Six new (1–6), together with seven known (7–13), trichothecenes were isolated from the soil-derived Trichoderma brevicompactum PSU-RSPG27. Their structures were established using spectroscopic data. The structure of 1 was confirmed by X-ray data. Trichodermin (7) exhibited the most potent activity against Plasmodium falciparum (K1 strain) with an IC₅₀ value of 0.1 μM, while other trichothecenes (1, 8, 9, and 12) were much less active, with IC₅₀ values in the range of 7.1–9.6 μM. Compound 7 displayed activity against noncancerous Vero cells with an IC₅₀ value of 0.4 μM. The remaining compounds showed moderate to weak activity, with IC₅₀ values in the range of 6.9–15.3 μM. Compounds 7 and 12 were active against human oral carcinoma (KB) cells with IC₅₀ values of 2.4 and 3.7 μM, respectively. Additionally, compounds 7 and 12 displayed antifungal activity against Candida albicans with the respective MIC values of 1 and 2 μg/mL and were active against Cryptococcus neoformans with equal MIC values of 4 μg/mL.

Seven new bisbibenzyls (1–7) were isolated from the methanol extract of the liverwort Lunularia cruciata along with one previously known bibenzyl and five known bisbibenzyls. The structures of compounds 1–7 were elucidated on the basis of the spectroscopic data. These newly isolated bisbibenzyls may be divided into two groups, the acyclic bisbibenzyls, perrottetins (1–3), and the cyclic analogues, riccardins (4–7). Besides standard perrottetin and riccardin structures (1 and 4, respectively), they contain phenanthrene (3 and 5), dihydrophenanthrene (2), and quinone moieties (6 and 7), rarely found in natural products. The new compounds 3 and 5, as well as the known riccardin G, exhibited cytotoxic activity against the A549 lung cancer cell line with IC₅₀ values of 5.0, 5.0, and 2.5 μM, respectively.

Porcine epidemic diarrhea virus (PEDV), a serious swine epidemic, has been rampant in Asia since the 1990s. Despite the widespread use of PEDV vaccines, the occurrence of PEDV variants requires the discovery of new substances that inhibit these viruses. During a search for PEDV inhibitory materials from natural sources, seven new sabphenosides (1–7) and a new flavonoid (8), as well as eight known phenolic compounds (9–16), were obtained from the leaves of Sabia limoniacea. The structural determination of the new phenolic derivatives (1–8) was accomplished using comprehensive spectroscopic methods. Their absolute configurations were assigned by a combination of the ECD exciton chirality method following selective reduction and calculation of their ECD spectra. The bioactivities of the isolated compounds were measured based on their abilities to inhibit viral replication of PEDV. Among the test compounds, 15 and 16 exhibited the most promising antiviral activities, with IC₅₀ values of 7.5 ± 0.7 μM and 8.0 ± 2.5 μM against PEDV replication. This study suggests that compounds 15 and 16 could serve as new scaffolds for the treatment of PEDV infection through the inhibition of PEDV replication.

Quassinoids are a class of highly oxygenated degraded triterpenoids exclusively discovered from plants of the Simaroubaceae family. In this study, eight new (1–8) and 15 known quassinoids (9–23) were isolated from an extract of the stems of Picrasma quassioides. The structures were elucidated by spectroscopic analysis and electronic circular dichroism spectra combined with quantum chemical calculations. Compounds 4 and 5 represent the first examples of 18-nor-quassinoids from P. quassioides. All isolates were screened for their neuroprotective activities toward H₂O₂-induced cell damage in SH-SY5Y cells. Further study revealed that the potential protective activities of these compounds appeared to occur via the suppression of cell apoptosis and downregulation of caspase-3 activation.

In a phytochemical investigation of the whole plant of Euphorbia glomerulans, 17 new (1–17) and five known jatrophane diterpenoids (18–22) were identified. The X-ray crystallographic data of compounds 1, 4, and 21 permitted the definition of the absolute configurations of these compounds. The cytotoxicity and multidrug resistance reversal activities of the 17 new compounds were evaluated on multidrug-resistant MCF-7/ADR cells overexpressing P-glycoprotein. Several compounds showed different chemoreversal activities and considerably decreased cytotoxicity. Compounds 11 (IC₅₀ value of 5.0 ± 0.8 μM) and 12 (IC₅₀ value of 5.2 ± 2.0 μM) possessed MDR reversal activities that were as good as that of verapamil (IC₅₀ value of 4.7 ± 0.6 μM).

The enantiomers (+)- and (−)-alternarilactone A (1), the first examples of dibenzo-α-pyrones bearing a diepoxy-cage-like moiety, were isolated from the endophytic fungus Alternaria sp. hh930. The deficiency in ¹H–¹H COSY and HMBC correlations caused by the highly oxidized caged system of 1 and the deceptive and ambiguous signals such as “W” couplings in NMR data increased the risk of structure misassignment of 1. By performing a quantum chemical calculation of the NMR chemical shifts together with a DP4+ probability analysis and single-crystal X-ray crystallographic experiment, their structures were unambiguously determined, and their absolute configurations were determined by ECD calculations.

