Synthesis and DNA interactions of benzimidazole dications which have activity against opportunistic infections

Abstract

Considerable evidence now indicates that DNA is the receptor site for dicationic benzimidazole anti-opportunistic infections agents (Bell, C.A.; Dykstra, C.C.; Naiman N.A.I.; Cory, M.; Fairley, T.A.; Tidwell, R.R. Antimicrob. Agents Chemother. 1993, 37, 2668-2673. Tidwell R.R.; Jones, S.K.; Naiman, N.A.; Berger, I.C.; Brake, W.R.; Dykstra, C.C.; Hall, J.E. Antimicrob. Agents Chemother. 1993, 37, 1713-1716). To obtain additional information on benzimidazole-receptor complexes, the syntheses and DNA interactions of series of symmetric benzimidazole cations, linked by alkyl or alkenyl groups, have been evaluated. Biophysical techniques, thermal denaturation measurement (deltaTm), kinetics, and circular dichroism (CD) have been used in conjunction with NMR and molecular modeling to evaluate the affinities, binding mode, and structure of complexes formed between these compounds and DNA. All the compounds bind strongly to DNA samples with four or more consecutive AT base pairs, and they bind negligibly to GC rich DNA or to RNA. Spectral and kinetics characteristics of the benzimidazole complexes indicate that the compounds bind in the DNA minor groove at AT sequences. NMR and molecular modeling of the complex formed between an ethylene-linked benzimidazole derivative, 5, and the self-complementary oligomer d(GCGAATTCGC) have been used to establish structural details for the minor groove complex. These results have been used as a starting point for molecular mechanics calculations to refine the model of the minor groove-benzimidazole complex and to draw conclusions regarding the molecular basis for the effects of substituent changes on benzimidazole-DNA affinities.