Metal Cation Complexation and Activation of Reversed CPyI Analogues of CC-1065 and Duocarmycin SA:  Partitioning the Effects of Binding and Catalysis

The synthesis and examination of a novel class of reversed CPyI analogues of CC-1065 and the duocarmycins are described. Capable of a unique metal cation activation of DNA alkylation, these agents allowed the effects of the DNA binding domain (10<sup>4</sup>-fold increase in DNA alkylation rate and efficiency) to be partitioned into two components:  that derived from enhanced DNA binding affinity and selectivity (10−80-fold) and that derived from a contribution to catalysis (250−5000-fold). In addition, the reversed enantiomeric selectivity of these sequence selective DNA alkylating agents provides further strong support for a previously disclosed model where it is the noncovalent binding selectivity of the compounds, and not the alkylation subunit or the source of catalysis, that controls the DNA alkylation selectivity.