1 constitution and its analogs toward coumarin linkages
    Isler, O.; Ruegg, R.; Studer, A.; Jurgens, R.
    Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie (1953), 295 (), 290-309CODEN: HSZPAZ; ISSN:0018-4888.
    Compds. in the vitamin K series were synthesized and their activity against the Dicumarol effect detd. The activity was tested by detg. the decrease in prothrombin time (guinea pigs) and in a longevity test among rats against Dicumarol poisoning. Among some compds. the action depends as much on the animal used as on the coumarin compd. This variation of action applies separately for those prepns. with side chains contg. phenyl groups, branch methyl groups, and double bonds in the side chain, which have a rapid but not an outstanding action. Vitamin K prepns. with a 3-position side chain of less than 8 C atoms are not active. Marked action is evident among those compds. closely resembling vitamin K1 or K2, with vitamin K being most active in both tests without regard to the nature of the coumarin used. Compds. studied are the following 1,4-naphthoquinones: 2-methyl-3-(3-methyl-2-butenyl), yellow oil, nD20 1.5840, max. absorption 248.5 mμ, ε = 18,200; 2-methyl-3-(3,7-dimethyl-2-octenyl), yellow oil, nD20 1.5509, max. 248.5 mμ, ε = 18,500; 2-methyl-3-(3,7,11-trimethyl-2-dodecenyl), yellow oil, nD20 1.5354, max. 248.5 mμ, ε = 18,300; 2-methyl-3-(3,7,11,15,19-pentamethyl-2-eicosenyl), yellow oil, nD27 1.5164, max. 248.5 mμ, ε = 18,150, and 2-methyl-3-(3,7,11,15,19,23-hexamethyl-2-tetracosenyl), yellow oil, nD20 1.5111, max. 248.5 mμ, ε = 18,000; also 4,8,12,16,20-pentamethylheneicosyl methyl ketone, colorless oil, b0.03 194-8°, nD20 1.4535, d420 0.8393; 3,7,11,15,19,23-hexamethyl-1-tetracosyn-3-ol, from the above ketone by addn. of acetylene, colorless oil, b0.04 207°, nD28 1.4587, d428 0.8466; and 3,7,11,15,19,23-hexamethyl-1-tetracosen-3-ol (from the acetylene compd. by partial hydrogenation, colorless oil, b0.02 201, nD28 1.4590, d428 0.8434. Compds. of the vitamin K2 series studied are the following 1,4-naphthoquinones: 2-methyl-3-geranyl, yellow, waxy crystals, m. about 20°, nD20 1.5699, max. 248.5 mμ, ε = 18,600; 2-methyl-3-farnesyl, yellow oil, nD21 1.5582, max. 248.5 mμ, ε = 18,500; 2-methyl-3-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl), yellow oil, nD20 1.5532, max. 248.5 mμ, ε = 18,800; 2-methyl-3-(3,7,11,15,19-pentamethyl-2,6,10,14,18-eicosapentaenyl), yellow oil, nD27 1.5378, max. 248.5 mμ, ε = 18,800; 2-methyl-3-(3-ethyl-2-pentenyl), yellow crystals, m. 44°, max. 249 mμ, ε = 18,450; and 2-methyl-3-(3-methyl-2-octadecenyl), yellow crystals, m. 52°, max. 249 mμ, ε = 18,750; also studied were 3-methyl-1-octadecyn-3-ol, b0.05 116°, m. 32°; 3-methyl-1-octadecen-3-ol, colorless crystals, m. 32-3°; 2-methyl-3-(3,7,11,15-tetramethylhexadecyl)-1,4-naphthoquinone, yellow oil, nD20 1.5178; 2-methyl-3-(3-pentadecyl-2-octadecenyl)-1,4-naphthoquinone, yellow oil, nD20 1.5075, max. 249 mμ, ε = 18,900; 3-pentadecyl-1-octadecyn-3-ol, colorless crystals, m. 54-5°; 3-pentadecyl-1-octadecene-3-ol, colorless oil, nD26 1.4523; and the 1,4-naphthoquinones: 2-methyl-3-(cyclohexylidene.ovrddot.ethyl), yellow crystals, m. 63-4°, max. 249 mμ, ε = 18,670; 2-methyl-3-(decahydronaphthylidene.ovrddot.ethyl), yellow oil, nD20 1.5935, max. 249 mμ, 18,500; 2-methyl-3-[5-(2,6,6-trimethyl-1-cyclohexenyl)-3-methyl-2-pentenyl], yellow oil, nD20 1.5723, max. 249 mμ, ε = 18,800; 2-methyl-3-(3-phenylbutenyl), yellow oil, which crystd. after some time, max. 249 mμ, ε = 31,600; 2-methyl-3-(3-phenylbutyl), yellow crystals, m. 107°, max. 248 mμ, ε = 17,900; 2-methyl-3-(3-phenyl-2-propenyl), yellow crystals, m. 124-5°, max. 250 mμ, ε = 35,600; and 2-methyl-3-(3-phenylpropyl), yellow crystals, m. 48°, max. 248 mμ, ε = 18,100.
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    Azerad, R.; Cyrot, M. O. Synthesis of Two Dihydrofarnesylnaphthoquinones Related to Vitamin K2(45)H from Mycobacterium phlei. Bull. Soc. Chim. Fr. 1965, 12, 3740– 3745
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  7. Margaret M. Braasch-Turi, Jordan T. Koehn, Debbie C. Crans. Chemistry of Lipoquinones: Properties, Synthesis, and Membrane Location of Ubiquinones, Plastoquinones, and Menaquinones. International Journal of Molecular Sciences 2022, 23 (21) , 12856. https://doi.org/10.3390/ijms232112856
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  10. Margaret Braasch-Turi, Debbie C. Crans. Synthesis of Naphthoquinone Derivatives: Menaquinones, Lipoquinones and Other Vitamin K Derivatives. Molecules 2020, 25 (19) , 4477. https://doi.org/10.3390/molecules25194477
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  • Abstract

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    Figure 1

    Figure 1. (A) Partially saturated menaquinone-9(II-H2) [abbreviated as MK-9(II-H2)] present within M. tuberculosis, (B) partially saturated menaquinone-2(II-H2) [abbreviated as MK-2(II-H2)], (C) fully saturated menaquinone-2(I,II-H4) [abbreviated as MK-2(I,II-H4)], (D) partially saturated menaquinone-3(II-H2) [abbreviated as MK-3(II-H2)], and (E) fully saturated menaquinone-3(I,II,III-H6) [abbreviated as MK-3(I,II,III-H6)].

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    Scheme 1

    Scheme 1. Synthetic Scheme for the Coupling Reaction Using a MgF2-48 Catalyst To Obtain MK-2(II-H2) 3 from Menadiol 1 and Isophytol 2 (40)
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    Figure 2

    Figure 2. Comparison of the 1D 1H NMR (400 MHz) spectra for the mixture of cis/trans-MK-2(II-H2) and trans-MK-2(II-H2) in C6D6 at 25 °C. (A) Structure of trans-MK-2(II-H2) with the proton labeling scheme key, (B) structure of cis-MK-2(II-H2), (C) 1D 1H NMR spectrum of the cis/trans mixture of MK-2(II-H2) in C6D6, and (D) 1D 1H NMR spectrum of trans-MK-2(II-H2) in C6D6.

