Journal of Natural Products 最新文献

Mauritamide B (1a) is a taurine-connected cyclic guanidino-bromopyrrole alkaloid originally isolated from the marine sponge Agelas linnaei. To date, the total synthesis of taurine-connected guanidino-bromopyrrole alkaloids, including this compound, has not yet been reported. Herein, a total synthesis of (±)-mauritamide B (1b) was achieved by oxidation of 2-aminoimidazole of dihydro-sventrin (10) using activated carbon and air in the presence of taurine. The synthetic precursor of 10, 4-(3-aminopropyl)-2-aminoimidazole (22), was synthesized via our original route. The NMR data of the obtained product agreed with that reported for mauritamide B (1a). However, a detailed analysis of the NMR data of synthetic (±)-mauritamide B (1b) including ¹H-¹⁵N HSQC spectrum revealed the need for a structural revision of the reported structure for mauritamide B (1b).

The G-protein coupled bile acid receptor 1 (GPBAR1 or TGR5) is the major cell membrane receptor for bile acids regulating metabolic and immunological functions. Its pharmacological modulation has been shown to alleviate inflammatory diseases, such as type 2 diabetes and atherosclerosis. The naturally occurring lignan leoligin and structural analogues have shown anti-inflammatory effects in vitro. However, the underlying molecular targets are still unknown. In this study, we identify the natural product-inspired synthetic structural analogue of leoligin, LT-188A (1), as a novel nonsteroidal TGR5 agonist. LT-188A (1) induced cyclic adenosine monophosphate (cAMP) accumulation and cAMP response element (CRE)-dependent luciferase activity in a concentration- and TGR5-dependent manner. Consistently, LT-188A (1) inhibited activation of the pro-inflammatory transcription factor nuclear factor κB (NFκB) only in TGR5 expressing cells. In macrophages, LT-188A (1) reduced the expression levels of pro-inflammatory cytokines and the production of nitric oxide (NO) as determined by qPCR and the Griess assay, respectively. We showed that LT-188A (1) decreased the levels of production of these inflammatory mediators in macrophages. In conclusion, we demonstrate that LT-188A (1) is a novel natural product-inspired TGR5 agonist with promising anti-inflammatory in vitro bioactivity in relevant cellular assays representing a promising tool compound with potential for further development.

A novel 19-membered cyclic depsipeptide, hedopeptolide (1), was isolated from Okeania sp., a marine cyanobacterium collected in Okinawa, Japan. Its gross structure was determined by spectroscopic analyses, and the absolute configuration of the chiral centers was determined by single-crystal X-ray diffraction analysis following crystallization. Hedopeptolide (1) inhibited the lipopolysaccharide-induced nitric oxide production in RAW264.7 cells.

The detection and analysis of chiral molecules have long been challenging in analytical chemistry. This study introduces a novel approach that utilizes 2-trifluoromethyl benzaldehyde as a small-molecule probe capable of forming a stable Schiff base with chiral amino acids in aqueous solution under alkaline conditions. The amino acid Schiff bases present a strong Cotton effect and UV absorption at wavelengths exceeding 260 nm, enabling chiral analysis, including assignment of absolute configuration, enantiomeric composition, and total concentration. An application of this method was the authentication of the herbal medicine Ophiopogon japonicus. Using principal component analysis and orthogonal partial least squares discriminant analysis, we successfully differentiated O. japonicus samples collected in two distinct locations with 20 samples. This rapid and convenient method offers a new approach to quality control of herbal medicine.

Fengycin is an antifungal drug that could be used as a biocontrol agent if it could be produced in high amounts. The ComQXPA quorum sensing (QS) system is a natural mechanism, regulating cell density-dependent behaviors in Bacillus subtilis. This study employed the QS-targeted promoter P_srfA to express the pps gene cluster in B. subtilis, coupling the ComQXPA system to produce fengycin. Mutations in the ComA regulatory protein-binding site RE3 exhibited a 2.45-fold increase in promoter expression intensity and resulted in an elevation of fengycin production from 489 to 1832 mg/L, a 2.74-fold enhancement. Transcriptomic analysis revealed the upregulation of genes associated with carbon source uptake and utilization and metabolic pathways related to amino acids and fatty acids, which are precursors for fengycin synthesis. Additionally, knockout of rapJ and rapE increased fengycin production to 3190 mg/L. In a coculture system constructed with Corynebacterium glutamicum, fengycin production reached 4005 mg/L. This work provides a strategy for dynamically regulating fengycin synthesis.

The [3,3] sigmatropic rearrangement of a lathyrane diterpene with various allylic thionoformates was carried out, affording C17-thioloformate-containing lathyrane derivatives (3a-3h) for the first time. The reaction features a mild, rapid, and easy operation. All newly synthesized derivatives were evaluated for potential antiviral activity against HIV-1 and HIV-2. The incorporation of an appropriate thionoformate into the lathyrane diterpene framework enhances their anti-HIV activity. The derivative 3d, featuring an O-(p-tolyl) carbonothionate substitution, exhibited the most potent anti-HIV activity, with an EC₅₀ value of 11.3 μM against HIV-1 NL 4.3 and an EC₅₀ value of 6.6 μM against HIV-2 ROD. Additionally, it demonstrated selectivity indices exceeding 4.0 and 6.8 against HIV-1 NL 4.3 and HIV-2 ROD, respectively.

