EVALUATION OF THE ELECTROPHILICITY OF DNA-BINDING PYRROLO[2, 1-c][1, 4]BENZODIAZEPINES BY HPLC

Abstract

An HPLC assay is described that can be used to study the covalent bonding interaction of carbinolamine-containing pyrrolo[2, 1-c][1, 4]benzodiazepines with the model nucleophile thiophenol, in order to evaluate electrophilicity at the C-11-position. Preliminary experiments with anthramycin, tomaymycin and neothramycin show that their reaction with thiophenol follows second-order kinetics, but the ranking order of reactivity (neothramycin > tomaymycin > anthramycin), does not correlate with either in vitro cytotoxicity or in vivo antitumour activity. This suggests that other factors such as non-covalent DNA-interaction or drug transport play a more crucial role in biological activity than simple alkylating ability. This assay should, however, prove a useful tool in the study of structure-activity relationships for this series of compounds and provide "C-11-electrophilicity" parameters for use in Hansch analysis and related studies.