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    Scheme 2

    Scheme 2. Synthetic Scheme for the Three-Step Synthesis To Obtain MK-2(I,II-H4) 7a
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    aThe first step forms the mesylate from 4. The second step forms aliphatic iodide 5 via a SN2 reaction. The final step couples menadione 6 and aliphatic iodide 5 using a radical alkylation initiated by benzoyl peroxide.

    Scheme 3

    Scheme 3. Synthetic Scheme for the Seven-Step Synthesis To Obtain MK-3(II-H2) 13 from β-Citronellol 8 (33,38)
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    Figure 3

    Figure 3. Comparison of the 1D 1H NMR (400 MHz) spectra for the mixture of cis/trans-MK-3(II-H2) and trans-MK-3(II-H2) in C6D6 at 25 °C. (A) Structure of trans-MK-3(II-H2) with the proton labeling scheme key, (B) structure of cis-MK-3(II-H2), (C) 1D 1H NMR spectrum of the cis/trans mixture of MK-3(II-H2) in C6D6, and (D) 1D 1H NMR spectrum of trans-MK-3(II-H2) in C6D6. Overlapping cis/trans peaks have been left unlabeled.

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    Scheme 4

    Scheme 4. Synthetic Scheme for the Four-Step Synthesis To Obtain MK-3(I,II,III-H6) 17a
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    aThe first step is a transfer hydrogenation to produce the fully saturated alcohol 15 from farnesol 14. The second step forms the mesylate from 15. The third step forms aliphatic iodide 16 via a SN2 reaction. The final step couples menadione 6 and aliphatic iodide 16 using a radical alkylation initiated by benzoyl peroxide.

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      Nakagawa, Kimie; Hirota, Yoshihisa; Sawada, Natsumi; Yuge, Naohito; Watanabe, Masato; Uchino, Yuri; Okuda, Naoko; Shimomura, Yuka; Suhara, Yoshitomo; Okano, Toshio
      Nature (London, United Kingdom) (2010), 468 (7320), 117-121CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Vitamin K occurs in the natural world in several forms, including a plant form, phylloquinone (PK), and a bacterial form, menaquinones (MKs). In many species, including humans, PK is a minor constituent of hepatic vitamin K content, with most hepatic vitamin K content comprising long-chain MKs. Menaquinone-4 (MK-4) is ubiquitously present in extrahepatic tissues, with particularly high concns. in the brain, kidney and pancreas of humans and rats. It has consistently been shown that PK is endogenously converted to MK-4. This occurs either directly within certain tissues or by interconversion to menadione (K3), followed by prenylation to MK-4 (refs. 9-12). No previous study has sought to identify the human enzyme responsible for MK-4 biosynthesis. Previously we provided evidence for the conversion of PK and K3 into MK-4 in mouse cerebra. However, the mol. mechanisms for these conversion reactions are unclear. Here we identify a human MK-4 biosynthetic enzyme. We screened the human genome database for prenylation enzymes and found UbiA prenyltransferase contg. 1 (UBIAD1), a human homolog of Escherichia coli prenyltransferase menA. We found that short interfering RNA against the UBIAD1 gene inhibited the conversion of deuterium-labeled vitamin K derivs. into deuterium-labeled-MK-4 (MK-4-d7) in human cells. We confirmed that the UBIAD1 gene encodes an MK-4 biosynthetic enzyme through its expression and conversion of deuterium-labeled vitamin K derivs. into MK-4-d7 in insect cells infected with UBIAD1 baculovirus. Converted MK-4-d7 was chem. identified by 2H-NMR anal. MK-4 biosynthesis by UBIAD1 was not affected by the vitamin K antagonist warfarin. UBIAD1 was localized in endoplasmic reticulum and ubiquitously expressed in several tissues of mice. Our results show that UBIAD1 is a human MK-4 biosynthetic enzyme; this identification will permit more effective decisions to be made about vitamin K intake and bone health.
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    4. 4
      Vos, M.; Esposito, G.; Edirisinghe, J. N.; Vilain, S.; Haddad, D. M.; Slabbaert, J. R.; Van Meensel, S.; Schaap, O.; De Strooper, B.; Meganathan, R.; Morais, V. A.; Verstreken, P. Vitamin K2 Is a Mitochondrial Electron Carrier That Rescues Pink1 Deficiency. Science 2012, 336, 1306– 1310,  DOI: 10.1126/science.1218632
      4
      Vitamin K2 Is a Mitochondrial Electron Carrier That Rescues Pink1 Deficiency
      Vos, Melissa; Esposito, Giovanni; Edirisinghe, Janaka N.; Vilain, Sven; Haddad, Dominik M.; Slabbaert, Jan R.; Van Meensel, Stefanie; Schaap, Onno; De Strooper, Bart; Meganathan, R.; Morais, Vanessa A.; Verstreken, Patrik
      Science (Washington, DC, United States) (2012), 336 (6086), 1306-1310CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Human UBIAD1 localizes to mitochondria and converts vitamin K1 to vitamin K2. Vitamin K2 is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Whether vitamin K2 exerts a similar carrier function in eukaryotic cells is unknown. We identified Drosophila UBIAD1/Heix as a modifier of pink1, a gene mutated in Parkinson's disease that affects mitochondrial function. We found that vitamin K2 was necessary and sufficient to transfer electrons in Drosophila mitochondria. Heix mutants showed severe mitochondrial defects that were rescued by vitamin K2, and, similar to ubiquinone, vitamin K2 transferred electrons in Drosophila mitochondria, resulting in more efficient ATP prodn. Thus, mitochondrial dysfunction was rescued by vitamin K2 that serves as a mitochondrial electron carrier, helping to maintain normal ATP prodn.
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    5. 5
      Dragh, M. A.; Xu, Z.; Al-Allak, Z. S.; Hong, L. Vitamin K2 Prevents Lymphoma in Drosophila. Sci. Rep. 2017, 7, 17047,  DOI: 10.1038/s41598-017-17270-9
      5
      Vitamin K2 Prevents Lymphoma in Drosophila
      Dragh Maytham A; Xu Zhiliang; Hong Ling; Dragh Maytham A; Al-Allak Zainab S
      Scientific reports (2017), 7 (1), 17047 ISSN:.
      Previous studies have established the anticancer effect of vitamin K2 (VK2). However, its effect on lymphoma induced by UBIAD1/heix mutation in Drosophila remains unknown. Therefore, we aimed to develop an in vivo model of lymphoma for the precise characterization of lymphoma phenotypes. We also aimed to improve the understanding of the mechanisms that underlie the preventative effects of VK2 on lymphoma. Our results demonstrated that VK2 prevents lymphoma by acting as an electron carrier and by correcting the function and structure of mitochondria by inhibiting mitochondrial reactive oxygen species production mtROS. Our work identifies mitochondria as a key player in cancer therapy strategies.
