Journal of Natural Products 最新文献

A Tripterygium wilfordii endophyte, Streptomyces sp. CB04723, was shown to produce an unusually highly reduced cytotoxic cinnamoyl lipid, tripmycin A (1). Structure–activity relationship studies revealed that both the cinnamyl moiety and the saturated fatty acid side chain are indispensable to the over 400-fold cytotoxicity improvement of 1 against the triple-negative breast cancer cell line MDA-MB-231 compared to 5-(2-methylphenyl)-4-pentenoic acid (2). Bioinformatical analysis, gene inactivation, and overexpression revealed that Hxs15 most likely acted as an enoyl reductase and was involved with the side chain reduction of 1, which provides a new insight into the biosynthesis of cinnamoyl lipids.

Artemisia annua is the plant that produces artemisinin, an endoperoxide-containing sesquiterpenoid used for the treatment of malaria. A. annua extracts, which contain other bioactive compounds, have been used to treat other diseases, including cancer and COVID-19, the disease caused by the virus SARS-CoV-2. In this study, a methyl ester derivative of arteannuin B was isolated when A. annua leaves were extracted with a 1:1 mixture of methanol and dichloromethane. This methyl ester was thought to be formed from the reaction between arteannuin B and the extracting solvent, which was supported by the fact that arteannuin B underwent 1,2-addition when it was dissolved in deuteromethanol. In contrast, in the presence of N-acetylcysteine methyl ester, a 1,4-addition (thiol-Michael reaction) occurred. Arteannuin B hindered the activity of the SARS CoV-2 main protease (nonstructural protein 5, NSP5), a cysteine protease, through time-dependent inhibition. The active site cysteine residue of NSP5 (cysteine-145) formed a covalent bond with arteannuin B as determined by mass spectrometry. In order to determine whether cysteine adduction by arteannuin B can inhibit the development of cancer cells, similar experiments were performed with caspase-8, the cysteine protease enzyme overexpressed in glioblastoma. Time-dependent inhibition and cysteine adduction assays suggested arteannuin B inhibits caspase-8 and adducts to the active site cysteine residue (cysteine-360), respectively. Overall, these results enhance our understanding of how A. annua possesses antiviral and cytotoxic activities.

Bioassay-guided fractionation of the essential oil of Santalum album led to the identification of α-santalol (1) and β-santalol (2) as new chemotypes of cannabinoid receptor type II (CB₂) ligands with K_i values of 10.49 and 8.19 μM, respectively. Nine structurally new α-santalol derivatives (4a–4h and 5) were synthesized to identify more selective and potent CB₂ ligands. Compound 4e with a piperazine structural moiety demonstrated a K_i value of 0.99 μM against CB₂ receptor and did not show binding activity against cannabinoid receptor type I (CB₁) at 10 μM. Compounds 1, 2, and 4e increased intracellular calcium influx in SH-SY5Y human neuroblastoma cells that were attenuated by CB₂ antagonism or inverse agonism, supporting the results that these compounds are CB₂ agonists. Molecular docking showed that 1 and 4e had similar binding poses, exhibiting a unique interaction with Thr114 within the CB₂ receptor, and that the piperazine structural moiety is required for the binding affinity of 4e. A 200 ns molecular dynamics simulation of CB₂ complexed with 4e confirmed the stability of the complex. This structural insight lays a foundation to further design and synthesize more potent and selective α-santalol-based CB₂ ligands for drug discovery.

Twelve new fungal polyketides, koningiopisins I–P (1–8) and trichoketides C–F (9–12), together with six known congeners (13–18), were isolated from Trichoderma koningiopsis, a rhizosphere fungus obtained from the medicinal plant Polygonum paleaceum. Their structures and absolute configurations were established by spectroscopic analysis, single-crystal X-ray diffraction, the modified Mosher’s method, chemical derivatization, the octant rule, and ¹³C NMR and ECD calculations. Compounds 1–5 are tricyclic polyketides possessing an octahydrochromene framework with a 6,8-dioxabicyclo[3.2.1]octane core. Compounds 7 and 8 contain a unique ketone carbonyl group at C-7 and differ from other members of this group of compounds with the ketone carbonyl group at C-1. Compounds 1, 2, and 13 showed inhibitory activity on LPS-induced BV-2 cells on NO production with IC₅₀ values of 14 ± 1, 3.0 ± 0.5, and 8.9 ± 2.7 μM, respectively.

In our ongoing study of fungal bioactive natural products, 12 previously undescribed triquinane sesquiterpene glycosides, namely, antrodizonatins A–L (1–12), and four known compounds (13–16) have been obtained from the fermentation of the basidiomycete Antrodiella zonata. The structures were established unambiguously via extensive spectroscopic analysis and theoretical calculations of electronic circular dichroism spectra. This is the first report of triquinane sesquiterpene glycosides. Compounds 1, 5, and 12 displayed antibacterial activity against Staphylococcus aureus with MIC₅₀ values of 35, 34, and 69 μM, respectively.

