Analysis of van der Waals and Electrostatic Contributions in the Interactions of Minor Groove Binding Benzimidazoles with DNA

Interest in cationic benzimidazoles has been stimulated by the extensive use of Hoechst 33258 (1) and analogs as DNA fluorophores and by the fact that bis-benzimidazoles (e.g., 2) have potent activity against a number of microorganisms including those that lead to AIDS-related opportunistic infections. Both 1 and 2 bind to DNA in the minor groove at AT-rich sequences. Interest in the molecular basis for specific minor groove interactions has been stimulated by theoretical studies, by extensive experimental analysis including X-ray studies of complexes, and by the need to develop a broad range of ligands with DNA recognition specificity. The latter idea led to development of "lexitropsins" and to dimer recognition agents. The dimer motif recognizes a sequence-dependent widening of the minor groove and is a dramatic variation on the usual model for binding of unfused aromatic cations. Analysis of DNA complexes of 1, netropsin, and analogs led to debate over the contributions of H-bonding, electrostatic, and van der Waals interactions to minor groove binding affinity and specificity. To design improved drugs that target the minor groove of DNA, it is essential to have a more detailed understanding of such interactions, but it has not been possible to experimentally determine the relative importance of these factors. We have synthesized and evaluated the DNA binding of a series of benzimidazoles, in which the cationic group, the number of charges, and the number of benzimidazole groups have been varied to experimentally address the importance of the factors involved in DNA complex formation.