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    6. 6
      Okamoto, H.; Shidara, K.; Hoshi, D.; Kamatani, N. Anti-arthritis Effects of Vitamin K2 (Menaquinone-4) - a New Potential Therapeutic Strategy for Rheumatoid Arthritis. FEBS J. 2007, 274, 4588– 4594,  DOI: 10.1111/j.1742-4658.2007.05987.x
      There is no corresponding record for this reference.
    7. 7
      Astudillo-Sánchez, P. D.; Morales-Martínez, D.; Sánchez, A.; Rocha-Ortiz, G.; Salas-Reyes, M. Electrochemical Study of the Interactions Between Anionic Species of Menadione and Alkylated Nucleobases in Dimethylsulfoxide. J. Electroanal. Chem. 2017, 801, 104– 113,  DOI: 10.1016/j.jelechem.2017.07.023
      There is no corresponding record for this reference.
    8. 8
      Josey, B. J.; Inks, E. S.; Wen, X.; Chou, C. J. Structure-Activity Relationship Study of Vitamin K Derivatives Yields Highly Potent Neuroprotective Agents. J. Med. Chem. 2013, 56, 1007– 1022,  DOI: 10.1021/jm301485d
      8
      Structure-Activity Relationship Study of Vitamin K Derivatives Yields Highly Potent Neuroprotective Agents
      Josey, Benjamin J.; Inks, Elizabeth S.; Wen, Xuejun; Chou, C. James
      Journal of Medicinal Chemistry (2013), 56 (3), 1007-1022CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Historically known for its role in blood coagulation and bone formation, vitamin K (VK) has begun to emerge as an important nutrient for brain function. While VK involvement in the brain has not been fully explored, it is well-known that oxidative stress plays a crit. role in neurodegenerative diseases. It was recently reported that VK protects neurons and oligodendrocytes from oxidative injury and rescues Drosophila from mitochondrial defects assocd. with Parkinson's disease. In this study, we take a chem. approach to define the optimal and min. pharmacophore responsible for the neuroprotective effects of VK. In doing so, we have developed a series of potent VK analogs with favorable drug characteristics that provide full protection at nanomolar concns. in a well-defined model of neuronal oxidative stress. Addnl., we have characterized key cellular responses and biomarkers consistent with the compds.' ability to rescue cells from oxidative stress induced cell death.
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    9. 9
      Rahn, J. J.; Bestman, J. E.; Josey, B. J.; Inks, E. S.; Stackley, K. D.; Rogers, C. E.; Chou, C. J.; Chan, S. S. L. Novel Vitamin K Analogs Suppress Seizures in Zebrafish and Mouse Models of Epilepsy. Neuroscience 2014, 259, 142– 154,  DOI: 10.1016/j.neuroscience.2013.11.040
      9
      Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy
      Rahn, J. J.; Bestman, J. E.; Josey, B. J.; Inks, E. S.; Stackley, K. D.; Rogers, C. E.; Chou, C. J.; Chan, S. S. L.
      Neuroscience (Amsterdam, Netherlands) (2014), 259 (), 142-154CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)
      Epilepsy is a debilitating disease affecting 1-2% of the world's population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by current medication suggesting a crit. need for new anti-epileptic drugs (AEDs). In an effort to discover new therapeutics for the management of epilepsy, we began our study by screening drugs that, like some currently used AEDs, inhibit histone deacetylases (HDACs) using a well-established larval zebrafish model. In this model, 7-day post fertilization (dpf) larvae are treated with the widely used seizure-inducing compd. pentylenetetrazol (PTZ) which stimulates a rapid increase in swimming behavior previously detd. to be a measurable manifestation of seizures. In our first screen, we tested a no. of different HDAC inhibitors and found that one, 2-benzamido-1 4-naphthoquinone (NQN1), significantly decreased swim activity to levels equal to that of valproic acid, 2-n-propylpentanoic acid (VPA). We continued to screen structurally related compds. including Vitamin K3 (VK3) and a no. of novel Vitamin K (VK) analogs. We found that VK3 was a robust inhibitor of the PTZ-induced swim activity, as were several of our novel compds. Three of these compds. were subsequently tested on mouse seizure models at the National Institute of Neurol. Disorders and Stroke (NINDS) Anticonvulsant Screening Program. Compd. 2h reduced seizures particularly well in the minimal clonic seizure (6 Hz) and corneal-kindled mouse models of epilepsy, with no observable toxicity. As VK3 affects mitochondrial function, we tested the effects of our compds. on mitochondrial respiration and ATP prodn. in a mouse hippocampal cell line. We demonstrate that these compds. affect ATP metab. and increase total cellular ATP. Our data indicate the potential utility of these and other VK analogs for the prevention of seizures and suggest the potential mechanism for this protection may lie in the ability of these compds. to affect energy prodn.
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    10. 10
      Chadar, D.; Camilles, M.; Patil, R.; Khan, A.; Weyhermüller, T.; Salunke-Gawali, S. Synthesis and Characterization of n-alkylamino Derivatives of Vitamin K3: Molecular Structure of 2-propylamino-3-methyl-1,4-naphthoquinone and Antibacterial Activities. J. Mol. Struct. 2015, 1086, 179– 189,  DOI: 10.1016/j.molstruc.2015.01.029
      There is no corresponding record for this reference.
    11. 11
      Kathawate, L.; Joshi, P. V.; Dash, T. K.; Pal, S.; Nikalje, M.; Weyhermüller, T.; Puranik, V. G.; Konkimalla, V. B.; Salunke-Gawali, S. Reaction Between Lawsone and Aminophenol Derivatives: Synthesis, Characterization, Molecular Structures and Antiproliferative Activity. J. Mol. Struct. 2014, 1075, 397– 405,  DOI: 10.1016/j.molstruc.2014.07.007
      There is no corresponding record for this reference.
    12. 12
      Itoh, H.; Tokumoto, K.; Kaji, T.; Paudel, A.; Panthee, S.; Hamamoto, H.; Sekimizu, K.; Inoue, M. Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic. J. Org. Chem. 2018, 83, 6924– 6935,  DOI: 10.1021/acs.joc.7b02318
      12
      Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic
      Itoh, Hiroaki; Tokumoto, Kotaro; Kaji, Takuya; Paudel, Atmika; Panthee, Suresh; Hamamoto, Hiroshi; Sekimizu, Kazuhisa; Inoue, Masayuki
      Journal of Organic Chemistry (2018), 83 (13), 6924-6935CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      WAP-8294A2 (lotilibcin) is a potent antibiotic with superior in vivo efficacy to vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). Despite the great medical importance, its mol. mode of action remains unknown. Here we report the total synthesis of complex macrocyclic peptide lotilibcin comprised of 12 amino acids with a β-hydroxy fatty-acid chain, and its deoxy analog. A full solid-phase synthesis of WAP-8294A2 and its deoxy analog enabled their rapid assembly and the first detailed investigation of their functions. Lotilibcin and deoxy analog were equipotent against various strains of Gram-pos. bacteria including MRSA. We present evidence that the antimicrobial activities of WAP-8294A2 and analog are due to lysis of the bacterial membrane, and their membrane-disrupting effects depend on the presence of menaquinone, an essential factor for the bacterial respiratory chain. The established synthetic routes and the menaquinone-targeting mechanisms provide valuable information for designing and developing new antibiotics based on their structures.