Four new flavonoids (1–4), a new benzyl benzoate derivative (5), five new oxepinones (6–10), and 14 known compounds (11–24) were isolated from the leaf and twig extracts of Desmos cochinchinensis. Their structures were established by spectroscopic methods. The structure of 1 was also confirmed by X-ray diffraction data. The absolute configurations of 3, 4, and 6–10 were determined from comparisons of their ECD spectra with those of relevant reported compounds. Compounds 1, 2, 6, 8, 10, 12–15, and 17 showed α-glucosidase inhibitory activities with IC₅₀ values ranging from 0.2 to 4.9 μM.

The known chalcone (±)-sanjuanolide (1) can be isolated from Dalea frutescens. This study presents a convergent strategy for the first total synthesis of (R)-, (S)-, and (±)-sanjuanolide (1). The key step for synthesizing (R)- and (S)-1 was a Corey–Bakshi–Shibata enantioselective carbonyl reduction to construct the C-2″ configuration. (R)-1 efficiently inhibited the lipopolysaccharides (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), while (S)-1 produced no significant anti-inflammatory effect. (R)-1 also effectively inhibited the mRNA expression of several inflammatory cytokines after the LPS challenge in vitro. The synthesis and biological properties of these compounds have confirmed (R)-sanjuanolide and (±)-sanjuanolide as promising new leads for developing anti-inflammatory agents.

Six new lathyrane diterpenoids (1–6) and 10 known analogues (7–16), were separated from the seeds of Euphorbia lathyris. The absolute configuration of 1 was determined by X-ray crystallography, and the C-2′ configuration of 5 was elucidated by comparing experimental and calculated ECD data. These compounds were studied for their inhibition against nitric oxide (NO) generation induced by lipopolysaccharide in RAW264.7 macrophage cells. Compounds 1–3, 7, 9, 11, 13, 14, and 16 displayed inhibitory effects on NO production, with IC₅₀ values of 2.6–26.0 μM. The new compound 1 (IC₅₀ 3.0 ± 1.1 μM), with no obvious cytotoxicity, was selected for further experiments. The production of cytokines such as IL-6 and IL-1β, as well as the protein expression of iNOS, NF-κB, and phosphorylated IκBα, was reduced by 1 dose-dependently. These results suggested that lathyrane diterpenoids may be used as potential anti-inflammatory agents and are worth being further researched.

Withania somnifera, commonly known as “Indian ginseng” or “ashwagandha”, is popular as a functional food because of its diverse purported therapeutic efficacies including invigorating, improvement of cognitive ability, and stress release activities. Chemical investigation of the MeOH extract of W. somnifera roots combined with LC/MS-based analysis resulted in the identification of six new withanolides, withasilolides A–F (1–6), as well as seven known compounds (7–13). The structures of the new compounds were established by application of spectroscopic methods, including 1D and 2D NMR, HRMS, and ECD measurements. The cytotoxicity of the isolated compounds was evaluated against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15). Compounds 1, 2, 4, 6, and withanone (11) each showed cytotoxicity for one or more of the four cancer cell lines used.

Eight isovaleryllignans (1–4 and 8–11), three isovalerylphenylpropanoids (5–7), three known lignans (12–14), and four known compounds were isolated from an extract of the aerial part of Brachanthemum gobicum. The structures of the isolated compounds were elucidated based on NMR and MS data analyses. The enantiomers of compounds 1–3, 5, 8, and 9 were isolated using chiral-phase HPLC, and the absolute configurations of 1a/1b–3a/3b, 5a/5b, 8a/8b, and 9a/9b were elucidated from their optical rotations and ECD spectra; the other lignans were assumed to be racemic or scalemic by chiral-phase HPLC analyses and optical rotation data. Some of the acylated lignans (racemic mixtures) (1–4, 8, 9, and 12–14) exhibited moderate inhibitory activities against Trypanosoma congolense, the causative agent of nagana disease in animals.