Rapamycin, a well-known macrocyclic natural product with myriad biological activities, has been the subject of intense study since its first isolation and characterization over five decades ago. Rapamycin has been found to adopt a single conformation in the solid state (both when protein bound and uncomplexed) and exists as a mixture of two conformations in solution. Early work established that the major conformer in solution is the trans amide isomer but left the minor conformer mostly uncharacterized. Since that time, it has been widely accepted that the minor conformer of rapamycin is the cis amide, based solely on analogy to FK-506, another potent immunosuppressive compound with some shared key structural elements. To address this long-standing and unresolved question, the solution structure of the minor conformer of rapamycin was investigated using a combination of NMR techniques and computational methods and determined to be a trans amide species with rotation about the ester linkage.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major human pathogen that causes a wide range of infections. Its resistance to β-lactam antibiotics complicates treatment due to the limited number of antibiotics with activity against MRSA. To investigate development of alternative therapeutics, the mechanisms that mediate antibiotic resistance in MRSA need to be fully understood. In this study, MRSA cells were subjected to antibiotic stress from methicillin in combination with three cannabinoid compounds and analyzed using proteomics to assess the changes in physiology. Subjecting MRSA to nonlethal levels of methicillin resulted in an increased production of penicillin-binding protein 2 (PBP2). Exposure to cannabinoids showed antibiotic activity against MRSA, and differential proteomics revealed reduced levels of proteins involved in the energy production as well as PBP2 when used in combination with methicillin.

The saprotrophic filamentous fungus Myrothecium inundatum represents a chemically underexplored ascomycete with a high number of putative biosynthetic gene clusters in its genome. Here, we present new linear lipopeptides from nongenetic gene activation experiments using nutrient and salt variations. Metabolomics studies revealed four myropeptins, and structural analyses by NMR, HRMS, Marfey’s analysis, and ECD assessment for their helical properties established their absolute configuration. A myropeptin biosynthetic gene cluster in the genome was identified. The myropeptins exhibit general nonspecific toxicity against all cancer cell lines in the NCI-60 panel, larval zebrafish with EC₅₀ concentrations of 5–30 μM, and pathogenic bacteria and fungi (MICs of 4–32 μg/mL against multidrug-resistant S. aureus and C. auris). In vitro hemolysis, cell viability, and ionophore assays indicate that the myropeptins target mitochondrial and cellular membranes, inducing cell depolarization and cell death. The toxic activity is modulated by the length of the lipid side chain, which provides valuable insight into their structure–activity relationships.

In the present study, the antiviral activity of cannabinoids isolated from Cannabis sativa L. was assessed in vitro against a panel of SARS-CoV-2 variants, indicating cannabidiolic acid (CBDA) was the most active. To overcome the instability issue of CBDA, its methyl ester was synthesized and tested for the first time for its antiviral activity. CBDA methyl ester showed a neutralizing effect on all the SARS-CoV-2 variants tested with greater activity than the parent compound. Its stability in vitro was confirmed by ultra-high-performance liquid chromatography (UHPLC) analysis coupled with high-resolution mass spectrometry (HRMS). In addition, the capacity of both CBDA and its derivative to interact with the virus spike protein was assessed in silico. These results showed that CBDA methyl ester can be considered as a lead compound to be further developed as a new effective drug against COVID-19 infection.

Cancer is a major disease threatening human health worldwide, among which non-small-cell lung cancer (NSCLC) is the most deadly. Clinically, almost all anticancer drugs eventually fail to consistently benefit patients due to serious drug resistance. AKT is a key effector of the PI3K/AKT/mTOR pathway, which is closely related to the occurrence, development, and drug resistance of tumors. Herein, we first designed and synthesized 20 kinds of novel hybrid molecules targeting both tubulin and AKT based on a podophyllotoxin (PPT) skeleton through computer-aided drug design. By CCK8 assay, we screened the compound D1-1 (IC₅₀ = 0.10 μM) with the strongest inhibitory activity against H1975 cells, and its activity was 100 times higher than PPT (IC₅₀ = 12.56 μM) and 300 times higher than gefitinib (IC₅₀ = 32.15 μM). Affinity analysis results showed that D1-1 not only retained the tubulin targeting of PPT but also showed strong AKT targeting. Subsequent pharmacological experiments showed that D1-1 significantly inhibited the proliferation and metastasis of H1975 cells and slightly induced their apoptosis by inhibiting both tubulin polymerization and the AKT pathway activation. Collectively, these data demonstrate that the novel hybrid molecule D1-1 may be an excellent lead compound for the treatment of human NSCLC as a dual inhibitor of tubulin and AKT.