Journal of Natural Products 最新文献

Prostate cancer is the fifth leading cause of cancer death in men, responsible for over 375,000 deaths in 2020. Novel therapeutic strategies are needed to improve outcomes. Cannabinoids, chemical components of the cannabis plant, are a possible solution. Preclinical evidence demonstrates that cannabinoids can modulate several cancer hallmarks of many tumor types. However, the therapeutic potential of cannabinoids in prostate cancer has not yet been fully explored. The aim of this study was to investigate the antiproliferative and anti-invasive properties of cannabidiol (CBD) in prostate cancer cells in vitro. CBD inhibited cell viability and proliferation, accompanied by reduced expression of key cell cycle proteins, specifically cyclin D3 and cyclin-dependent kinases CDK2, CDK4, and CDK1, and inhibition of AKT phosphorylation. The effects of CBD on cell viability were not blocked by cannabinoid receptor antagonists, a transient receptor potential vanilloid 1 (TRPV1) channel blocker, or an agonist of the G-protein-coupled receptor GPR55, suggesting that CBD acts independently of these targets in prostate cancer cells. Furthermore, CBD reduced the invasiveness of highly metastatic PC-3 cells and increased protein expression of E-cadherin. The ability of CBD to inhibit prostate cancer cell proliferation and invasiveness suggests that CBD may have potential as a future chemotherapeutic agent.

Spinosyn A (SPA), derived from a soil microorganism, Saccharopolyspora spinosa, and its derivative, LM2I, has potential inhibitory effects on a variety of cancer cells. However, the effects of SPA and LM2I in inhibiting the growth of human colorectal cancer cells and the molecular mechanisms underlying these effects are not fully understood. Cell viability was tested by using a 3-(4,5-dimethylthiazol-2-yl-)-2,5-diphenyltetrazolium bromide (MTT) assay and a colony formation assay. On the basis of the IC₅₀ values of SPA and LM2I in seven colorectal cancer (CRC) cell lines, sensitive (HT29 and SW480) and insensitive (SW620 and RKO) cell lines were screened. The GSE2509 and GSE10843 data sets were used to identify 69 differentially expressed genes (DEGs) between sensitive and insensitive cell lines. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein–protein interactions (PPI) were performed to elucidate the molecular mechanisms of the DEGs. The hub gene of the DEGs was detected by Western blot analysis and verified using the CRISPR/Cas9 system. Our data indicate that SPA and its derivative LM2I have significant antiproliferative activity in seven colorectal cancer cell lines and colorectal xenograft tumors. On the basis of bioinformatics analysis, it was demonstrated that epidermal growth factor receptor (EGFR) was the hub gene of the DEGs and was associated with the inhibitory effects of SPA and LM2I in CRC cell lines. The study also revealed that SPA and LM2I inhibited the EGFR pathway in vitro and in vivo.

Nine new ergosteroids (1–9) and seven known ones (10–16) were isolated from Talaromyces adpressus. Their structures and absolute configurations were determined by the interpretation of NMR spectroscopic data, HRESIMS, ECD calculations, and single-crystal X-ray diffraction analyses. Structurally, compound 1 was an ergosteroid with two epoxy and a 3α-OH group at ring A, while compounds 8 and 9 had a contracted ring A with a peroxy bridge between C-3 and C-9, which were reported for the first time. Compounds 2–6, 9, 11, and 15 displayed cytotoxic activities with IC₅₀ values ranging from 0.4 to 32 μM, and compound 7 exhibited an immunosuppressive effect against LPS-induced B lymphocyte proliferation with an IC₅₀ value of 8.6 μM. The structure–activity relationships of these compounds are briefly discussed.

This article describes the structure revision of nine triterpenoids that have been reported corresponding to the same ¹³C NMR data set. In addition, ¹³C NMR calculation shows that some chemical shift assignments must be swapped. Our analysis improves the fit between the experimental and calculated data. Correcting misassigned structures and correctly assigning each signal is essential for elucidating new structurally related compounds. Furthermore, the ambiguity of several compounds, the structure of which differs in the literature and the Sci-Finder database, has been eliminated. Misassigned structures were found by chemical shift searches in NAPROC-13, and the results provide two or more different compounds with the same ¹³C NMR data. The process to determine the correct, most likely structural proposal in agreement with the experimental ¹³C NMR data was carried out by DFT calculations.

