Isolated Cembranoid Diterpenes From Sarcophyton tenuispiculatum and Semi‑Synthetic Derivatives with Pro‑Apoptotic Activity in Breast Cancer Cells.

The soft coral Sarcophyton tenuispiculatum was investigated for its secondary metabolites, leading to the isolation of four natural isolates, including 7α,8α-epoxy-1(15),3,11-cembratriene-16,2β-olide (1), 2β,16,7α,8α-diEpoxy-1(15),3,11-cembratriene (2), apo-9'-fucoxanthinone (3), and (+)-viridiflorol (4). Semi-synthetic modification of compound 1 produced five new cembranoids: epi-Trochelioid B (5), chlorobenzocembrin (6), benzocembrin (7), nitrobenzocembrin (8), and Trochelioid C (9). Structural elucidation was achieved using extensive spectroscopic analyses, including 1D/2D NMR and HR-ESI-MS. Biological evaluation demonstrated that chlorobenzocembrin (6) exhibited more cytotoxic activity against breast cancer cell lines MCF-7 and MDA-MB-231, inducing apoptosis through ROS accumulation and caspase-6 activation. Acute toxicity studies in mice revealed hepatotoxicity and nephrotoxicity in doses > 250 mg/kg. Preliminary antiproliferative SAR highlights that epoxide ring opening followed by aryl substitution at C‑7 on 7α,8α-epoxy-1(15),3,11-cembratriene-16,2β-olide enhanced cytotoxic activity and suggests that incorporating substituents associated with enhanced cytotoxic activity at the same position may represent a promising strategy for semi‑synthetic optimization of cembranoid scaffolds toward more potent and selective anticancer agents.