Journal of Natural Products 最新文献

The medically important immunosuppressant FK506 is a structurally complex macrolactone biosynthesized by a combined polyketide synthase and a nonribosomal peptide synthetase enzyme complex. Its acyltransferase domain 4 (AT4) selects an unusual extender unit, resulting in an allyl moiety on carbon 21 of the macrolactone backbone. Based on the AT4 domain, chemobiosynthetic processes have been developed that enable the introduction of diverse moieties at the carbon 21 position. However, the novel moieties that were introduced into the polyketide backbone are chemically inert. Reported here is a novel and efficient chemobiosynthetic approach that ensures high titer of an FK506 analogue containing a propargyl moiety. The novel FK506 analogue displays lower immunosuppression activity than FK506 with significantly reduced cytotoxicity. More importantly, the propargyl moiety contains a terminal alkyl group, which makes click chemistry reactions possible; this approach may potentially be translated to other medically important drugs of polyketide origin.

Halogenation is commonly utilized in medicinal chemistry for the improvement of drug leads. Flavin-dependent halogenases (FDHs) are ubiquitous across all domains of life, yet iterative FDHs are rare in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs). Herein, we characterize a novel iterative FDH, ChlH, which orchestrates nonsequential chlorination of two specific Trp within the core peptide of a lasso precursor containing three Trp. Biochemical and computational studies enable the characterization of ChlH, which employs unique protein-peptide interactions (PPIs) between its distinct N- and C-terminal motifs and a crucial recognition sequence (RS-II) downstream of RS-I in the leader peptide. Previous studies have demonstrated the indispensability of RS-I for lasso peptide biosynthesis, while RS-II was considered to be replaceable. Furthermore, we find that the core peptide substantially contributes to the PPI. Bioinformatic analysis reveals the prevalence of homologous FDHs in the biosynthetic gene clusters (BGCs) of various RiPP classes. Heterologous expression of the chl BGC yields non-, mono-, and dichlorinated lasso peptides, with chlorination, particularly dichlorination, enhancing their antibacterial activity. This study expands the FDH activity spectrum to include iterative catalysis on ribosomal peptides and underscores the significance of RS-II in tailoring enzymes for the combinatorial biosynthesis of lasso peptides.

An in-depth chemical study of the fungus Gymnopus fusipes led to the discovery of two new cyclooctadecapeptides, gymnopeptides C and D, besides the known gymnopeptides A and B. Spectroscopic studies, as well as Marfey's analysis, and molecular modeling studies revealed the characteristic structural features of these cyclopeptides. Gymnopeptides A-D demonstrated antiproliferative activity on the A375 human cancer cell line, induced apoptosis by upregulation of caspase-3 activity, and acted as a suppressor of cell migration.

Camptothecin (CPT) and its derivatives have garnered significant interest due to their potent anticancer activity. In this study, 62 novel CPT derivatives (1a-31a and 1b-31b) were designed and synthesized through Pd-catalyzed late-stage modification at the C-5 position. The anticancer efficacy of these compounds against three human cancer cell lines was evaluated. Compounds 5R-12a (IC₅₀ = 0.05 ± 0.01 μM against HCT-116) and 5R-6a (IC₅₀ = 0.04 ± 0.03 μM against MCF-7) exhibited enhanced antitumor activity when compared to CPT. The preliminary mechanism of apoptosis was investigated through cell viability assays, protein expression, and docking analysis. The results indicated that compounds 12a and 6a exhibited a greater ability to induce apoptosis and G2/M phase arrest than did CPT. Docking results provided a possible explanation for the superior activity of the 5R configuration. This work would offer new insights for CPT lead compound development.