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    13. 13
      Thomson, R. H. Naturally Occurring Quinones; Academic Press Inc., 1971.
      There is no corresponding record for this reference.
    14. 14
      Collins, M. D.; Jones, D. Distribution of Isoprenoid Quinone Structural Types in Bacteria and Their Taxonomic Implications. Microbiol. Rev. 1981, 45, 316– 354
      14
      Distribution of isoprenoid quinone structural types in bacteria and their taxonomic implication
      Collins M D; Jones D
      Microbiological reviews (1981), 45 (2), 316-54 ISSN:0146-0749.
      There is no expanded citation for this reference.
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    15. 15
      Collins, M. D.; Shah, H. N.; Minnikin, D. E. A Note on the Separation of Natural Mixtures of Bacterial Menaquinones using Reverse Phase Thin-layer Chromatography. J. Appl. Bacteriol. 1980, 48, 277– 282,  DOI: 10.1111/j.1365-2672.1980.tb01227.x
      15
      A note on the separation of natural mixtures of bacterial menaquinones using reverse phase thin-layer chromatography
      Collins, M. D.; Shah, H. N.; Minnikin, D. E.
      Journal of Applied Bacteriology (1980), 48 (2), 277-82CODEN: JABAA4; ISSN:0021-8847.
      Natural mixts. of bacterial menaquinones were sepd. according to the length and degree of satn. of the polyisoprenyl side-chain with Merck RP-18F254 reverse-phase, thin-layer chromatog. plates. This system affords a simple and rapid means of menaquinone characterization.
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    16. 16
      Dunphy, P. J.; Brodie, A. F. The Structure and Function of Quinones in Respiratory Metabolism. Methods in Enzymology; Academic Press, 1971; Vol. 18, pp 407– 461.
      There is no corresponding record for this reference.
    17. 17
      Dunphy, P. J.; Gutnick, D. L.; Phillips, P. G.; Brodie, A. F. A New Natural Naphthoquinone in Mycobacterium phlei. Cis-dihydromenaquinone-9, Structure and Function. J. Biol. Chem. 1968, 243, 398– 407
      17
      New natural naphthoquinone in Mycobacterium phlei. cis-Dihydromenaquinone-9, structure and function
      Dunphy, Patrick J.; Gutnick, David L.; Phillips, Philip G.; Brodie, Arnold F.
      Journal of Biological Chemistry (1968), 243 (2), 398-407CODEN: JBCHA3; ISSN:0021-9258.
      The natural quinone, II-dihydromenaquinone-9 [MK9(II-H)] (I), from M. phlei has been resolved into 2 components by adsorption thin-layer chromatog. Chem. anal. of the sepd. products indicated that they were both 1,4-naphthoquinones of I type, differing only in the geometry of the double bond in the ring-terminal isoprene unit. By N.M.R. spectroscopy it was possible to show that the major component was all-trans form of I, while the minor product was the 3'-methyl-cis-MK9(2H) isomer. This new quinone appeared to be biol. active, since T was incorporated into the cis isomer. In contrast, very little incorporation of T was found in the trans isomer. The incorporation into the cis isomer was phosphate-dependent. 37 references.
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    18. 18
      Ogawa, T.; Isobe, K.; Mori, T.; Asakawa, S.; Yoshimura, T.; Hemmi, H. A novel geranylgeranyl reductase from the methanogenic archaeon Methanosarcina acetivorans displays unique regiospecificity. FEBS J. 2014, 281, 3165– 3176,  DOI: 10.1111/febs.12851
      There is no corresponding record for this reference.
    19. 19
      Bang, C.; Schmitz, R. A. Archaea Associated with Human Surfaces: Not To Be Underestimated. FEMS Microbiol. Rev. 2015, 39, 631– 648,  DOI: 10.1093/femsre/fuv010
      There is no corresponding record for this reference.
    20. 20
      Gale, P. H.; Arison, B. H.; Trenner, N. R.; Page, A. C.; Folkers, K.; Brodie, A. F. Characterization of Vitamin K9(H) from Mycobacterium phlei. Biochemistry 1963, 2, 200– 203,  DOI: 10.1021/bi00901a038
      20
      Characterization of vitamin K9(H) from Mycobacterium phlei
      Gale, P. H.; Arison, B. H.; Trenner, N. R.; Page, A. C., Jr.; Folkers, K.; Brodie, A. F.
      Biochemistry (1963), 2 (1), 200-3CODEN: BICHAW; ISSN:0006-2960.
      A newly characterized naphthoquinone has been isolated from M. phlei. Spectral data and chromatographic results revealed that it is closely related structurally to vitamin K2(45), but differs in that one of the side-chain isoprenoid units is reduced. Nuclear magnetic resonance data also show that the satd. isoprenoid unit is not located at either end of the side-chain. This compd. is designated vitamin K5(H) by the same nomenclature used for the new coenzyme Q10(H-10).
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    21. 21
      Azerad, R.; Cyrot, M.-O.; Lederer, E. Structure of the Dihydromenaquinone-9 of Mycobacterium phlei. Biochem. Biophys. Res. Commun. 1967, 27, 249– 252,  DOI: 10.1016/s0006-291x(67)80069-x
      There is no corresponding record for this reference.
    22. 22
      Azerad, R.; Cyrot-Pelletier, M.-O. Structure and Configuration of the Polyprenoid Side Chain of Dihydromenaquinones from Myco- and Corynebacteria. Biochimie 1973, 55, 591– 603,  DOI: 10.1016/s0300-9084(73)80421-3
      There is no corresponding record for this reference.
    23. 23
      Upadhyay, A.; Fontes, F. L.; Gonzalez-Juarrero, M.; McNeil, M. R.; Crans, D. C.; Jackson, M.; Crick, D. C. Partial Saturation of Menaquinone in Mycobacterium tuberculosis: Function and Essentiality of a Novel Reductase, MenJ. ACS Cent. Sci. 2015, 1, 292– 302,  DOI: 10.1021/acscentsci.5b00212
      23
      Partial Saturation of Menaquinone in Mycobacterium tuberculosis: Function and Essentiality of a Novel Reductase, MenJ
      Upadhyay, Ashutosh; Fontes, Fabio L.; Gonzalez-Juarrero, Mercedes; McNeil, Michael R.; Crans, Debbie C.; Jackson, Mary; Crick, Dean C.
