Small Structural Changes in Chili-Derived Capsaicin Resulting in Nonivamide Analogs of Significantly Improved Cytotoxicity and Good Tumor/Non-Tumor Cell Selectivity

Capsaicin, the major pungent alkaloid in Capsicum species, has been reported to exhibit cytotoxic activity through various mechanisms. In this study, capsaicin and 37 structurally related vanillylamide and ester analogs were synthesized and evaluated for cytotoxic activity and tumor cell/non-tumor cell selectivity in vitro and compared with a Capsicum baccatum ( Aji mochero ) extract. Seven analogs with superior potency and selectivity compared to capsaicin were identified. Notably, vanillylamides with a C 16 –C 18 chain exhibited IC 50 values five-fold lower than capsaicin (15–84 µM), with selectivity indices up to 35. The extract obtained from the dried chili fruit, known to hold capsaicin as its primary component, however, exhibited significantly lower cytotoxic activity against tumor cells than pure capsaicin. These data demonstrate that even minor modifications to the acyl chain (as exemplified for the nonivamide analogs) can enhance the cytotoxicity and selectivity of these derivatives and that isolated compounds are able to offer even greater efficacy than whole-fruit extracts.