Structure-cytotoxicity relationship of tilivalline derivatives

Tilivalline (TV) possesses a pyrrolo[1,4]benzodiazepine nucleus and an indole substituent in its structure, and is cytotoxic toward mouse leukemia L1210 cells. In order to obtain more effective compounds, we have previously synthesized a variety of TV analogues. In this study, the cytotoxicity of these compounds has been evaluated. Among the compounds tested, the 11-beta-cyano compound, a TV analogue bearing the cyano group instead of the indole group, is approximately 100 times more cytotoxic than TV itself. The alpha-epimer of this cyano compound has about one-hundredth the cytotoxicity of the 11-beta-cyano compound. Structure-cytotoxicity relationships are discussed, including the effects of stereoisomers (alpha and beta) at the 11 position and substitution at the benzene moiety of TV.