Cytotoxic metabolites from the endophytic fungus Penicillium chermesinum: discovery of a cysteine-targeted Michael acceptor as a pharmacophore for fragment-based drug discovery, bioconjugation and click reactions

Abstract

Fungal metabolites (1–8) including known compounds, TMC-264 (1), PR-toxin (6) and a sesquiterpene (7), and new natural products 2–5 and 8, were isolated from the mangrove endophytic fungus Penicillium chermesinum. Compound 2 was a novel tetracyclic polyketide uniquely spiro-attached with a γ-lactone ring. Compounds 1 and 6 exhibited comparable cytotoxic activity to that of doxorubicin, and they selectively exhibited activity toward certain cancer cell lines. The cytotoxicity of 1 might be due to the β-chloro substituted α,β-unsaturated ketone functionality, which was reactive toward glutathione and peptides containing a thiol group. The polyketide 1 reacted with glutathione and peptides under physiological conditions, and its thiol-reactive pharmacophore is possibly applicable to the design of glutathione modulation agents, fragment-based drug discovery (for irreversible enzyme inhibitors), bioconjugation, and click reactions. Facile C–S bond formation in water (catalyst-free conditions) inspired by 1 could also be useful for green chemistry.