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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 of the American Chemical Society

Alkylating Agents, chemical synthesis, chemistry, pharmacology, Animals, Antibiotics, Antineoplastic, Catalysis, DNA, metabolism, Indoles, Kinetics, Leucomycins, Leukemia L1210, drug therapy, Pyrroles, Quinolones, Stereoisomerism

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      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(4)-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.

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