The tropical plant Aglaia perviridis is known to produce cyclopenta[b]benzofuran and other types of rocaglate derivatives including silvestrol (3) and 5‴-episilvestrol (4) that are of current pharmacological interest. In the present work, further investigation of A. perviridis roots collected in Vietnam has yielded two new rocaglate acetonide derivatives (1 and 2) and a known pentanor-3,4-seco-dammarane triterpenoid (7) found for the first time as a natural product, in addition to four known rocaglates (3-6). The structures of compounds 1 and 2 were confirmed by partial synthesis experiments, and their potential occurrence as extraction artifacts was investigated by targeted selective ion monitoring using UHPLC-MS. All compounds obtained were evaluated against a panel of four human cancer cell lines, in which the six rocaglate derivatives (1-6) tested all showed submicromolar potencies.

Four structurally unprecedented tricyclic depsi-tripeptides, ohauamines A-D (1-4), were isolated from the New Zealand endemic ascidian Pycnoclavella kottae. Planar structures were elucidated by extensive use of ¹H-, ¹³C-, and ¹⁵N-based NMR experiments, with absolute configurations established by computational methods.

Twelve guanidine derivatives (1-12), including seven new compounds (martensiiagms A-G, 1-7), one new hypoxanthine derivative (martensiiagm H, 13), and 15 known compounds (14-28) were isolated from the whole body of Buthus martensii Karsch and identified by analysis of data. Subsequent biological evaluations revealed the anti-inflammatory activity of compound 1. It attenuates the neuroinflammation and oxidative stress levels prompted by lipopolysaccharide. This attenuation is accomplished by a specific action on mitochondria, which, in turn, caused a significant decrease in reactive oxygen species and pro-inflammatory cytokines.

Ten new grayanane-derived diterpenoids, rhodomollein LVII-LXVI (1-10), along with the known compound rhodomollein XLIII (11), were isolated from the flowers of Rhododendron molle. Their structures were elucidated by detailed spectroscopic analysis, X-ray diffraction crystallography, and ECD calculations. Rhodomollein LVII-LIX (1-3) are the first-discovered 3-O-(E)-p-coumaroylquinic acid, nicotinic acid, and 2-furoic acid derivatives of grayanane diterpenoids, respectively. In an acetic acid-induced writhing test, compounds 1 and 3 demonstrated significant antinociceptive effects with writhing inhibition rates of 77.2% and 71.5%, respectively, at a dose of 0.2 mg/kg. Compound 1 was found to be twice as potent as morphine, exhibiting significantly lower toxicity (LD₅₀ = 130.90 mg/kg, i.p.) compared to rhodojaponin VI (LD₅₀ = 1.79 mg/kg, i.p.).

Five complex indoline alkaloids, alstolarsines A-E (1-5) possessing two unprecedented carbon skeletons of 6/5/5/7/6/6(5) fused polycyclic systems, were isolated from Alstonia scholaris. Their structures were characterized using various methods including spectroscopic data, ECD spectra, and single-crystal X-ray diffraction. The inhibitory activities of alstolarsines A-D (1-4) on DRAK2 phosphorylation and ATP-citrate lyase were evaluated, but all of them were inactive.

Centella asiatica (L.) Urban (Apiaceae) has been utilized for centuries in traditional medicine systems in Southeast Asia and Southern Africa, including Madagascar. Previous studies have reported evidence of the therapeutic potential of C. asiatica formulations in models of Alzheimer's Disease and other dementias. Caffeoylquinic acids (CQAs) have been identified to be among the pharmacologically relevant metabolites contributing to the botanical's cognitive enhancement and neuroprotective effects. Isomers of CQAs are, however, difficult to differentiate by commonly used LC-MS techniques, making the characterization, standardization, and batch-to-batch consistency of these formulations challenging. Individual CQAs have unique proton Spin Network Fingerprints (pSNFs) that can be used to distinguish between CQA regioisomers within complex extracts. This work describes the development of a CQA-focused pSNF library that can be used to complement LC-MS methods for the accurate metabolite identification and characterization of bioactive C. asiatica fractions and extracts. The isolation of two new (1 and 2) and four known (3-6) CQAs and CQA analogues from C. asiatica and their contribution to the pSNF library are also discussed herein.