Phenylbenzopyrones structure-activity studies identify betuletol derivatives as potential antitumoral agents

We have analyzed the cytotoxicity of 22 compounds with a phenylbenzo-γ-pirone core structure, most of them obtained from natural sources, in five human tumor cell lines (HL-60, A431, SK-OV-3, HeLa and HOS). Betuletol 3-methyl ether and its diacetate were the most cytotoxic compounds. The HL-60 cell line was especially sensitive to these compounds, with IC50 values of approximately 1 μM. Treatment of HL-60 cells with betuletol 3-methyl ether was associated with apoptosis induction which was prevented by a non-specific caspase inhibitor (z-VAD-fmk) and also by a specific inhibitor of caspase-8 (z-IETD-fmk) indicating activation of the extrinsic apoptotic pathway. The results suggest that betuletol 3-methyl ether has potential as new anticancer agent.