Two new prenylated acylphloroglucinols, paleacenins A (1) and B (2), were isolated from the rhizome n-hexane and chloroform extracts of the fern Elaphoglossum paleaceum. Both compounds were found to possess the same geranylated filicinic acid moiety but have a different phloroglucinol ring substituent. Their structures were determined using ¹H and ¹³C NMR spectroscopic, HRMS, and ECD analysis. The plant extracts and purified compounds were assayed for inhibition of monoamine oxidase (MAO) activity, and the n-hexane and chloroform extracts displayed 25.0% and 26.5% inhibition of MAO-A, respectively, as well as 42.5% and 23.7% inhibition of MAO-B, respectively. Compounds 1 and 2 exhibited IC₅₀ values of 31.0 (1.3) μM for MAO-A and 4.7 (4.4) μM for MAO-B. Paleacenin A (1) showed a higher selective index (SI) toward MAO-B (SI_MAO-B/MAO-A 0.1), and paleacenin B (2) exhibited selectivity to MAO-A (SI_MAO-B/MAO-A, 3.5). The extracts showed cytotoxicity against a panel of prostate, cervix, breast, and colon cancer cell lines (IC₅₀ values between 1.7 and 10.6 μg/mL); the pure compounds were more active against the prostate, cervix, and colon cancer cell lines. Paleacenins A (1) and B (2), with IC₅₀ values of 46 and 41 μM, respectively, inhibited nitric oxide production by the RAW264.7 murine macrophage model.

Six novel aromatic polyketide dimers, bialternacins A–F (1–6), were isolated from a plant endophytic Alternaria sp. The structures of compounds 1–6 were elucidated on the basis of extensive spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism analysis. Compounds 1, 2, 5, and 6 were characterized as four pairs of racemic mixtures. Compound (+)-5 was demonstrated to show acetylcholinesterase inhibitory activity with an IC₅₀ value of 15.5 μM. A putative biosynthetic pathway for these compounds was proposed.

Plants possess an outstanding chemical diversity of specialized metabolites developed to adapt to environmental niches and increase fitness. The observed diversity is hypothesized to result from various evolutionary mechanisms, such as the continuous branching off and extension of existing biosynthetic pathways or enhanced levels of catalytic promiscuity in certain enzymes. In this study, ChemGPS-NP has been employed to chart the distribution and diversity of physicochemical properties for selected types of specialized metabolites from the angiosperms. Utilizing these charts, it is analyzed how different properties of various types of specialized metabolites change in different plant groups, and the chemical diversity from the volume they occupy in chemical property space is evaluated. In this context, possible underlying evolutionary mechanisms are discussed, which could explain the observed distribution and behavior in chemical property space. Based on these studies, it is demonstrated that evolutionary processes in plant specialized metabolism and the resultant metabolic diversification are reflected in chemical property space.

Colletotrichum higginsianum is the causal agent of crucifer anthracnose disease, responsible for important economic losses in Brassica crops. A mutant lacking the CclA subunit of the COMPASS complex was expected to undergo chromatin decondensation and the activation of cryptic secondary metabolite biosynthetic gene clusters. Liquid-state fermentation of the ΔcclA mutant coupled with in situ solid-phase extraction led to the production of three families of compounds, namely, colletorin and colletochlorin derivatives with two new representatives, colletorin D (1) and colletorin D acid (2), the diterpenoid α-pyrone higginsianin family with two new analogues, higginsianin C (3) and 13-epi-higginsianin C (4), and sclerosporide (5) coupling a sclerosporin moiety with dimethoxy inositol.

The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) (7) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate (8), which was derived from (−)-abietic acid (1). Biological comparison was conducted according to the different functional groups, leading to some basic structure–activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10–16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SW1573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species (L. infantum, L. donovani, L. amazonensis, and L. guyanensis). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABA_A receptors (α₁β₂γ_2s) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks.

Organic anion transporters 1 (OAT1) and 3 (OAT3) play important roles in the renal elimination of a range of substrate molecules. Little is known about natural products that can modulate OAT1 and OAT3 activities. The medullae of Juncus effusus is often used for the treatment of dysuria in traditional Chinese medicine. To study the interactions of phytochemicals in J. effusus with human OAT1 and OAT3, a bioactivity guided phytochemical investigation led to seven new phenanthrenoids along with nine known compounds, including eight phenanthrenoids and a benzophenone from the dichloromethane soluble fraction of a methanol extract of the medullae of J. effusus. The structures were established by physical data analysis, including high-resolution electrospray ionization mass spectrometry and 1D and 2D NMR. The compounds were evaluated for inhibition of OAT1 and OAT3 in vitro. Compounds 10 and 16 were inhibitors for OAT1, and compounds 1–3, 10, and 16 were inhibitors for OAT3 with IC₅₀ values less than 5.0 μM. Dihydrophenanthrene 1 markedly altered the pharmacokinetic parameters of the diuretic drug furosemide, a known substrate of both OAT1 and OAT3, in vivo.