      ACS Central Science (2015), 1 (6), 292-302CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      Menaquinone (MK) with partially satd. isoprenyl moieties is found in a wide range of eubacteria and Archaea. In many Gram-pos. organisms, including mycobacteria, it is the double bond found in the β-isoprene unit that is reduced. Mass spectral characterization of menaquinone from mycobacterial knockout strains and heterologous expression hosts demonstrates that Rv0561c (designated menJ) encodes an enzyme which reduces the β-isoprene unit of menaquinone in Mycobacterium tuberculosis, forming the predominant form of menaquinone found in mycobacteria. MenJ is highly conserved in mycobacteria species but is not required for growth in culture. Disruption of menJ reduces mycobacterial electron transport efficiency by 3-fold, but mycobacteria are able to maintain ATP levels by increasing the levels of the total menaquinone in the membrane; however, MenJ is required for M. tuberculosis survival in host macrophages. Thus, MK with partially hydrogenated isoprenyl moieties represents a novel virulence factor and MenJ is a contextually essential enzyme and a potential drug target in pathogenic mycobacteria and other Gram-pos. pathogens.
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    24. 24
      Sitkowski, J.; Bocian, W.; Szterk, A. The application of multidimensional NMR analysis to cis/trans isomers study of menaquinone-7 (vitamine K2MK-7), identification of the (E,Z3,E2,ω)-menaquinone-7 isomer in dietary supplements. J. Mol. Struct. 2018, 1171, 449– 457,  DOI: 10.1016/j.molstruc.2018.06.029
      There is no corresponding record for this reference.
    25. 25
      Szterk, A.; Zmysłowski, A.; Bus, K. Identification of cis/trans isomers of menaquinone-7 in food as exemplified by dietary supplements. Food Chem. 2018, 243, 403– 409,  DOI: 10.1016/j.foodchem.2017.10.001
      There is no corresponding record for this reference.
    26. 26
      Koehn, J. T.; Magallanes, E. S.; Peters, B. J.; Beuning, C. N.; Haase, A. A.; Zhu, M. J.; Rithner, C. D.; Crick, D. C.; Crans, D. C. A Synthetic Isoprenoid Lipoquinone, Menaquinone-2, Adopts a Folded Conformation in Solution and at a Model Membrane Interface. J. Org. Chem. 2018, 83, 275– 288,  DOI: 10.1021/acs.joc.7b02649
      26
      A Synthetic Isoprenoid Lipoquinone, Menaquinone-2, Adopts a Folded Conformation in Solution and at a Model Membrane Interface
      Koehn, Jordan T.; Magallanes, Estela S.; Peters, Benjamin J.; Beuning, Cheryle N.; Haase, Allison A.; Zhu, Michelle J.; Rithner, Christopher D.; Crick, Dean C.; Crans, Debbie C.
      Journal of Organic Chemistry (2018), 83 (1), 275-288CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Menaquinones (naphthoquinones, MK) are isoprenoids that play key roles in the respiratory electron transport system of some prokaryotes by shuttling electrons between membrane-bound protein complexes acting as electron acceptors and donors. Menaquinone-2 (MK-2), a truncated MK, was synthesized and the studies presented here characterize the conformational and chem. properties of the hydrophobic MK-2 mol. Using 2D NMR spectroscopy, we established for the 1st time that MK-2 has a folded conformation defined by the isoprenyl side-chain folding back over the naphthoquinone in a U-shape, which depends on the specific environmental conditions found in different solvents. We used mol. mechanics to illustrate conformations found by the NMR expts. The measured redox potentials of MK-2 differed in 3 org. solvents, where MK-2 was most easily reduced in DMSO, which may suggest a combination of solvent effect (presumably in part because of differences in dielec. consts.) and/or conformational differences of MK-2 in different org. solvents. Furthermore, MK-2 was found to assoc. with the interface of model membranes represented by Langmuir phospholipid monolayers and reverse micelles. MK-2 adopted a slightly different U-shaped conformation within reverse micelles compared to within soln., which was in sharp contrast to the extended conformations illustrated in literature for MKs.
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    27. 27
      Daines, A. M.; Payne, R. J.; Humphries, M. E.; Abell, A. D. The Synthesis of Naturally Occurring Vitamin K and Vitamin K Analogues. Curr. Org. Chem. 2003, 7, 1625– 1634,  DOI: 10.2174/1385272033486279
      27
      The synthesis of naturally occurring vitamin K and vitamin K analogues
      Daines, Alison M.; Payne, Richard J.; Humphries, Mark E.; Abell, Andrew D.
      Current Organic Chemistry (2003), 7 (16), 1625-1634CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
      A review. The synthesis of vitamin K and its analogs has been an important goal since the biochem. roles of the K vitamins were elucidated. This review presents a detailed account of syntheses of natural K vitamins and analogs that contain side chain functionality.
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    28. 28
      IUPAC-IUB Nomenclature of Quinones with Isoprenoid Side-Chains. Pure Appl. Chem. 1974, 38, 439– 447
      There is no corresponding record for this reference.
    29. 29
      Phoenix, J.; Edwards, R. H. T.; Jackson, M. J. The effect of vitamin E analogues and long hydrocarbon chain compounds on calcium-induced muscle damage. A novel role for α-tocopherol?. Biochim. Biophys. Acta, Mol. Basis Dis. 1991, 1097, 212– 218,  DOI: 10.1016/0925-4439(91)90037-a
      29
      The effect of vitamin E analogs and long hydrocarbon chain compounds on calcium-induced muscle damage. A novel role for α-tocopherol?
      Phoenix, Joanne; Edwards, Richard H. T.; Jackson, Malcolm J.
      Biochimica et Biophysica Acta, Molecular Basis of Disease (1991), 1097 (3), 212-18CODEN: BBADEX; ISSN:0925-4439.
      Previous studies have demonstrated that supplemental α-tocopherol inhibited calcium-induced cytosolic enzyme efflux from normal rat skeletal muscles incubated in vitro and suggested that the protective action was mediated by the phytyl chain of α-tocopherol. In order to investigate this further a no. of hydrocarbon chain analogs of tocopherol (7,8-di-Me tocol, 5,7-di-Me tocol, tocol, α-tocotrienol, α-tocopherol [10], vitamin K1, vitamin K1 [10], vitamin K1 diacetate, vitamin K2 [20], phytyl ubiquinone and retinol) were tested for any ability to inhibit calcium ionophore, A23187, induced creatine kinase (CK) enzyme efflux. Some compds. were very effective inhibitors and comparison of their structures and ability to inhibit thiobarbituric acid-reactive substances prodn. in muscle homogenates revealed that the effects did not appear related to antioxidant capacity or chromanol Me groups, but rather the length and structure of the hydrocarbon chain was the important mediator of the effects seen.
