As part of our ongoing investigation of filamentous fungi for anticancer leads, an active fungal extract was identified from the Mycosynthetix library (MSX 63935; related to Phoma sp.). The initial extract exhibited cytotoxic activity against the H460 (human non-small cell lung carcinoma) and SF268 (human astrocytoma) cell lines and was selected for further study. Bioactvity-directed fractionation yielded resorcylic acid lactones (RALs) 1 (a new natural product) and 3 (a new compound) and the known RALs zeaenol (2), (5E)-7-oxozeaenol (4), (5Z)-7-oxozeaenol (5), and LL-Z1640-1 (6). Reduction of (5E)-7-oxozeaenol (4) with sodium borohydride produced 3, which allowed assignment of the absolute configuration of 3. Other known resorcylic acid lactones (7-12) were purchased and assayed in parallel for cytotoxicity with isolated 1-6 to investigate structure activity relationships in the series. Moreover, the isolated compounds (1-6) were examined for activity in a suite of biological assays, including antibacterial, mitochondria transmembrane potential, and NF-kappa B. In the latter assay, compounds 1 and S displayed sub-micromolar activities that were on par with the positive control, and as such, these compounds may serve as a lead scaffold for future medicinal chemistry studies
Resorcylic Acid Lactones with Cytotoxic and NF-kappa B Inhibitory Activities and Their Structure-Activity Relationships
Ayers, S., Graf, TN., Adcock, A., Kroll, DJ., Matthew, S., de Blanco, EJC., Shen, Q., Swanson, SM., Wani, M., Pearce, CJ., & Oberlies, NH. (2011). Resorcylic Acid Lactones with Cytotoxic and NF-kappa B Inhibitory Activities and Their Structure-Activity Relationships. Journal of Natural Products, 74(5), 1126-1131.