A series of functionalized sesquiterpenoids derived from benzocyclooctene, including natural parvifoline (1), isoparvifoline (3), epoxyparvifoline (5), epoxyisoparvifoline (7), 8,12-oxyparfivoline (9), 8,14-oxyparvifoline (11), and the respective benzoyl derivatives 2, 4, 6, 8, 10, and 12, were prepared and tested for their inhibitory effect on the in vitro α,β-tubulin polymerization process. The structural analysis and characterization of the new compounds 5–7 and 9–12 were achieved by 1D and 2D NMR spectroscopy, mass spectrometry, and X-ray diffraction analysis of 6, 7, and 9. Preparation of 9 and 12 involved molecular rearrangements of the epoxide group with transannular 1,5-hydride shifts. At 10 μM compounds 1, 5, and 8 inhibited the polymerization of the α,β-tubulin heterodimer by 24%, 49%, and 90% as compared to colchicine. These compounds were subjected to docking analysis that supported their interactions in a colchicine binding site located in the α-tubulin subunit, in the pocket formed by Phe296, Pro298, Pro307, His309, Tyr312, Lys338, Thr340, Ile341, and Gln342. Competitive inhibition assays with colchicine were also performed for the three compounds, which supported their binding at the colchicine secondary site in α-tubulin. Also, evaluations of their cytotoxicity on MCF7 breast carcinoma, HeLa cervix carcinoma, and HCT 116 colon carcinoma cell lines were carried out and showed that 8 is active against the HeLa and HCT 116 cell lines with IC₅₀ 3.3 ± 0.2 and 5.0 ± 0.5 μM, respectively.

Examination of the EtOH extract of the leaves of the Malayan Tabernaemontana corymbosa resulted in the isolation of four new (1–4) and two known bisindole alkaloids (5, 6) of the Aspidosperma–Aspidosperma type. The structures of these alkaloids were determined based on analysis of the spectroscopic data (NMR and HRESIMS). X-ray diffraction analyses of the related bisindole alkaloids conophylline (5) and conophyllinine (6) established the absolute configurations. Treatment of the bisindole alkaloid conophylline (5) with benzeneselenic anhydride gave, in addition to the known bisindole polyervinine (7) previously isolated from another Malayan Tabernaemontana, another bisindole product, 8, an isolable tautomer of 7. X-ray diffraction analyses yielded the absolute configurations of both bisindoles and in addition showed that polyervinine (7) exists primarily as the neutral dione structure. The bisindoles (1–8) and the related conophylline-type bisindoles (9–13) showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, A549, HT-29, and HCT 116 cells, with IC₅₀ values for the active compounds in the 0.01–5 μM range.

Five new phloroglucinol derivatives, eucalyptins C–G (1–5), together with 13 known analogues (6–18) were isolated from the fruits of Eucalyptus globulus. The structures and absolute configurations of 1–5 were established by means of spectroscopic data analysis, computational calculation methods, and single-crystal X-ray diffraction. Compounds 1–18 were investigated for their immunosuppressive effects in vitro, and 1, 2, 6, and 7 displayed moderate inhibitory activities with IC₅₀ values of 11.8, 10.2, 18.2, and 19.1 μM, respectively. The stimulation index (SI) of 1 was 64.2 and was compared to that of cyclosporine A (SI = 149.57). Further study demonstrated that 1 exhibited an immunosuppressive effect through inducing apoptosis and inhibiting cytokine secretion.

Karamomycins A–C (2–4), the first natural 2-naphthalen-2-yl-thiazole derivatives, were isolated along with a plausible precursor molecule, 1-hydroxy-4-methoxy-2-naphthoic acid (1), uracil, 1-acetyl-β-carboline, and actinomycin C2 from the culture broth of the terrestrial actinomycete strain GW58/450, identified as Nonomuraea endophytica. These compounds were characterized by analysis of their NMR and mass spectrometry (MS) data; the absolute configurations of 2 and 4 were determined by comparison of ¹³C NMR, NOESY, and circular dichroism (CD) spectra with density functional theory (DFT)-calculated data. In karamomycin C (4), the thiazole of 2 is connected to an unusual iminothiazolo[4,3-c][1,4]thiazepinone, for which we proposed a biosynthetic origin from two cysteine residues. It is closely related to ulbactin F; however, the heterocycle is enantiomeric to the latter and connected to phenol instead of 4-methoxy-1-naphthol. Karamomycins A (2) and C (4) were cytotoxic.

ERK is a component of mitogen-activated protein kinases that controls a range of cellular processes including cell proliferation and survival. The upregulation of ERK has been associated with apoptosis inhibition in response to various stimuli including chemotherapeutic agents. Research has suggested that the upregulation of ERK signaling by the anticancer agent paclitaxel leads to acquired resistance of cells to this compound. The presented research focused on determining the role of plumbagin, a naturally derived naphthoquinone, in the sensitization of breast cancer cells to paclitaxel-induced cell death and the involvement of ERK signaling in this process. The results of the study indicated that plumbagin increases the sensitivity of breast cancer cells to paclitaxel. Moreover, a synergistic effect between plumbagin and paclitaxel was observed. Plumbagin was shown to decrease levels of phosphorylated ERK in breast cancer cells and abrogated paclitaxel-induced ERK phosphorylation. The role of ERK in plumbagin-mediated sensitization of breast cancer cells to paclitaxel was shown through the enhancement of the synergistic effect between compounds in cells with decreased ERK expression. Furthermore, plumbagin reduced p-ERK levels in paclitaxel-resistant breast cancer cells and resensitized paclitaxel-resistant cells to this compound. These results imply that plumbagin inhibits ERK activation in breast cancer cells, which plays a role in the sensitization of cells to paclitaxel-induced cell death.

