Reversed and sandwiched analogs of duocarmycin SA: establishment of the origin of the sequence-selective alkylation of DNA and new insights into the source of catalysis

The origin of the DNA alkylation selectivity was evaluated through analysis of the reversed and sandwiched analogs of duocarmycin SA. Studies suggested that the ground state destabilization of the substrate disrupted the amide stabilization of the alkylation subunit and increased its reactivity toward nucleophiles. The DNA adenine-thymine minor grove binding mediates the reaction.