A Study of Comparative Chemical and Biological Activities of Alkylating Agents

A method was developed for determining the comparative chemical alkylating activities of various types of nitrogen mustards and aziridines. A series of 10 new and 25 known compounds were studied with respect to their relative alkylating activities, rates of hydrolysis, toxicities, and tumor-inhibitory effects. Results of the chemical studies led to a new mechanistic interpretation of the Sn1- and S\2-type reactions of the aromatic nitrogen mustards; clear distinction between the alternative mechanisms was possible with the aid of the newly synthesized iodo- and "branched-chain" mustards. Comparison of the relative biological activities of the latter compounds with their relative Sn1- and SN2-type reactivities ("% hydrolysis" and "alkylating activity," respectively) indicated that their biologically significant in vivo reactions must follow an Sn1 course. It is suggested that the general structure proposed for the transition state may be helpful in the design of more selective agents.