THE ALKYLATING PROPERTIES OF CHLORAMBUCIL

Previous work has indicated an aziridinium ion mechanism in the hydrol ysis of chlorambucil, and the present work on the alkylation of nucleo philes fully supports this mechanism. This mechanism forms the basis f or understanding the kinetics of alkylation reactions because their ra tes are limited by the rate of formation of the aziridinium ion and th e alkylation reaction competes with the hydrolytic reaction. We have m easured alpha(N), where alpha(N)(N) is the rate of reaction of the azi ridinium 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 th an 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 ve ry difficult to alkylate a nucleophile extensively at pH 7.5 before ch lorambucil has hydrolyzed. Therefore, it is not clear why angiotensin- converting enzyme is completely inhibited by low concentrations of chl orambucil. On the other hand, damage to DNA is easily understood.