A Rhizopus sp. culture containing an endosymbiont partner (Burkholderia sp.) was obtained through a citizen-science-based soil-collection program. An extract prepared from the pair of organisms exhibited strong inhibition of Ewing sarcoma cells and was selected for bioassay-guided fractionation. This led to the purification of rhizoxin (1), a potent antimitotic agent that inhibited microtubule polymerization, along with several new (2–5) and known (6) analogues of 1. The structures of 2–6 were established using a combination of NMR data analysis, while the configurations of the new stereocenters were determined using ROESY spectroscopy and comparison of GIAO-derived and experimental data for NMR chemical shift and ³J_HH coupling values. Whereas compound 1 showed modest selectivity for Ewing sarcoma cell lines carrying the EWSR1/FLI1 fusion gene, the other compounds were determined to be inactive. Chemically, compound 2 stands out from other rhizoxin analogues because it is the first member of this class that is reported to contain a one-carbon-smaller 15-membered macrolactone system. Through a combination of experimental and computational tests, we determined that 2 is likely formed via an acid-catalyzed Meinwald rearrangement from 1 because of the mild acidic culture environment created by the Rhizopus sp. isolate and its symbiont.

The expedient synthesis of alphitolic acid (1) as well as its natural C-3-epimer and 2-O-ester derivatives was accomplished in a few steps from the readily commercially available betulin (9). A Rubottom oxidation delivered an α-hydroxy group in a stereo- and chemoselective manner. The diastereoselective reduction of the α-hydroxy ketone was key to accessing the 1,2-diol moiety of this class of natural products. Our concise and stereoselective synthetic protocol allowed the gram-scale synthesis of these natural products, which will facilitate future biological evaluations.

Chemical studies of gut bacteria of the carpenter ant Camponotus kiusiuensis led to the discovery of two new alkaloids, camporidines A and B (1 and 2), from Streptomyces sp. STA1. The structures of 1 and 2 were established as new polyketide alkaloids bearing a piperidine–cyclopentene–epoxide 6/5/3 tricyclic system based on NMR spectroscopic and mass spectrometric analysis. The relative configurations of the camporidines were determined by their ¹H–¹H NOESY/ROESY and 1D NOE NMR correlations. The experimental ECD spectra of 1 and 2 were compared with their calculated ECD spectra to assign their absolute configurations. Camporidine A (1) displayed antimetastatic activity by suppression of cell invasion against the metastatic breast cancer cell line MDA-MB-231 and showed an anti-inflammatory effect by suppressing nitric oxide production induced by lipopolysaccharide. In addition, the putative biosynthetic gene cluster of the camporidines was identified, and the biosynthetic pathway of the camporidines was proposed based on bioinformatic analysis of the full genome of Streptomyces sp. STA1. Camporidines A and B (1 and 2) could be biosynthesized by a modular type I PKS containing an acyl transferase domain that accepts an unusual extender unit, which becomes the (C1′–C6′) hexyl side chain. The post-PKS modification enzymes were predicted to perform an amination and an oxidation along with spontaneous Schiff base formation and generate the unique piperidine–cyclopentene–epoxide 6/5/3 tricyclic framework.

Peribysins O (1), P (3), and Q (4) were isolated from Periconia macrospinosa KT3863. The relative configuration of the 6,7-epoxide of 1 was elucidated by performing quantitative NOE experiments. The structure of 2, which is a tautomer of 1 present in CDCl₃ solutions in 5% abundance, was also fully characterized by NMR analysis. Their absolute configurations were independently determined by the modified Mosher’s method (for 1 and 3), the electronic circular dichroism (ECD) exciton coupling theory after conversion into dibenzoate 9 (for 3), and theoretical ECD calculations (for 1, 3, and 4). The obtained relative structures 1, 3, and 4 were verified by calculating their ¹³C chemical shifts using density functional theory (DFT). Although the established (4S)-enantiomer for 1–4 is in accordance with that of other peribysins isolated from the related fungus Periconia byssoides OUPS-N133, Danishefsky’s total synthesis of peribysin E (5) led to the subsequent revision of the (2R,4S,5R,6S,7S,8R,10S)-enantiomer to the (2S,4R,5S,6R,7R,8S,10R)-enantiomer. This discordance led us to reinvestigate the configuration using time-dependent DFT-based ECD spectral calculations, which supported the original (4S)-enantiomer.

