Journal of Natural Products 最新文献

Eight pairs of undescribed trichostatin analogue enantiomers, (±)-karstmycins A–H (1a/1b–8a/8b), and three new enantiomers (9a–11a) together with five known analogues (9b–11b, 12, and 13) were isolated from karst cave-derived Streptomyces sp. DX6D14. The structures and absolute configurations of the new compounds were determined by extensive spectroscopic analysis, as well as nuclear magnetic resonance chemical shifts, optical rotation, and electronic circular dichroism calculations. Compounds 1 and 2 were rare trichostatins featuring a nitrile group, and compounds 3–5 were characterized by a unique piperidin-2-one moiety at the end of the branched C₇ side chain. Compounds 3a and 3b showed PTP1B inhibitory activity with IC₅₀ values of 27 ± 2 and 12 ± 2 μM, respectively, compared to the positive control, sodium orthovanadate (IC₅₀: 14 ± 1 μM). A kinetic study indicated that the most potent compound 3b was a mixed-type inhibitor for PTP1B. Molecular docking simulation revealed that 3b simultaneously interacted with the catalytic site and the peripheral site of PTP1B.

Methicillin-resistant Staphylococcus aureus (MRSA) poses a major clinical threat due to resistance to β-lactam antibiotics, such as cefazolin. Although several conventional antibiotics can be used for the treatment of MRSA, the rapid emergence of resistant strains limits their utility. To address this challenge, we envisioned that a combination therapy using β-lactam potentiators would be a promising approach to expand the application of cefazolin to MRSA. In this study, with our aim to explore natural products that potentiate the β-lactams against clinical MRSA strains, we identified a new atromentin A congener, named atromentin B (1), from the culture broth of Aspergillus sp. FKI-9941. Although our structural analysis revealed the presence of a 2,5-dihydroxycyclohexa-2,5-diene-1,4-dione motif in 1, the inherent ¹³C NMR propensity of this class of compounds made definitive structural confirmation difficult. In addition, its low productivity through fermentation limited detailed biological evaluation. The total synthesis of 1 enabled unambiguous structural determination and provided sufficient information for biological studies. The synthetic sample of 1 exhibited cefazolin potentiation activity comparable to the naturally occurring product. Combination assays demonstrated that 1 enhanced cefazolin activity, even against clinical MRSA isolates. These findings show that atromentin B (1) is a promising β-lactam potentiator.

Chemical investigation of an actinomycete isolated from forest soil near a royal tomb site in the Republic of Korea (Streptomyces sp. YNK18) led to the discovery of two peptides: sadoamides A (1) and B (2). Spectroscopic analysis established 1 and 2 as all-aromatic tripeptides composed of phenylalanine (Phe) and two nonproteinogenic amino acids, 4-hydroxyphenylglycine (Hpg) and β-methyltryptophan (β-MeTrp). The relative configuration of the β-MeTrp residue was determined by J-based configuration analysis utilizing coupling constants and diagnostic ROESY correlations. The absolute configurations of sadoamides were determined using the advanced Marfey’s method. Both compounds effectively inhibited the proteolytic activity of purified proteasomes in vitro and cellular proteasomes in HeLa cells, with 1 exhibiting greater potency. Sadoamide A (1) stabilized the short-lived antiapoptotic protein MCL1 and exerted significant cytoprotective effects against apoptosis-inducing chemical stimuli. These findings identify sadoamides as new microbial peptides that modulate the ubiquitin–proteasome system and highlight the potential of microbial metabolites to regulate critical eukaryotic signaling pathways, including apoptosis.

Insect-associated fungi are prolific producers of peptidic natural products with potent biological activities. Paraisaria is a genus of insect-pathogenic fungi (Family Ophiocordycipitaceae) in the Order Hypocreales, which also includes other Cordyceps-like fungi. Such fungi are increasingly used as functional foods and nutraceuticals, but Paraisaria may also be unintentionally consumed through infected, potentially toxic, edible insects. Here we report the discovery, isolation, and structure elucidation of paraisariamides A–D (1–4) from Paraisaria cascadensis and paraisariamides E–H (5–8) from P. insignis. Total synthesis of 1 and 5–8 was instrumental for comprehensive structure assignment and provided pure compounds for advanced biological testing. The paraisariamide family of N-methylated cyclic heptapeptides has been detected in all Paraisaria specimens analyzed to date from a variety of ecological niches. Paraisariamides A–H (1–8) display differential cell-type specific toxicity to human cancer cells, and we demonstrate that the most cytotoxic paraisariamides E–H (5–8) potently and rapidly inhibit mammalian protein synthesis. Molecular cartography was used to visualize the spatial distribution of paraisariamides in a lyophilized specimen of a beetle larva parasitized by P. insignis. Localization of paraisariamides to the fungal endosclerotium within the host larva is consistent with a role in localized disruption of host protein synthesis.

