Evaluation of electronic effect of phenyl ring substituents on the DNA minor groove binding properties of novel bis and terbenzimidazoles: synthesis and spectroscopic studies of ligand-DNA interaction.

Several minor groove binding agents (MGBD) were synthesized to study their binding behaviors and sequence specificity with DNA. In order to further understand the binding interactions of the MGBD to DNA, we have synthesized some novel benzimidazoles, which have electron donating (OCH(3), OCH(2)CH(3), OH, O(CH(2))(3)NH(2)) and electron withdrawing cyano groups on the phenyl ring. The interaction of these new benzimidazoles along with parent compounds Hoechst 33342 have been studied with CT DNA, two A-T rich [d(GA(5)T(5)C) and d(CGCA(3)T(3)G)] and one G-C rich [d(GCATGGCCATGC)] oligonucleotide sequences using electrospray ionization mass spectrometry (ESI-MS), absorption, fluorescence, and circular dichroism (CD) spectroscopy. Bisubstituted analogs, which have electron-donating groups, were found to form more stable ligand-DNA complex than Hoechst 33342, while the benzimidazole with electron withdrawing cyano group resulted comparatively in less stable ligand DNA complex. The ESI-MS also gave reliable information about the A-T sequence selectivity as we did not observe any signal with G-C sequence in mass with parent as well as novel ligands. Similar studies with ESI-MS suggest that Hoechst 33342, ETBBZ, and MMBBZ form complexes of 2:1 stoichiometry with d(GA(5)T(5)C) duplex while rest of the ligands form complexes of 1:1 stoichiometry with d(GA(5)T(5)C). Thus, this present study provides the rationalization for the difference in binding behaviors of minor groove binding benzimidazole analogs having different substitution on the phenyl ring.