Determination of the Decomposition of Aspirin

Abstract

Bis(truns-2,3-dimethylaziridinyl)phosphinyl urethan (IV) was synthesized and compared with the corresponding cis-2,3- dimethyl derivative (111). The comparative alkylating activities and rates of hydrolysis of these two stereoisomeric aziridine derivatives, 111 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 (11). The structures of the final hydrolysis products of 111, IV, and V were determined and confirmed by direct synthesis. The results indicate that the mechanisms of hydrolysis of 111, IV, and V (as that of the unsubstituted aziridine derivative, AB-100) are essentially sN2, in contrast to the much faster hy- drolysis of the 2,2-dimethylaziridine analog, AB-132, which in- volves 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. Keyphrases 0 Antineoplastic agents-reaction mechanisms 0 Bis- (trans-2,3-dimethylaziridinyl)phosphinyl urethan-synthesis 0 Alkylating activity-cis-, trans-2,3-dimethylaziridine analogs 0 Hydrolysis mechanism-ring-substituted aziridine derivatives 0 IR spectrophotometry-identity 0 NMR spectroscopy-identity The synthesis of a series of bis( 1-aziridiny1)phosphinyl carbamates, termed “dual antagonists” (I and its analogs containing different carbamate moieties) (1, 2), and their antineoplastic activities in experimental animals (3, 4) and in man (5-9) were previously reported. In an effort to decrease the hematologic toxicity due to the “alkylating” aziridine groups, derivatives were syn- thesized in which the C-atoms of the aziridine rings were substituted with methyl or ethyl groups (10). One member of this new series, ethyl bis(2,Zdimethyl1- aziridiny1)phosphinyl carbamate (AB-132, 11), has been studied to a considerable extent experimentally (1 1) as well as clinically (12-17). Its interesting pharmaco- logic properties [e.g., cholinesterase inhibition (1 8-20)] and its radiation potentiating effect (2 1-23) suggested that this compound may act by a different mechanism than the C-unsubstituted aziridine derivatives (24). This conclusion was supported by chemical studies of its hydrolytic and alkylation reactions (1 1, 25), which in- dicated that the unique properties of I1 may be related to the ability of the 2,2-dimethylaziridine group to participate in S N ~ reactions with its substituted carbon (by forming a tertiary carbonium ion) and, alternatively,