Six new 36-membered polyol macrolides, kronopolitides A–F (1–6), active against Trypanosoma cruzi were isolated by bioassay-guided fractionation from an extract of the strain Streptomyces kronopolitis CA-143054. Kronopolitides were identified from the screening of microbial natural products libraries using a high-throughput parasite cell-based phenotypic imaging platform targeting identification of new bioactive compounds against the parasites Leishmania donovani and Trypanosoma cruzi. The planar structures were determined using a combination of 1D and 2D NMR data and HRMS. The relative and absolute configuration of their chiral centers was established using a combination of NMR spectroscopy (NOE analysis and coupling constants), the Kishi’s universal NMR database, J-based configuration analysis (JBCA), and comparison with NMR data of structurally related macrolides. Genome sequence mining and bioinformatic analysis of their biosynthetic gene cluster (BGC) have shed light on the polyketide biosynthesis and post-PKS (polyketide synthase) modifications. Kronopolitides have shown potent antiparasitic activity against T. cruzi (IC₅₀ = 0.10–1.49 μM) and moderate to low activity against L. donovani (IC₅₀ = 0.84–9.25 μM) with kronopolitide A being the most potent compound. The presence of a glycosylated 2-methyl-1,4-naphthoquinone/2-methyl-1,4-dihydroxynaphthalene moiety seems to be a key structural element in the biological activity displayed by the compounds.

Grayanotoxin III (GTX III), isolated from Leucothoe grayana Max., was chemically converted into kalmanol, seco-rhodomollone, rhodomollein XXIV, and rhodomollein XXIII in accordance with their proposed biosynthetic hypotheses. The key skeletal rearrangement from the grayanane to the kalmane framework was achieved at low temperature by introducing triflate as the leaving group of the C14 hydroxyl group. Subsequent regio- and stereoselective hydration and global deprotection gave kalmanol in a total of six steps from GTX III. Further conversion to seco-rhodomollone, rhodomollein XXIV, and XXIII demonstrated the putative biosynthetic pathway of these natural products. The present findings establish the route to structurally complex and rare kalmane diterpenoids, which can serve as potential lead compounds for drug discovery and advance the overall understanding of the biogenetic pathway of grayanoids.

We recently discovered and characterized a novel family of peptide toxins, the alpha-nemertides, from the marine ribbon worm Lineus longissimus. These 31-residue peptides show potent neurotoxicity against invertebrate voltage-gated sodium (Na_v) channels, making them promising candidates for biopesticide development. To explore structure–activity relationships, we synthesized 20 nemertide alpha-1 mutants (17 alanine, 3 lysine substitutions) to identify residues critical for activity and selectivity. Key positions, including S12, T17, N19, W22, and F24, were found to influence activity on Na_v channels significantly. Notably, the S12A mutant showed high selectivity for invertebrate Na_vs, suggesting its potential as a selective tool or lead scaffold. Our findings highlight critical interaction points likely to be involved in binding to site 3 of domain IV on Na_v channels and demonstrate how targeted modifications can sharpen selectivity. These insights support the rational design of more selective peptides and identify S12A as a promising candidate for further development as a biopesticide.

Eight new decahydrofluorene-class alkaloids, pyrrospirones R–Y (1–8), together with 13 known analogues (9–21) were isolated from the marine-derived fungal strain Penicillium sp. SCSIO 41512. Their structures were determined by extensive spectroscopic analysis, and their absolute configurations were established by quantum chemical calculations of electronic circular dichroism (ECD) spectra, by a comparison of experimental ECD spectra, or by single-crystal X-ray diffraction analysis. Compound 1 rarely contains an oxime hydroxy with a 6/5/6/5/6/13 polycyclic system. A plausible biosynthetic pathway for 1 and 2 was proposed. Biologically, compounds 1, 4, 6, 8, 10–12, 14–15, 18–19, and 21 had cytotoxicity against human cancer cell lines A549 and HCT116 with IC₅₀ values of 7.3–79.3 μM, and 1, 4, 6, 11, 15, 18, and 21 also showed significant inhibitory activity against six pathogenic bacteria with MIC values of 1.6–13.0 μg/mL. Their structure–bioactivity relationship was also discussed.

Hypericin, a π-rich anthraquinone natural product, exhibits anomalously high triplet yields despite inherently weak spin–orbit coupling. Using long-time-scale molecular dynamics integrated with time-dependent density functional theory calculations, it is demonstrated that early stage supramolecular aggregation modulates hypericin’s excited-state dynamics through vibronic control. Dimerization constrains low-frequency nuclear motions, reducing nonadiabatic couplings and thereby suppressing internal conversion. Concurrently, excitonic redistribution compresses singlet–triplet energy gaps, enabling efficient intersystem crossing in the absence of heavy atoms. Quantitative coupling analysis reveals mixed vibronic–excitonic regimes that account for the experimentally observed enhancement of triplet formation under self-assembly conditions. These findings establish a mechanistic basis for hypericin’s photodynamic activity.