The integration of NMR-metabolomic and genomic analyses can provide enhanced identification of structural properties as well as key biosynthetic information, thus achieving the targeted discovery of new natural products. For this purpose, NMR-based metabolomic profiling of the marine-derived Streptomyces sp. S063 (CGMCC 14582) was performed, by which N-methylated peptides possessing unusual negative ¹H NMR chemical shift values were tracked. Meanwhile, genome mining of this strain revealed the presence of an unknown NRPS gene cluster (len) with piperazic-acid-encoding genes (lenE and lenF). Under the guidance of the combined information, two cyclic decapeptides, lenziamides D1 (1) and B1 (2), were isolated from Streptomyces sp. S063, which contains piperazic acids with negative ¹H NMR values. The structures of 1 and 2 were determined by extensive spectroscopic analysis combined with Marfey’s method and ECD calculations. Furthermore, we provided a detailed model of lenziamide (1 and 2) biosynthesis in Streptomyces sp. S063. In the cytotoxicity evaluation, 1 and 2 showed moderate growth inhibition against the human cancer cells HEL, H1975, H1299, and drug-resistant A549–taxol with IC₅₀ values of 8–24 μM.

Fourteen new verticillane diterpenoids, heterolactone (1) and heterolactams A–M (2–14), were isolated from the soft coral Heteroxenia ghardaqensis. They structurally share the same 6/12 bicyclic carbon skeleton that is not commonly encountered in marine organisms. The structures, including the absolute configurations, were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, calculated ECD spectra, and DP4+ probability analyses. Compounds 5, 8, and 9 showed anti-inflammatory activities, and 2, 8, and 12 displayed hepatoprotective activities in zebrafish assays.

Thirty-five diverse polyphenols, belonging to seven structure classes, were isolated from Garcinia gracilis, a medicinal and edible plant sampled from Laos. The structures of nine new compounds, gargarcilones A–I (1–3, 5–7, 10, 12, and 17), were established using spectroscopic, X-ray diffraction, and experimental and calculated ECD methods. Additionally, we revised the stereochemical assignment of cochinchinoxanthone and cochinchinoxanthone C. The compounds were evaluated for antiproliferative activity against five human tumor cell lines (HL-60, A549, SMMC-7721, MDA-MB-231, and SW480). Compounds 1–4, 7, and 8 exhibited cytotoxic activity with IC₅₀ values of 0.5–8.9 μM. Compound 3 significantly induced apoptosis in SMMC-7721 cells.

This review provides a critical analysis of shielding effects induced by an aromatic (indole) ring of small molecules mainly including three members of naturally occurring secondary metabolites asterric acid analogs, diketopiperazines (DKPs) possessing an aromatic or an indole ring, and rubrolides. Empirical rules about the shielding effects induced by an aromatic (indole) ring are classified, based on which some ¹H NMR chemical shift values in the A-ring and structures of asterric acid analogs are revised, and the relative configurations of some DKPs possessing an indole ring are also assigned or revised. The empirical rules could provide an efficient and convenient method for NMR data analysis and configuration determination for the three members of small molecules mentioned above.

High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype. Lack of early detection methods, limited therapeutic agents, and low 5-year survival rate reflect the urgent need to develop new therapies. Eupenifeldin, a bistropolone, originally isolated from Eupenicillium brefeldianum, is a cytotoxic fungal metabolite. In three HSGOC cell lines (OVCAR3, OVCAR5, OVCAR8), eupenifeldin was found to have an IC₅₀ value less than 10 nM, while 10 times higher concentrations were required for cytotoxicity in nontumorigenic fallopian tube secretory epithelial cell lines (FTSEC). An in vivo hollow fiber assay showed significant cytotoxicity in OVCAR3. Eupenifeldin significantly increased Annexin V staining in OVCAR3 and -8, but not OVCAR5. Eupenifeldin activated caspases 3/7 in OVCAR3, OVCAR5, and OVCAR8; however, cleaved PARP was only detected in OVCAR3. Quantitative proteomics performed on OVCAR3 implicated ferroptosis as the most enriched cell death pathway. However, validation experiments did not support ferroptosis as part of the cytotoxic mechanism of eupenifeldin. Autophagic flux and LC3B puncta assays found that eupenifeldin displayed weak autophagic induction in OVCAR3. Inhibition of autophagy by cotreatment with bafilomycin reduced the toxicity of eupenifeldin, supporting the idea that induction of autophagy contributes to the cytotoxic mechanism of eupenifeldin.

Given that the essence of Science is a search for the truth, one might expect that those identifying as scientists would be conscientious and observant of the demands this places on them. However, that expectation is not fulfilled universally as, not too surprisingly, egregious examples of unethical behavior appear and are driven by money, personal ambition, performance pressure, and other incentives. The reproducibility-, fact-, and truth-oriented modus operandi of Science has come to face a variety of challenges. Organized into 11 cases, this article outlines examples of compromised integrity from borderline to blatant unethical behavior that disgrace our profession unnecessarily. Considering technological developments in neural networks/artificial intelligence, a host of factors are identified as impacting Good Ethical Practices. The goal is manifold: to raise awareness and offer perspectives for refocusing on Science and true scientific evidence; to trigger discussion and developments that strengthen ethical behavior; to foster the recognition of the beauty, simplicity, and rewarding nature of scientific integrity; and to highlight the originality of intelligence.