| Abstract
| - The solution-phase, parallel synthesis and evaluation of a library of 132 (+)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and the duocarmycins containingdimeric monocyclic, bicyclic, and tricyclic heteroaromatic replacements for the DNA-binding domainare described. This systematic study revealed clear trends in the structural requirements forobservation of potent cytotoxic activity and DNA alkylation efficiency, the range of which spans amagnitude of ≥10 000-fold. Combined with related studies, these results highlight that the role ofthe DNA-binding domain goes beyond simply providing DNA-binding selectivity and affinity (10−100-fold enhancement in properties), consistent with the proposal that it contributes significantlyto catalysis of the DNA alkylation reaction accounting for as much as an additional 1000-foldenhancement in properties.
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