Journal of Natural Products 最新文献

A triple mutant (strain KA57) of Streptomyces rochei 7434AN4 produces an azoxy-alkene compound, KA57A, which was not detected in a parent strain or other single and double mutants. This strain accumulated several additional minor components, whose structures were elucidated. HPLC analysis of strain KA57 indicated the presence of two UV active components (KA57D1 and KA57D2) as minor components. They exhibited a maximum UV absorbance at 218 nm, whereas a UV absorbance of azoxy-alkene KA57A was detected at 236 nm, suggesting that both KA57D1 and KA57D2 contain a different chromophore from KA57A. KA57D1 has a molecular formula of C₁₂H₂₂N₂O₂, and NMR analysis revealed KA57D1 is a novel hydrazide-alkene compound, (Z)-N-acetyl-N′-(hex-1-en-1-yl)isobutylhydrazide. Labeling studies indicated that nitrogen Nβ of KA57D1 is derived from l-glutamic acid, and the isobutylamide unit (C-1 to C-3, 2-Me, and Nα) originates from valine. KA57D2 has a molecular formula of C₁₃H₂₄N₂O₂, and its structure was determined to be (Z)-N-acetyl-N′-(hex-1-en-1-yl)-2-methylbutanehydrazide, in which a 2-methylbutanamide unit was shown to originate from isoleucine. Different biogenesis of the Nα atom (l-serine for KA57A, l-valine for KA57D1, and l-isoleucine for KA57D2) indicates the relaxed substrate recognition for nitrogen–nitrogen bond formation in the biosyntheses of KA57A, KA57D1, and KA57D2.

In the present study, a natural product database of compounds associated with herbs traditionally verified to treat gout/hyperuricemia/arthritis was constructed. 3D-shape and docking-based virtual screening was conducted. To identify potential xanthine oxidase (XOD) inhibitors in the database, eight compounds with commercial availability were identified as high 3D-shape similarity with febuxostat (1), a known XOD inhibitor. Docking was used to further predict the possible interactions between XOD and these compounds. Moracin C (2), moracin D (3), and isoformononetin (8) exhibited higher docking scores and binding energies than other compounds. In vitro, 2 inhibited XOD with an IC₅₀ value of 0.25 ± 0.14 μM, which is similar to that of 1 (0.16 ± 0.08 μM). In a hyperuricemic mouse model, 5–20 mg/kg 2 exhibited satisfying urate-lowering and XOD inhibitory effects. Compound 2 also exhibited antiarthritis activities. In RAW264.7 cells, 2 at 1–10 μM inhibited the expression of IL-1β and TNF-α induced by MSU. In an acute gouty arthritis model in SD rats, 5–20 mg/kg 2 significantly alleviated the toe swelling, inflammatory response, and dysfunction disorder caused by monosodium urate (MSU). Compound 2 inhibited serum IL-1β and TNF-α cytokines as well as reduced the expression of the NLRP3/ASC/caspase-1 inflammasome in joints. In summary, 2 was an effective compound for the treatment of hyperuricemia/gouty arthritis.

Six new isoquinoline alkaloids, including aporphine alkaloids (2, 3, 9, and 10), a benzylisoquinoline alkaloid (13), and a protoberberine alkaloid (17), were isolated from the roots of Fissistigma polyanthum, along with a new furanone (20) and 13 known isoquinoline alkaloids (1, 4–8, 11, 12, 14–16, 18, and 19). The structures of the new compounds were elucidated by the analysis of spectroscopic data. Compounds 1 and 2 are rare oxalyl-fused dehydroaporphine alkaloids. Compound 12 presented the most potent dual-target activities on AChE inhibition and Aβ aggregation inhibition, while compounds 13 and 19 simultaneously exhibited discernible AChE and BChE inhibitions with antioxidant activities. The activity results indicate that F. polyanthum alkaloids have a potential of inhibition and prevention of Alzheimer’s disease mainly through both ChEs and β-amyloid pathways in addition to antioxidant activity.

Six new thiazole-containing cyclic peptides, the cyclotheonellazoles D–I (1–6), were isolated from the Australian marine sponge Theonella sp. (2131) with their structures assigned by comprehensive 1D and 2D NMR spectroscopic and MS spectrometric analyses, Marfey’s derivatization studies, and comparison with time-dependent density functional theory (TDDFT) calculated ECD data. The Type 2 azole-homologated peptides herein comprise up to five nonproteinogenic amino acids, including the protease transition state mimic α-keto-β-amino acid residue 3-amino-4-methyl-2-oxohexanoic acid (Amoha), while 1–3 also contain a terminal hydantoin residue not previously found in cyclotheonellazoles. The keramamides A (7) and L (8) were reisolated affording expanded exploration of their biological activities. The peptides were examined for protease inhibitory activities against two mammalian serine proteases (elastase and chymotrypsin) and SARS-CoV-2 3-chymotrypsin-like protease (3CL^pro), a validated antiviral therapeutic target for COVID-19. Peptides 1–6 and keramamide A (7) displayed potent nanomolar inhibition of elastase (IC₅₀ 16.0 to 61.8 nM), while 7 also contained modest inhibition of chymotrypsin and SARS-CoV-2 3CL^pro (IC₅₀ 0.73 and 1.1 μM, respectively). The cyclotheonellazoles D–E (1–3) do not affect the viability of human breast, ovarian, and colon cancer cells (>100 μM), with the cytotoxicity previously reported for keramamide L (8) not replicated (inactive >20 μM).