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    30. 30
      Wiss, O.; Weber, F.; Rüegg, R.; Isler, O. The Biological Activity of Vitamins K1 and K2 and their Isoprenologs. Hoppe-Seyler’s Z. Physiol. Chem. 1959, 314, 245– 249,  DOI: 10.1515/bchm2.1959.314.1.245
      30
      The biological activity of vitamins K1 and K2 and their isoprenologs
      Wiss, O.; Weber, F.; Ruegg, R.; Isler, O.
      Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie (1959), 314 (), 245-9CODEN: HSZPAZ; ISSN:0018-4888.
      The biol. activities of vitamin K1 and its homologs with 5, 10, 15, 25, and 30 C atoms as well as those of vitamin K2 and its homologs with 10, 15, 20, 25, and 35 C atoms in the side chain were tested on vitamin K depleted chickens. Normalization of blood clotting, measured by detg. prothrombin time, served as criterion. The length of the side chain was shown to greatly affect activity. The natural form of vitamin K1 was more effective than any of its homologs. In the vitamin K2 series the homolog with a side chain of 25 C atoms was superior to all the others, including vitamin K1. This compd. has not been found in nature as yet.
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    31. 31
      Noll, H. Physicochemical Characterization of Vitamin K Homologs. I. Identification by a Novel Method of Quantitative Infrared Spectrophotometry. J. Biol. Chem. 1960, 235, 2207– 2216
      There is no corresponding record for this reference.
    32. 32
      Isler, O.; Rüegg, R.; Studer, A.; Jürgens, R. Specificity of the Vitamin K1 Constitution and its Analogs Toward Coumarin Linkages. Hoppe-Seyler’s Z. Physiol. Chem. 1953, 295, 290– 309,  DOI: 10.1515/bchm2.1953.295.1.290
      32
      Specificity of the vitamin K1 constitution and its analogs toward coumarin linkages
      Isler, O.; Ruegg, R.; Studer, A.; Jurgens, R.
      Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie (1953), 295 (), 290-309CODEN: HSZPAZ; ISSN:0018-4888.
      Compds. in the vitamin K series were synthesized and their activity against the Dicumarol effect detd. The activity was tested by detg. the decrease in prothrombin time (guinea pigs) and in a longevity test among rats against Dicumarol poisoning. Among some compds. the action depends as much on the animal used as on the coumarin compd. This variation of action applies separately for those prepns. with side chains contg. phenyl groups, branch methyl groups, and double bonds in the side chain, which have a rapid but not an outstanding action. Vitamin K prepns. with a 3-position side chain of less than 8 C atoms are not active. Marked action is evident among those compds. closely resembling vitamin K1 or K2, with vitamin K being most active in both tests without regard to the nature of the coumarin used. Compds. studied are the following 1,4-naphthoquinones: 2-methyl-3-(3-methyl-2-butenyl), yellow oil, nD20 1.5840, max. absorption 248.5 mμ, ε = 18,200; 2-methyl-3-(3,7-dimethyl-2-octenyl), yellow oil, nD20 1.5509, max. 248.5 mμ, ε = 18,500; 2-methyl-3-(3,7,11-trimethyl-2-dodecenyl), yellow oil, nD20 1.5354, max. 248.5 mμ, ε = 18,300; 2-methyl-3-(3,7,11,15,19-pentamethyl-2-eicosenyl), yellow oil, nD27 1.5164, max. 248.5 mμ, ε = 18,150, and 2-methyl-3-(3,7,11,15,19,23-hexamethyl-2-tetracosenyl), yellow oil, nD20 1.5111, max. 248.5 mμ, ε = 18,000; also 4,8,12,16,20-pentamethylheneicosyl methyl ketone, colorless oil, b0.03 194-8°, nD20 1.4535, d420 0.8393; 3,7,11,15,19,23-hexamethyl-1-tetracosyn-3-ol, from the above ketone by addn. of acetylene, colorless oil, b0.04 207°, nD28 1.4587, d428 0.8466; and 3,7,11,15,19,23-hexamethyl-1-tetracosen-3-ol (from the acetylene compd. by partial hydrogenation, colorless oil, b0.02 201, nD28 1.4590, d428 0.8434. Compds. of the vitamin K2 series studied are the following 1,4-naphthoquinones: 2-methyl-3-geranyl, yellow, waxy crystals, m. about 20°, nD20 1.5699, max. 248.5 mμ, ε = 18,600; 2-methyl-3-farnesyl, yellow oil, nD21 1.5582, max. 248.5 mμ, ε = 18,500; 2-methyl-3-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl), yellow oil, nD20 1.5532, max. 248.5 mμ, ε = 18,800; 2-methyl-3-(3,7,11,15,19-pentamethyl-2,6,10,14,18-eicosapentaenyl), yellow oil, nD27 1.5378, max. 248.5 mμ, ε = 18,800; 2-methyl-3-(3-ethyl-2-pentenyl), yellow crystals, m. 44°, max. 249 mμ, ε = 18,450; and 2-methyl-3-(3-methyl-2-octadecenyl), yellow crystals, m. 52°, max. 249 mμ, ε = 18,750; also studied were 3-methyl-1-octadecyn-3-ol, b0.05 116°, m. 32°; 3-methyl-1-octadecen-3-ol, colorless crystals, m. 32-3°; 2-methyl-3-(3,7,11,15-tetramethylhexadecyl)-1,4-naphthoquinone, yellow oil, nD20 1.5178; 2-methyl-3-(3-pentadecyl-2-octadecenyl)-1,4-naphthoquinone, yellow oil, nD20 1.5075, max. 249 mμ, ε = 18,900; 3-pentadecyl-1-octadecyn-3-ol, colorless crystals, m. 54-5°; 3-pentadecyl-1-octadecene-3-ol, colorless oil, nD26 1.4523; and the 1,4-naphthoquinones: 2-methyl-3-(cyclohexylidene.ovrddot.ethyl), yellow crystals, m. 63-4°, max. 249 mμ, ε = 18,670; 2-methyl-3-(decahydronaphthylidene.ovrddot.ethyl), yellow oil, nD20 1.5935, max. 249 mμ, 18,500; 2-methyl-3-[5-(2,6,6-trimethyl-1-cyclohexenyl)-3-methyl-2-pentenyl], yellow oil, nD20 1.5723, max. 249 mμ, ε = 18,800; 2-methyl-3-(3-phenylbutenyl), yellow oil, which crystd. after some time, max. 249 mμ, ε = 31,600; 2-methyl-3-(3-phenylbutyl), yellow crystals, m. 107°, max. 248 mμ, ε = 17,900; 2-methyl-3-(3-phenyl-2-propenyl), yellow crystals, m. 124-5°, max. 250 mμ, ε = 35,600; and 2-methyl-3-(3-phenylpropyl), yellow crystals, m. 48°, max. 248 mμ, ε = 18,100.
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    33. 33
      Azerad, R.; Cyrot, M. O. Synthesis of Two Dihydrofarnesylnaphthoquinones Related to Vitamin K2(45)H from Mycobacterium phlei. Bull. Soc. Chim. Fr. 1965, 12, 3740– 3745
      There is no corresponding record for this reference.
