Structural and biological insights into obscurolides: obscurolide A2 induces apoptosis in prostate cancer cells.

We isolated and characterised seven obscurolides: obscurolide A2 (1), B2α (2), B2β(3), A1 (4), streptalbonin G (5), streptalbonin F (6), and (3 R)-obscurolide A (7), from Streptomyces chartreusis SA-7, a soil actinomycete from the Northwestern Himalayas, India. Preliminary screening revealed that obscurolide A2 (1) exhibited better cytotoxicity against prostate cancer (PC-3) cells (IC50: 12.16 ± 2.12 μM). Mechanistic studies confirmed that A2 (1) significantly inhibits PC-3 cells' clonogenic formation and induces mitochondrial-mediated apoptosis via modulation of Bax/Bcl-2 and caspase 3 expression. Structure-activity relationship (SAR) analysis identified the C-4' aldehydic substituent and the intact γ-butyrolactone core (GBL) as key pharmacophores for cytotoxicity. This study provides the first mechanistic evidence of the anticancer potential of obscurolides, highlighting A2 (1) as a promising GBL scaffold for further preclinical investigation.