New and bioactive natural products from an endophyte of Panax notoginseng

Five new derivatives of macrolide antibiotic Brefeldin A (BFA, 6), named as Brefeldin E1-E5 (1-5), along with Brefeldin A 7-O-acetate (7), mycotoxins (8-9) and mangrovamides A (10) were produced by an endophytic fungus, Penicillium sp., which was isolated from the healthy root of Panax notoginseng. The structures of 1-5 were established on the basis of their spectroscopic data, while the absolute configurations were assigned using a modified Mosher's method. All compounds were evaluated for their cytotoxic, antiviral and antimicrobial activities. Compounds 1-5 and 8-10 displayed low or moderate cytotoxicity against a panel of cancer cell lines. Compounds 1, 2, 4, 5, and 8-10 showed moderate antimicrobial activity. Compound 6 showed strong anticancer and antiviral properties. Additionally, it demonstrated broad-spectrum activity against human pathogenic bacteria and fungal pathogens that can cause root-rot disease in Panax notoginseng, including Escherichia coli, Staphylococcus aureus, Bacillus cereus, Klebsiella pneumonia, Candida albicans, Fusarium solani, Cylindrocarpon didynum and Alternaria panax. Compound 7, which could be mediated by 6 through the acetylation at the 7-hydroxyl, showed similar bioactivities to compound 6. Further studies of the cellular mechanism of compounds 6 and 7 showed that they arrested HepG2 cells at the S phase. Due to the similarities in the basic carbon skeleton and the chemical construction correlations between compounds 1-7, the plausible biosynthetic pathway of the BFA series of compounds has been proposed and their structure-activity relationships are also discussed.