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Metal Cation Complexation and Activation of Reversed CPyI Analogues of CC-1065 and Duocarmycin SA: Partitioning the Effects of Binding and Catalysis
journal contribution
posted on 2001-08-30, 00:00 authored by David A. Ellis, Scott E. Wolkenberg, Dale L. BogerThe 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 (104-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.