    34. 34
      Karrer, P.; Yap, K. S. Über ein weiteres niederes Homologe des α-Tocopherols. Helv. Chim. Acta 1940, 23, 581– 584,  DOI: 10.1002/hlca.19400230177
      There is no corresponding record for this reference.
    35. 35
      Zakharov, A. V.; Vogt, N. Conformational Analysis of Vitamin K1 Model Molecule: A Theoretical Study. Struct. Chem. 2011, 22, 305– 311,  DOI: 10.1007/s11224-010-9706-7
      35
      Conformational analysis of vitamin K1 model molecule: a theoretical study
      Zakharov, Alexander V.; Vogt, Natalja
      Structural Chemistry (2011), 22 (2), 305-311CODEN: STCHES; ISSN:1040-0400. (Springer)
      Isomerism, conformations, and mol. structure of a model mol. of vitamin K1 with a truncated side chain have been studied by the d. functional theory calcns. using B3LYP method and double- and triple-ζ correlation consistent basis sets. The conformations of two possible (E and Z) isomers, formed by the rotations around three single C-C bonds closest to the naphthoquinone ring, have been studied. The lowest energy conformers are stabilized by addnl. hydrogen bonds between hydrogen atoms of the side chain and an oxygen atom in the naphthoquinone subunit. It is interesting to note that the structure of the energetically preferred conformer of the E-isomer (3c) has been found to be similar to the solid state structures of phylloquinones in the photosystem I of cyanobacterium Synechococcus elongatus. The excited electronic states of two lowest energy conformers have also been investigated.
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    36. 36
      Glaziou, P.; Sismanidis, C.; Floyd, K.; Raviglione, M. Global Epidemiology of tuberculosis. Cold Spring Harbor Perspect. Med. 2015, 5, a017798,  DOI: 10.1101/cshperspect.a017798
      There is no corresponding record for this reference.
    37. 37
      Coppa, F.; Fontana, F.; Minisci, F.; Barbosa, M. C. N.; Vismara, E. Homolytic alkylation of naphthoquinone and methyl-naphtoquinone. Enthalpic steric and polar effects. Tetrahedron 1991, 47, 7343– 7352,  DOI: 10.1016/s0040-4020(01)89736-2
      There is no corresponding record for this reference.
    38. 38
      Suhara, Y.; Wada, A.; Tachibana, Y.; Watanabe, M.; Nakamura, K.; Nakagawa, K.; Okano, T. Structure-activity Relationships in the Conversion of Vitamin K Analogues into Menaquinone-4. Substrates Essential to the Synthesis of Menaquinone-4 in Cultured Human Cell Lines. Bioorg. Med. Chem. 2010, 18, 3116– 3124,  DOI: 10.1016/j.bmc.2010.03.035
      There is no corresponding record for this reference.
    39. 39
      Wuttke, S.; Coman, S. M.; Scholz, G.; Kirmse, H.; Vimont, A.; Daturi, M.; Schroeder, S. L. M.; Kemnitz, E. Novel Sol–Gel Synthesis of Acidic MgF2-x(OH)x Materials. Chem.—Eur. J. 2008, 14, 11488– 11499,  DOI: 10.1002/chem.200801702
      39
      Novel sol-gel synthesis of acidic MgF2-x(OH)x materials
      Wuttke, Stefan; Coman, Simona M.; Scholz, Gudrun; Kirmse, Holm; Vimont, Alexandre; Daturi, Maro; Schroeder, Sven L. M.; Kemnitz, Erhard
      Chemistry - A European Journal (2008), 14 (36), 11488-11499CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Novel magnesium fluorides MgF2-x(OH)x have been prepd. by a new fluorolytic sol-gel synthesis for fluoride materials based on aq. HF. By changing the amt. of water at const. stoichiometric amt. of HF, it is possible to tune the surface acidity of the resulting partly hydroxylated magnesium fluorides. These materials possess medium-strength Lewis acid sites and, by increasing the amt. of water, Bronsted acid sites as well. Magnesium hydroxyl groups normally have a basic nature and only with this new synthetic route is it possible to create Bronsted acidic magnesium hydroxyl groups. XRD, MAS NMR, TEM, thermal anal., and elemental anal. have been applied to study the structure, compn., and thermal behavior of the bulk materials. XPS measurements, FTIR with probe mols., and the detn. of N2/Ar adsorption-desorption isotherms have been carried out to investigate the surface properties. Furthermore, activity data have indicated that the tuning of the acidic properties makes these materials versatile catalysts for different classes of reactions, such as the synthesis of (all-rac)-[α]-tocopherol through the condensation of 2,3,6-trimethylhydroquinone (TMHQ) with isophytol (IP).
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    40. 40
      Coman, S. M.; Parvulescu, V. I.; Wuttke, S.; Kemnitz, E. Synthesis of Vitamin K1 and K1-Chromanol by Friedel–Crafts Alkylation in Heterogeneous Catalysis. ChemCatChem 2010, 2, 92– 97,  DOI: 10.1002/cctc.200900205
      There is no corresponding record for this reference.
    41. 41
      Coman, S. M.; Patil, P.; Wuttke, S.; Kemnitz, E. Cyclisation of citronellal over heterogeneous inorganic fluorides-highly chemo- and diastereoselective catalysts for (±)-isopulegol. Chem. Commun. 2009, 460– 462,  DOI: 10.1039/b817572a
      There is no corresponding record for this reference.
    42. 42
      DiMari, S. J.; Rapoport, H. The Reconstitution of Oxidative Phosphorylation in Mycobacterium phlei with cis- and trans-Phylloquinone. Evidence against Isomerization. Biochemistry 1968, 7, 2650– 2652,  DOI: 10.1021/bi00847a030
      42
      The reconstitution of oxidative phosphorylation in Mycobacterium phlei with cis- and trans-phylloquinone. Evidence against isomerization
      DiMari, Samuel J.; Rapoport, Henry
      Biochemistry (1968), 7 (7), 2650-2CODEN: BICHAW; ISSN:0006-2960.
      The interconversion of cis-and transphylloquinones during oxidative phosphorylation by cell-free exts. from M. phlei was studied using phylloquinone-5,6,7,8-t4. Both cis-and trans-phylloquinone restored oxidative phosphorylation to light-inactivated exts., but the cis isomer did so to a distinctly lesser extent. Recovered quinone from test systems to which trans-phylloquinone was added showed no evidence of isomerization. Test systems to which cis-phylloquinone had been added did lead to a small fraction of trans isomer in the recovered quinone, but this was due to exptl. manipulations and not enzymic action. In particular, ordinary lab. light caused cis-trans interconversions.
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    43. 43
      Creed, D.; Werbin, H.; Daniel, T. The Mechanism of Photooxidation of the Menaquinones. Tetrahedron Lett. 1981, 22, 2039– 2042,  DOI: 10.1016/s0040-4039(01)93271-x
      There is no corresponding record for this reference.
