Journal of Natural Products 最新文献

Six-heptyl-5,6-dihydro-2H-pyran-2-ones and their analogues, named in this work as hyptolactones, are substances that have great antitumor potential because they are structurally related to pironetin, an important natural product with well-established antitumor effects. To investigate the cytotoxic potential and other biological effects of natural hyptolactones, a systematic review was performed according to the PRISMA guidelines. The search was conducted on databases: PubMed Central, ScienceDirect, Scopus and Web of Science. The authors independently evaluated 272 records after insertion into the Rayyan platform, including 61 articles (Cohen’s Kappa: 0.94), which indicated the existence of 72 hyptolactones originating from plants and 14 from fungi. Of these, 58 demonstrated some type of biological activity, the main ones being cytotoxic, antibacterial and antifungal effects. The SYRCLE tool was used to assess the risk of bias in animal studies. As only the α,β-unsaturated δ-lactones were cytotoxic, it is assumed that the biological effects of the hyptolactones are due to the α,β-unsaturated lactone group, also present in pironetin. Despite promising results, there is a lack of data regarding the biological effects of these lactones, especially in vivo models. Thus, scientific evidence of their therapeutic potential motivates more in-depth biological studies, enabling greater expansion of their potential.

The first asymmetric total synthesis of the bisbenzylisoquinoline alkaloids berbamine (1a) and oxyacanthine (1b) has been accomplished by employing Noyori asymmetric hydrogenation for chirality installation and leveraging copper-mediated Ullmann coupling for macrocycle formation. Our synthesis unequivocally confirmed the sample misidentification of 1a, as indicated in our previous work. Evaluation of anti-inflammatory activities revealed that both synthetic and natural berbamine or oxyacanthine comparably suppressed gene expression of pro-inflammatory cytokines IL-6 and IL-1β in LPS-stimulated RAW 264.7 macrophages. Notably, intermediate 15a displayed potent anti-inflammatory activity coupled with minimal cytotoxicity, emerging as a promising lead candidate for the development of novel anti-inflammatory agents.

We describe a bioinspired approach to the synthesis of the sulfur-containing marine pyridoacridine alkaloids kuanoniamine D and shermilamine B. The reaction sequence introduces a biogenic thia-substituent to N-acetyldopamine early in the overall pathway, mimicking the known chemistry of pheomelanin/trichochrome pigment biosynthesis. Subsequent oxidative coupling with kynuramine elaborated the pyridoacridine core, affording the target natural products, spectroscopic data of which were in excellent agreement with those reported for the isolated natural products. The use of mild reaction conditions will enable structure–activity studies of these bioactive alkaloids and open new avenues for the biomimetic synthesis of other structurally related natural products.

We report the divergent total synthesis of marine natural products nocarterphenyl A (1), 2-dehydroxymethylnocarterphenyl A (2), and nocarterphenyl D (3). The thiazole-fused p-terphenyl core was synthesized via Suzuki–Miyaura coupling, and dibrominated precursor 6 was obtained by dibromination of a multisubstituted benzothiazole 7 using NBS/morpholine/HFIP. Nocarterphenyl D (3) was synthesized through palladium-catalyzed dehydrogenation cross-coupling. Biological evaluation revealed that nocarterphenyl A (1) inhibited HCT116 cell proliferation by 71% at 10 μM. Preliminary structure–activity relationships are discussed.

The first total synthesis of one out of four Kikai Island polybrominated C3′–N1 bisindole alkaloids from red alga Laurencia brongniartii is described. The key steps involve both dehydration of trans-hemiaminal and a C2′-methylthiolation of bisindole using dimethyl disulfide through directed metalation, followed by C3-methylthiolation using a N-SMe succinimide reagent.

Integrating genome mining with LC-MS/MS-based molecular networking analysis has revealed that the extract of the endophytic fungus Penicillium sclerotiorum represents a promising source for the discovery of new azaphilone analogues. Two rare polyketide derivatives (1 and 2), along with 11 new sclerotiorin-type azaphilones (3–13) and eight known compounds (14–21), were isolated from the macroalga-associated fungus P. sclerotiorum. The structural elucidation of these compounds was achieved using ECD, HR-ESI-MS, and NMR spectroscopic analyses. The absolute configurations of compounds 1 and 2 were determined through X-ray single-crystal diffraction. The antilymphangiogenic potential of these isolates was assessed in vitro using human lymphatic endothelial cells (LECs). Compounds 4 and 14, both nitrogenated azaphilones, exhibited significant inhibitory activity, displaying IC₅₀ values of 5.7 ± 0.2 and 5.8 ± 0.2 μg/mL, respectively.

