Theoretical studies employing an ab initio and molecular modeling combination method on the DNA binding of bis-benzimidazoles designed for bioreductive activation.

Ab initio calculations (Hartree-Fock) using the 3-21G and the STO-3G Gaussian basis sets were performed on synthetic analogues of the minor groove binding bis-benzimidazole Hoechst 33258 designed to be subject to bioreductive activation. Such compounds have been shown experimentally to react with DNA to exhibit sequence dependent inhibition of human placental helicase and display significant anticancer properties. Geometry optimized conformations and energies were derived. The binding of the optimized conformations of the drugs to both alternating and non-alternating (AT)n and to (G)n-(C)n sequences were studied. The energetics of reaction at alternative DNA base sites are calculated and compared.