Catalysis of the CC-1065 and duocarmycin DNA alkylation reaction: DNA binding induced conformational change in the agent results in activation

Abstract

A number of indirect observations are summarized that suggest the rate acceleration for the CC-1065 and duocarmycin DNA alkylation reaction is derived in part from a DNA binding-induced conformational change in the agents which substantially increases their inherent reactivity. This ground-state destabilization of the agent, which we suggest results from a binding-induced twist in the linking N2 amide and requires a rigid extended N2 amide substituent, disrupts the vinylogous amide stabilization and activates the agents for DNA alkylation. A number of observations are reviewed that suggest the rate acceleration for the CC-1065 and duocarmycin DNA alkylation reaction is derived in part from a DNA binding-induced conformational change in the agents which increases their inherent reactivity. This activation for DNA alkylation, which requires a rigid extended N2 amide substituent, results from a binding-induced twist in the linking N2 amide which disrupts the vinylogous amide stabilization of the reacting alkylation subunit.