Ten new sesquiterpene lactones, carlipsines A–J (1–10), and 12 known analogues (11–22) were isolated from the whole plant of Carpesium lipskyi. Their structures were elucidated by using 1D and 2D NMR and HRESIMS analyses, and their absolute configurations were confirmed by X-ray diffraction studies. All compounds were identified as germacranolides with diverse substructural features. Compounds 1–4 are 2,5-hemiacetal-linked germacranolides. Compounds 5 and 6 possess a 1,2-epoxy moiety. Compounds 7 and 8 represent unusual 1,5-hemiacetal-linked germacranolides. Compounds 9 and 10 contain a tetrahydrofuran unit with the oxygen atom bridging C-1 and C-8. Compounds 6, 7, 8, 19, 20, 21, and 22 showed cytotoxicity against HL-60 and A-549 cell lines with IC₅₀ values ranging from 2.8 to 10.3 μM.

An extract of the plant Anacolosa clarkii was obtained from the NCI Natural Products Repository, and it showed cytotoxic activity toward several types of pediatric solid tumor cell lines. Bioassay-guided fractionation led to the purification of eight new clerodane diterpenes [anacolosins A–F (1–6) and corymbulosins X and Y (7 and 8)] and two known compounds (9 and 10) that contained an isozuelanin skeleton. The structures of the new natural products were determined using 1D and 2D NMR and HRESIMS data, while the relative and absolute configurations of the compounds were assessed using a combination of ¹H NMR coupling constant data, ROESY experiments, ECD (electronic circular dichroism) and VCD (vibrational circular dichroism) spectroscopy, chemical methods (including Mosher and 2-naphthacyl esterification), and chiral HPLC analyses. The purified natural products exhibited a range of cytotoxic activities against cell lines representing four pediatric cancer types (i.e., rhabdomyosarcoma, Ewing sarcoma, medulloblastoma, and hepatoblastoma) with total growth inhibitory (TGI) values in the range 0.2–4.1 μM. The rhabdomyosarcoma and medulloblastoma cell lines showed higher sensitivity to compounds 1–4, which are the first compounds reported to contain an isozuelanin skeleton and feature keto carbonyl groups at the C-6 positions. In contrast, the hepatoblastoma cell line was modestly more sensitive to 7–10, which contained a C-6 hydroxy group moiety.

Tuberculosis is an infectious disease of global concern. Members of the diazaquinomycin (DAQ) class of natural products have shown potent and selective activity against drug-resistant Mycobacterium tuberculosis. However, poor solubility has prevented further development of this compound class. Understanding DAQ biosynthesis may provide a viable route for the generation of derivatives with improved properties. We have sequenced the genomes of two actinomycete bacteria that produce distinct DAQ derivatives. While software tools for automated biosynthetic gene cluster (BGC) prediction failed to detect DAQ BGCs, comparative genomics using MAUVE alignment led to the identification of putative BGCs in the marine Streptomyces sp. F001 and in the freshwater Micromonospora sp. B006. Deletion of the identified daq BGC in strain B006 using CRISPR-Cas9 genome editing abolished DAQ production, providing experimental evidence for BGC assignment. A complete model for DAQ biosynthesis is proposed based on the genes identified. Insufficient knowledge of natural product biosynthesis is one of the major challenges of productive genome mining approaches. The results reported here fill a gap in knowledge regarding the genetic basis for the biosynthesis of DAQ antibiotics. Moreover, identification of the daq BGC shall enable future generations of improved derivatives using biosynthetic methods.

Eight new dimeric sorbicillinoids (1–3, 5–9) and 12 new monomeric sorbicillinoids (10–20, 25), along with five known analogues (4 and 21–24), were isolated from the marine-derived fungus Trichoderma reesei 4670. Their structures were elucidated on the basis of extensive spectroscopic analyses (1D and 2D NMR, HR-ESIMS, and ECD) and X-ray crystallography. Compound 1, containing a pyrrolidin-2-one moiety, is reported for the first time in the sorbicillinoid family. Compounds 8 and 9 are the first examples of bisorbicillinoids possessing a benzofuro[2,3-h]chromene scaffold from a natural source. Compounds 3–11, 13–16, 18, 21, 22, 24, and 25 exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by lipopolysaccharide with IC₅₀ values in the range from 0.94 to 38 μM. Structure–activity relationships of the sorbicillinoids were discussed.

In a screening of Iranian plants for antiprotozoal activity a dichlomethane extract from the aerial parts of Helichrysum oocephalum showed in vitro antiprotozoal activity against Plasmodium falciparum and Leishmania donovani, with IC₅₀ values of 4.01 ± 0.50 and 5.08 ± 0.07 μg/mL, respectively. The activity in the extract was tracked by HPLC-based activity profiling, and subsequent targeted preparative isolation afforded 24 compounds, including pyrones 22–24, phloroglucinol derivatives 12–19, and compounds containing both structural motifs (1–11, 20, and 21). Of these, 15 compounds were new natural products. The in vitro antiprotozoal activity of isolates was determined. Compound 3 showed good potency and selectivity in vitro against L. donovani (IC₅₀ 1.79 ± 0.17 μM; SI 53).