    44. 44
      Lowenthal, J.; Chowdhury, M. N. R. Synthesis of Vitamin K1 analogs. A New Class of Vitamin K1 Antagonists. Can. J. Chem. 1970, 48, 3957– 3958,  DOI: 10.1139/v70-662
      There is no corresponding record for this reference.
    45. 45
      Kim, J.; Matsuyama, S.; Suzuki, T. Deuterated Analogues of 4,8-dimethyldecanal, the Aggregation Pheromone of Tribolium castaneum: Synthesis and Pheromonal Activity. J. Labelled Compd. Radiopharm. 2004, 47, 921– 934,  DOI: 10.1002/jlcr.881
      45
      Deuterated analogues of 4,8-dimethyldecanal, the aggregation pheromone of Tribolium castaneum: Synthesis and pheromonal activity
      Kim, Junheon; Matsuyama, Shigeru; Suzuki, Takahisa
      Journal of Labelled Compounds & Radiopharmaceuticals (2004), 47 (13), 921-934CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      To elucidate the deuterium isotope effect (DIE) in pheromonal activity and to investigate the biosynthetic pathway of 4,8-dimethyldecanal (4,8-DMD), the aggregation pheromone of the red flour beetle (Tribolium castaneum), deuterated analogs of 4,8-DMDs, were synthesized and their pheromonal activities tested using a two-hole pitfall olfactometer. Although no apparent DIE was obsd. in their pheromonal activities, 4,8-DMD-1-d1 was less attractive than other analogs, which suggested that the bond distance between the formyl group and its receptor was crit. in pheromone recognition by T. castaneum.
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    46. 46
      Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York, 1967; Vol. 1, pp 581– 595.
      There is no corresponding record for this reference.
    47. 47
      Lerman, L.; Weinstock-Rosin, M.; Nudelman, A. An Improved Synthesis of Hydroxyindoles. Synthesis 2004, 18, 3043– 3046,  DOI: 10.1055/s-2004-834924
      There is no corresponding record for this reference.
    48. 48
      Bennett, C. J.; Caldwell, S. T.; McPhail, D. B.; Morrice, P. C.; Duthie, G. G.; Hartley, R. C. Potential Therapeutic Antioxidants that Combine the Radical Scavenging Ability of Myricetin and the Lipophilic Chain of Vitamin E to Effectively Inhibit Microsomal Lipid Peroxidation. Bioorg. Med. Chem. 2004, 12, 2079– 2098,  DOI: 10.1016/j.bmc.2004.02.031
      48
      Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation
      Bennett, Christopher J.; Caldwell, Stuart T.; McPhail, Donald B.; Morrice, Philip C.; Duthie, Garry G.; Hartley, Richard C.
      Bioorganic & Medicinal Chemistry (2004), 12 (9), 2079-2098CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)
      The flavonol myricetin, reacts with oxygen-centered galvinoxyl radicals 28 times faster than d-α-tocopherol (vitamin E), the main lipid-sol. antioxidant in biol. membranes. Moreover, each myricetin mol. reduces twice as many such radicals as vitamin E. However, myricetin fails to protect vitamin E-deficient microsomes from lipid peroxidn. as assessed by the formation of thiobarbituric acid reactive substances (TBARS). Novel and potentially therapeutic antioxidants have been prepd. that combine the radical-scavenging ability of a myricetin-like head group with a lipophilic chain similar to that of vitamin E. C6-C12 alkyl chains are attached to the A-ring of either a 3,3',4',5'-tetrahydroxyflavone or a 3,2',4',5'-tetrahydroxyflavone head group to give lipophilic flavonoids (ClogP=4 to 10) that markedly inhibit iron-ADP catalyzed oxidn. of microsomal prepns. Orientation of the head group as well as total lipophilicity are important determinants of antioxidant efficacy. MM2 models indicate that our best straight chain 7-alkylflavonoids embed to the same depth in the membrane as vitamin E. The flavonoid head groups are prepd. by aldol condensation followed by Algar-Flynn-Oyamada (AFO) oxidn. or by Baker-Venkataraman rearrangement. The alkyl tails are introduced by Suzuki or Negishi palladium-catalyzed cross-coupling or by cross-metathesis catalyzed by first generation Grubbs catalyst, which tolerate phenolic hydroxyl and ketone groups.
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    49. 49
      Upadhyay, A.; Kumar, S.; Rooker, S. A.; Koehn, J. T.; Crans, D. C.; McNeil, M. R.; Lott, J. S.; Crick, D. C. Mycobacterial MenJ: An Oxidoreductase Involved in Menaquinone Biosynthesis. ACS Chem. Biol. 2018, 13 (9), 2498– 2507,  DOI: 10.1021/acschembio.8b00402
      49
      Mycobacterial MenJ: An Oxidoreductase Involved in Menaquinone Biosynthesis
      Upadhyay, Ashutosh; Kumar, Santosh; Rooker, Steven A.; Koehn, Jordan T.; Crans, Debbie C.; McNeil, Michael R.; Lott, J. Shaun; Crick, Dean C.
      ACS Chemical Biology (2018), 13 (9), 2498-2507CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      MenJ, annotated as a geranylgeranyl reductase, was recently demonstrated to catalyze the redn. (satn.) of a single double bond in the isoprenyl side-chain of mycobacterial menaquinone. This modification was shown to be essential for bacterial survival in J774A.1 macrophage-like cells suggesting that MenJ may be a conditional drug target in Mycobacterium tuberculosis and other pathogenic mycobacteria. Recombinant protein was expressed in a heterologous host and the activity was characterized. Although highly regiospecific in vivo, the activity was not absolutely regiospecific in vitro; in addn., the enzyme was not specific for naphthoquinones vs benzoquinones. Coenzyme Q-1 (a benzoquinone, UQ-1) was used as the lipoquinone substrate and NADH oxidn. was followed spectrophotometrically as the activity readout. NADPH could not be substituted for NADH in the reaction mixt. The enzyme contained a FAD-binding site that was 72% occupied in the purified recombinant protein. Enzyme activity was maximal at 37° and pH 7.0; the addn. of divalent cations, EDTA and reducing agents, such as dithiothreitol, to the reaction mixt. had no effect on activity. The addn. of detergents did not stimulate activity and addn. of satg. levels of FAD had relatively little effect on the obsd. kinetic parameters. These properties allowed the development of a facile assay needed to study this potential drug target, which is also amenable to high throughput screening. The Km for UQ-1 using recombinant MenJ from Mycobacterium smegmatis or M. tuberculosis without satg. concns. of FAD were found to be 52 and 44 μM, resp. while the KmNADH values were detd. to be 59 and 64 μM. The Km for MK-1, the menaquinone analog of UQ-1, using recombinant MenJ from M. tuberculosis without satg. concns. of FAD, but in the presence of 0.5% Tween 80, was shown to be 30 μM. Thus, this is the 1st report of a kinetic characterization of a member of the geranylgeranyl reductase family of enzymes.
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