Ten new norterpene alkaloids, coscinoderines A–J (1–10), were isolated from the marine sponge Coscinoderma bakusi. Each coscinoderine contains a 1,2,5-trisubstituted pyridinium moiety bearing a terpene unit at the C-2 position. Their structures were elucidated by analysis of NMR and HRMS data, and the absolute stereochemistry of 4 with a 2-methylbutyl group attached to the nitrogen was determined from a comparison of the calculated and measured ECD spectra. The isolation of coscinoderines expands the repertoire of pyridinium alkaloids isolated from marine sponges.

Amyloid protein aggregates are linked to the progression of neurodegenerative conditions and may play a role in life stages of Plasmodium falciparum, the parasite responsible for malaria. We hypothesize that amyloid protein aggregation inhibitors may show antiplasmodial activity and vice versa. To test this hypothesis, we screened antiplasmodial active extracts from 25 Australian eucalypt flowers using a binding affinity mass spectrometry assay to identify molecules that bind to the Parkinson’s disease-implicated protein α-syn. Myrtucommulone P (1) from a flower extract of Eucalyptus cloeziana was shown to have α-syn affinity and antiplasmodial activity and to inhibit α-syn aggregation. 1 exists as a mixture of four interconverting rotamers. Assignment of the NMR resonances of all four rotamers allowed us to define the relative configuration, conformations, and ratios of rotamers in solution. Four additional new compounds, cloeziones A–C (2–4) and cloeperoxide (5), along with three known compounds were also isolated from E. cloeziana. The structures of all compounds were elucidated using HRMS and NMR analysis, and the absolute configurations for 2–4 were determined by comparison of TDDFT-calculated and experimental ECD data. Compounds 1–3 displayed antiplasmodial activities between IC₅₀ 6.6 and 16 μM. The α-syn inhibitory and antiplasmodial activity of myrtucommulone P (1) supports the hypothesized link between antiamyloidogenic and antiplasmodial activity.

Dihydroobionin B (1), a chiral congener of known obionin B, was isolated from Pseudocoleophoma sp. KT4119, a freshwater fungus collected from a submerged wood block in Kochi Prefecture, Japan, in 2020. The planar structure of 1 was characterized by mass and NMR spectral analysis and confirmed by density functional theory (DFT)-based chemical shift calculations. Its absolute structure was determined by electronic circular dichroism spectral analysis. Notably, 1 exhibited an extraordinarily large specific rotation [[α]²⁰_D +1080 (c 0.056, CHCl₃)], which was verified by DFT-based specific rotation calculations. However, these calculations indicated that the sign of the specific rotation based on static analysis was insufficient to determine the absolute configuration in this case. Furthermore, Pseudocoleophoma KT4119 produced coleophomapyrones A (2) and B (3) and coleophomaldehyde A (4). While this is the first report of 2 isolated from a natural source, it has also been prepared previously using a synthetic approach. Compound 1 potently inhibited HIV type 1 integrase (IC₅₀ = 0.44 μM) without significant cytotoxicity. Finally, docking experiments were conducted to propose a plausible mechanism for the behavior of 1.

Feature-based molecular networking analysis suggested the presence of naphthol tetramers in Daldinia childae 047219, the same species but a different strain from one used previously for the discovery of naphthol trimers promoting adiponectin synthesis. The new tetramers were composed of 5-methoxy-4-naphthol, each of which was connected to one another in various positions. Targeted isolation afforded six previously unreported naphthol tetramers (1–6) together with 13 known polyketides (7–19) including naphthol monomers, dimers, and trimers. Structures of the isolated compounds were established by using NMR and mass spectroscopic analysis. Nodulisporin A (13), nodulisporin B (14), and 1,1′,3′,3″-ternaphthalene-5,5′,5″-trimethoxy-4,4′,4″-triol (16) demonstrated anti-inflammatory activities against NO production, but the new compounds were less active.

Sixteen new quinolizidine alkaloids (QAs), named ormosianines A–P (1–16), and 18 known congeners (17–34) were isolated from the stems and leaves of Ormosia yunnanensis. The structures were elucidated based on spectroscopic analyses and electron circular dichroism (ECD) calculations. Structurally, ormosianines A (1) and B (2) are the first examples of cytisine and Ormosia-type alkaloids with the cleavage of the piperidine ring. Results of the acetylcholinesterase (AChE) inhibitory assay revealed that the pentacycline Ormosia-type QAs, including 1, 16, 24, and 27–29, are good AChE inhibitors. Ormosianine A (1) exhibited more potent AChE inhibitory activity with an IC₅₀ value of 1.55 μM. Molecular docking revealed that 1 might bind to the protein 1DX4, forming two hydrogen bonds with residues SER-238 and HIS-480.