Twelve hitherto undescribed cis-decalinoyltetramic acid derivatives (arengasetins A – L), a unique spiro[2.4]heptendione (spiroarengarone) and two benzoquinones (arengaquinones A and B), together with the highly oxygenated polycyclic molecule, epicolactone, were isolated from the palm fungus Leptosporella arengae TBRC-BCC 32590. Chemical structures were determined by extensive analyses of 2D NMR spectroscopic data and chemical means. The absolute configuration of arengasetin A (1) was confirmed by X-ray crystallographic information, while the absolute configurations of other related compounds were corroborated by comparison of NMR spectroscopic data and chemical reactions. The isolated compounds exhibited activity against Plasmodium falciparum (K1, multidrug-resistant strain, IC₅₀ 6.42 – > 38.76 μM), Bacillus cereus (MIC 0.78 – > 50.0 μg/mL), Staphylococcus aureus (MIC 1.56 – > 50.0 μg/mL), and Mycobacterium tuberculosis (MIC 6.25 – > 50.0 μg/mL). Cytotoxicity against both cancerous (MCF-7 and NCI-H187) and noncancerous (Vero) was also reported.

Two novel macrolide hybrids, cladoescherins A and B (1 and 2), and a rare macrolide dimer, dithiocladospolide (3), were identified from cocultures of Cladosporium sp. and Escherichia coli. Compounds 1 and 2 feature a hybrid structural skeleton consisting of a 12-membered macrolide skeleton and a phenolate–thiazole–cysteine moiety. Compound 3 represents a rare example of symmetrical macrocyclic polyketide dimers connected by an intermolecular disulfide bridge. Biosynthetic study revealed that 1 and 2 were derived from the hybridization of the macrolide encoded by a fungal polyketide synthase (PKS) and the siderophore produced by a bacterial nonribosomal peptide synthetase (NRPS) via a spontaneous abiotic reaction. The discovery of cladoescherins reveals an unprecedented nonenzymatic inactivation of an exogenous electrophilic antibiotic by bacterial metabolite.

Hypecoleptopines B–H (1–5, 7, and 8), seven pairs of racemic spiro-benzylisoquinoline alkaloids with a complicated ring system, together with four key biosynthetic precursors (9–12) were isolated from Hypecoum leptocarpum by molecular networking approach. Hypecoleptopines B–H possess a rarely reported 6/6/5/6/6 pentacyclic system with a spirocyclic amide scaffold or fused spironolactone skeleton. Their structures were established by employing a combination of spectroscopic analysis, chiral separation, computational calculations, and X-ray crystal diffraction. The anti-neuroinflammatory effects of all isolates were assessed in lipopolysaccharide (LPS)-stimulated BV-2 microglial model. Remarkably, compounds (+)-11 and (−)-11 demonstrated the most significant inhibition effects with IC₅₀ values of 9.9 and 8.6 μM, compared with the positive control, minocycline (IC₅₀: 25 μM). A further mechanistic study revealed that the two compounds exert the effects by inhibiting the release of inflammatory factors and downregulating iNOS and COX-2 protein expression.

The human sigma-2 receptor/transmembrane protein 97 (σ₂R/TMEM97) has been identified as a promising target to modulate neuronal excitability in chronic pain and address the unmet need for nonopioid therapeutics. We report the chemical and biological characterization of the cyclic depsipeptide, veraguamide E (Ver E), isolated from a Panamanian marine cyanobacterial collection, as a novel σ₂R/TMEM97 ligand and modulator of calcium in neurons. Ver E’s structure was confirmed using 1D and 2D-NMR, HRMS, and MS/MS molecular networking analyses. NMR titration and computational docking confirmed direct, saturable, and tight binding of Ver E to σ₂R/TMEM97. Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca²⁺ levels without modulating store-operated calcium entry (SOCE). Multiwell microelectrode array experiments using human induced pluripotent stem cell (hiPSC) nociceptors showed that Ver E reduced neuronal activity at physiological temperatures, but not under heat-stress. Ver E exhibited no cytotoxicity in HEK293 cells, and immunocytochemistry confirmed it does not alter phosphorylated eIF2α (p-eIF2α) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a nontoxic σ₂R/TMEM97 ligand capable of selectively modulating neuronal excitability, creating a starting point for developing novel pain therapeutics.