AB-100

The chemical alkylating activities of four prototype phosphoraziridine antineoplastic agents were compared with their biological effects on V-79 Chinese hamster lung fibroblasts. It was found that the chemical reactivity patterns correlate well with all of the biological parameters examined in this study, i.e. cytotoxicity, DNA synthesis, and production of alkali labile strand breaks. Specifically, the 2,2-dimethylaziridine derivatives (AB-132 and AB-163) showed higher initial activities reaching a plateau after a short reaction time in all of the systems used in this study while the unsubstituted aziridine derivatives (AB-100 and D-63) reacted more slowly but continued to exert their action in a linear fashion to produce greater overall effects. These findings are consistent with the conclusion that the difference between the time-dependent biological activities of these drugs closely follows the different chemical mechanisms of their alkylating reactions (SN1 vs SN2). The more rapid action and subsequent hydrolytic inactivation of the 2,2-dimethylphosphoraziridines as effective alkylators could be the basis of their lower hemopoietic toxicity compared to conventional alkylating agents including their own C-unsubstituted aziridine analogs. The much more rapid action of the 2,2-dimethylphosphoraziridines on DNA inside the cell may have some bearing on their radiation potentiating activity, but this aspect and the cholinesterase inhibitory activity of these agents (which may depend on phosphorylation) were not investigated in the present study.

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