Mechanisms of Reactions of Ring-Substituted Bis(1-aziridinyl) phosphinyl Urethan Antineoplastic Agents

Abstract

Bis(trans-2,3-dimethylaziridinyl)phosphinyl urethan (IV) was synthesized and compared with the corresponding cis-2,3-dimethyl derivative (III). The comparative alkylating activities and rates of hydrolysis of these two stereoisomeric aziridine derivatives, III and IV, were determined and compared with corresponding data for the monomethyl derivative (V) and two other clinically tested members of this series of antineoplastic agents (dual antagonists), AB-100 (I) and AB-132 (II). The structures of the final hydrolysis products of III, IV, and V were determined and confirmed by direct synthesis. The results indicate that the mechanisms of hydrolysis of III, IV, and V (as that of the unsubstituted aziridine derivative, AB-100) are essentially SN2, in contrast to the much faster hydrolysis of the 2,2-dimethylaziridine analog, AB-132, which involves a carbonium-ion mechanism. These studies give further support to the hypothesis that the unique pharmacologic properties of AB-132, as compared to other members of this series, may be related to the unique chemical properties of the 2,2-dimethyl-aziridine moieties.