Parallel synthesis and evaluation of 132 (+)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and the duocarmycins defining the contribution of the DNA-binding domain

The solution-phase, parallel synthesis and evaluation of a library of 132 ( +)-1,2,9,9a-tetrahydro-cyclopropa[c]benz[e]indol-4-one (CBI) analogues of C C-1065 and the duocarmycins containing dimeric monocyclic, bicyclic, and tr icyclic heteroaromatic replacements for the DNA-binding domain are describe d. This systematic study revealed clear trends in the structural requiremen ts for observation of potent cytotoxic activity and DNA alkylation efficien cy, the range of which spans a magnitude of greater than or equal to 10 000 -fold. Combined with related studies, these results highlight that the role of the DNA-binding domain goes beyond simply providing DNA-binding selecti vity and affinity (10-100-fold enhancement in properties), consistent with the proposal that it contributes significantly to catalysis of the DNA alky lation reaction accounting for as much as an additional 1000-fold enhanceme nt in properties.