Four new cycloheptapeptides, fuscasins A–D (1–4), were isolated from the marine sponge Phakellia fusca collected from the South China Sea. Their planar structures were fully characterized by spectroscopic methods, and the absolute configurations of amino acid residues were determined using the advanced Marfey’s method. Structurally, 1 is a unique cycloheptapeptide with a backbone bearing a pyrrolidine-2,5-dione unit. Among the isolated compounds, 1 exhibited potent growth-inhibitory activity against HepG2 cells with an IC₅₀ value of 4.6 μM, whereas it did not show apparent inhibitory effects against the other five human cancer cell lines, MCF-7, HeLa, NCI-H460, PC9, and SW480. Encouragingly, 1 exhibited no cytotoxicity against nonmalignant cells even with a concentration up to 100 μM. These findings suggest that 1 may display a selective inhibitory effect on the growth of HepG2 cells.

Aconitum carmichaelii is a traditional Chinese herbal medicine used for the treatment of pain and inflammation in the joints. However, the strong cardiotoxicity hinders its use. Although diester- and monoester-type diterpenoids, e.g., aconitine, mesaconitine, and hypacaonitine, are commonly considered as the toxic components, the toxicity of A. carmichaelii cannot be completely explained by the compounds reported. To investigate further the cardiotoxic compounds and their potential mechanism, the chemical constituents were first isolated by column chromatography and identified using mass spectrometry and NMR spectroscopy. Two new hetisine-type (1 and 2) and four new aconitine-type alkaloids (3–6) were assigned. The cardiac cytotoxicity assessed on H9c2 cells indicated that the new compound 4 as well as six known alkaloids (7 and 9–13) exhibited significant toxicities. A preliminary structure–toxicity relationship study suggested that substitution at C-8 and C-10 both have a significant influence on cardiotoxicity, and such toxicity decreased in the order OBz-8, OBu-8, and OMe-8. The presence of an OH-10 group abolished the toxicity. Finally, it was found that ion channel disorder and induction of mitochondrial-mediated cell apoptosis are the possible mechanisms of cardiotoxicity among the compounds studied.

Identified through a bioinformatics approach, a nonribosomal peptide synthetase gene cluster in Alcanivorax pacificus encodes the biosynthesis of the new siderophore pacifibactin. The structure of pacifibactin differs markedly from the bioinformatic prediction and contains four bidentate metal chelation sites, atypical for siderophores. Genome mining and structural characterization of pacifibactin is reported herein, as well as characterization of pacifibactin variants accessible due to a lack of adenylation domain fidelity during biosynthesis. A spectrophotometric titration of pacifibactin with Fe(III) and ¹³C NMR spectroscopy of the Ga(III)-pacifibactin complex establish 1:1 metal:pacifibactin coordination and reveal which of the bidentate binding groups are coordinated to the metal. The photoreaction of Fe(III)-pacifibactin, resulting from Fe(III) coordination of the β-hydroxyaspartic acid ligands, is reported.

Two new polyketides modified with a rare methylsulfonyl group, 3-methoxy-6-methyl-5-(methylsulfonyl)benzene-1,2,4-triol (1) and neosartoryone A (2), along with a biogenetically related compound (3), were isolated from Neosartorya udagawae HDN13-313 cultivated with the DNA methyltransferase inhibitor 5-azacytidine. The methylsulfonyl group of 1 and 2 was proven to be derived from DMSO, which was used as the solvent to dissolve 5-azacytidine. This is the first report of a fungus that can achieve a sulfonylation-like modification of natural products utilizing DMSO as a sulfur source. Compound 2 showed lipid-lowering activity in vitro comparable to simvastatin.

Imperatorin is one of the furanocoumarin derivatives and exists in many medicinal herbs with anticancer, antiviral, antibacterial, and antihypertensive activities. In this study, we examined the anti-inflammatory effects of imperatorin on inflammation-associated lung diseases. Imperatorin reduced iNOS and COX-2 expression and also IL-6 and TNFα production enhanced by zymosan. Imperatorin also inhibited the signaling pathways of JAK/STAT and NF-κB. Moreover, in vivo study also revealed that zymosan-induced immune cell infiltration, pulmonary fibrosis, and edema were relieved by imperatorin in mice. We found that imperatorin exerts anti-inflammatory effects that are associated with amelioration of lung inflammation, edema, and rapid fibrosis. Studies on alveolar macrophages also reveal that imperatorin reduced the production of pro-inflammatory mediators and cytokines and inhibited pro-inflammatory JAK1/STAT3 and NF-κB signaling pathways. These results indicate that imperatorin may be a potential anti-inflammatory agent for inflammatory-associated lung diseases.

