The alkylating properties of chlorambucil.

Previous work has indicated an aziridinium ion mechanism in the hydrolysis of chlorambucil, and the present work on the alkylation of nucleophiles fully supports this mechanism. This mechanism forms the basis for understanding the kinetics of alkylation reactions because their rates are limited by the rate of formation of the aziridinium ion and the alkylation reaction competes with the hydrolytic reaction. We have measured alpha N, where alpha N(N) is the rate of reaction of the aziridinium ion with a nucleophile N relative to its reaction with water for several nucleophiles that are related to those found in proteins. The alpha values for hydroxide ion and some other bases are greater than 10(3), but the effective values at pH 7.5 are much smaller because there is little base present. The kinetic equations show that it is very difficult to alkylate a nucleophile extensively at pH 7.5 before chlorambucil has hydrolyzed. Therefore, it is not clear why angiotensin-converting enzyme is completely inhibited by low concentrations of chlorambucil. On the other hand, damage to DNA is easily understood.