Six novel dichloromethyl-containing polyketides (1-6), including four pyranone analogs (1-4) and two furanone isomers (5, 6), were isolated from Streptomyces agglomeratus 5-2-6, which was obtained from the Qinghai-Tibet Plateau, China. Additionally, two new linear dichloromethyl compounds (7, 8) were obtained via heterologous expression of agg(A-K) in Streptomyces coelicolor M1152. The structures and absolute configurations of these compounds were primarily elucidated via high-resolution ESIMS, NMR, Mo₂(OAc)₄-induced electronic circular dichroism, and application of the modified Mosher's method. Notably, 1-6 feature a dichloromethyl moiety, which is reported for the first time in pyranone- and furanone-type natural products. Furthermore, the results of in vivo gene deletion, isotope labeling, and in vitro enzyme reaction experiments revealed a rare single-component flavin-dependent halogenase, AggA, which catalyzes the dichlorination of activated sp³-methylene groups.

This study employed structural information from cocrystals of rufomycin 4 (1a) and caseinolytic protein C1 (ClpC1)-NTD-wt to guide design and semisynthesis of rufomycin analogues, evaluate their antituberculosis (TB) biological profiles, and establish structure-activity relationships (SAR). Covering three regions of interest (ROIs, A-C) as modification sites, 14 of the 30 semisynthetic analogues (2-31) showed similar or improved MICs relative to the main natural precursors, rufomycins 4/6 (1a/b). Compounds 5 and 27 exhibited up to 10-fold enhanced potency against Mycobacterium tuberculosis (Mtb) in vitro, with MIC values of 1.9 and 1.4 nM, respectively. Evaluation of ClpC1-binding properties used existing ClpC1-NTD complexes with rufomycin 4 (PDB: 6cn8) and ecumicin (PDB: 6pbs) as references. The newly reported X-ray ClpC1-NTD cocrystal structure of 11 (syn. But4-Cl) revealed significant conformational effects involving the side chains of certain amino acids of the heptapeptide and confirmed the importance of ROIs A-C for medicinal chemistry efforts. Observed interactions of the N-terminal tail of ClpC1 with the rufomycin analogues vs ecumicin explains their different modes of inactivating the ClpC1/P1/P2 homeostatic machinery. Collectively, the observations inform further SAR optimization strategies for the rufomycin class of antibiotics and complement our understanding of their mode of action.

Six new N-alkylpyrrole alkaloids (1–6) were isolated from the marine-derived actinomycete Streptomyces xiamenensis 1310KO-148 from a sponge sample. The structures of xiapyrroles A–F (1–6) were elucidated by detailed analysis of extensive spectroscopic data, including 1D, 2D NMR, and HRESIMS data. The absolute configurations of 2, 3, 4, and 6 were determined by a comparison of their calculated and experimental electronic circular dichroism (ECD) spectra. The position of the hydroxamate group in 6 was confirmed through NO-methylation and NOESY data analysis. All compounds (1–6) were tested for their anti-inflammatory effects in LPS-stimulated RAW 264.7 cells, a mouse macrophage cell line. The treatment of RAW 264.7 cells with 30 μM of 1–6 showed no significant cytotoxic effects. However, 1 dose-dependently suppressed the LPS-induced production of NO (IC₅₀ = 29.5 μM) and interleukin-6 (IL-6) (IC₅₀ = 10.9 μM). Compound 1 exhibited no potential cytotoxicity against six solid cancer cell lines and eight blood cancer cell lines at a concentration of 30 μM.

An investigation of living phosphatic stromatolites from Schoenmakerskop barrage pool near Gqeberha (Port Elizabeth), South Africa, yielded new cyclic octadepsipeptides, amatyemides A (1) and B (2), named using the Xhosa word ‘amatye’ for ‘rock’. The amatyemides were isolated from methanol extracts of a targeted stromatolite sample collection, following an initial metabolomic survey of the Schoenmakerskop pool. Planar structure elucidation of 1 and 2 relied on NMR and LCMS² data, which delineated the same six amino acids and one 2-hydroxy-3-methylpentanoic acid (Hmpa) residues in each compound. The two octadepsipeptides differed only in the presence of a 2-hydroxydodecanoic acid (Hdda) residue in 1 and a 2-hydroxydecanoic acid (Hda) residue in 2. The absolute configurations of most amino acid residues in 1 were determined using an enhanced Marfey’s reagent. The configurations of the 2-hydroxy acids and O-methylthreonine were assigned, and the absolute structures of amatyemides A (1) and B (2) were confirmed, by total solid-phase peptide synthesis of two possible diastereomers for each natural product. Biological testing of natural and synthetic amatyemides against human U87-MG glioblastoma, HCT116 colon, and SH-SY5Y neuroblastoma cells revealed weak, cell-type specific, cytotoxic potential where 2 > 1, and this was attributed to induction of oxidative stress by 2.