Co-culturing the endophytic fungus Phoma sp. YUD17001 from Gastrodia elata with Armillaria sp. in liquid nutrient medium resulted in the production of five new secondary metabolites, including two phenolic compounds, phexandiols A and B (1 and 2), three aliphatic ester derivatives, phomesters A–C (3–5), and a known fatty acid (6). The structures and absolute configurations of these compounds were elucidated by the interpretation of data from detailed spectroscopic analysis, Mosher’s method, and electronic circular dichroism spectra, together with consideration of the biogenetic origins. None of the five new compounds were detected in single-strain cultures under identical fermentation conditions. The results of this work indicated that the production of 1–5 involved a complicated interaction process. None of the new compounds possessed significant cytotoxicity or antimicrobial activities.

Casein kinase 2 (CK2) is an anti-apoptotic cancer-sustaining protein kinase. Its crystallographic structures with the natural compounds coumestrol, a phytoestrogen, and boldine, an alkaloid, are reported. Coumestrol shows different inhibitory activity against the isolated catalytic α-subunit and the α₂β₂ holoenzyme and is able to discriminate between two conformations of the hinge/αD region, whose intrinsic flexibility is a relevant selectivity determinant among kinases. Boldine explores a small cavity at the bottom of the ATP-binding pocket through a local deviation from planarity, a unique case among CK2 inhibitors. The two compounds have different impacts on protein flexibility, which correlate with their different properties.

A new oxidized xanthene, acrotrione (1), and two known acetophenones (2 and 3) were isolated from a methanol extract of the roots of Acronychia pubescens. The structure of 1 was elucidated on the basis of its (+)-HRESIMS, 2D NMR, and ECD data. Acritrione (1) contains an unusual oxidized furo[2,3-c]xanthene moiety that has not been previously reported. Moderate antiplasmodial activity for these natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum was determined with IC₅₀ values ranging from 1.7 to 4.7 μM.

Three new pyoluteorin analogues, mindapyrroles A–C (1-3), were purified from Pseudomonas aeruginosa strain 1682U.R.0a.27, a gill-associated bacterium isolated from the tissue homogenate of the giant shipworm Kuphus polythalamius. Mindapyrroles B and C inhibit the growth of multiple pathogenic bacteria, with mindapyrrole B (2) showing the most potent antimicrobial activity and widest selectivity index over mammalian cells. Preliminary structure–activity relationship analysis showed that dimerization of the pyoluteorin moiety through a C–C linkage is detrimental to the antimicrobial activity, but addition of an aerugine unit in the methylene bridge is favorable for both the antimicrobial activity and selectivity index.

A highly reducing polyketide synthase gene cluster from the Magnaporthe oryzae genome was previously identified to produce phytotoxic compounds including pyriculol. A homologous gene cluster was found in Neurospora crassa through bioinformatics analysis. Heterologous expression of this cluster led to the production of the salicylic aldehyde sordarial and related intermediates. A series of combinatorial gene expression experiments established the set of enzymes required to produce sordarial and the likely biosynthetic pathway.

Herein, we clarify the structure and relative configurations of two prorocentrolide analogues (1 and 2) isolated from the benthic marine dinoflagellate Prorocentrum lima. The results of NMR spectroscopy show that 1 is prorocentrolide substituted by a hydroxy group at C-4, while the newly isolated compound 2 can be thought of as 1 lacking one ether ring and having one extra double bond. The relative configurations of all stereogenic centers and the configurations of the double bonds in 1 and 2 were determined utilizing ROESY correlations and J-based configuration analysis. Furthermore, 2 was shown to exhibit cytotoxicity against HCT-116 and Neuro-2a cells (IC₅₀ 2.2 and 5.2 μM, respectively.

The structures of the commercially available microginins 674 and 690 isolated from a cultured strain of Microcystis aeruginosa and only recently characterized have been revisited. Using NMR and HRMS/MS data, an inversion of two amino acids, N-methylmethionine and tyrosine, in the structure of these metabolites is unambiguously demonstrated. These results highlight the importance of careful examination of spectroscopic data for the proposition of structures of natural products, especially when they are of commercial value.

The novel N-acyldehydrotyrosine analogues known as thalassotalic acids A–C were isolated from a marine bacterium by Deering et al. in 2016. These molecules were shown to have tyrosinase inhibition activity and thus are an attractive set of molecules for further study and optimization. To this end, a concise and modular synthesis has been devised and executed to produce thalassotalic acids A–C and two unnatural analogues. This synthesis has confirmed the identity and inhibitory data of thalassotalic acids A–C, more potent synthetic analogues (IC₅₀ = 65 μM), and provides a route for further structure–activity relationship studies to optimize these molecules.