| Abstract
| - Considerable evidence now indicates that DNA is the receptor sitefor dicationic benzimidazoleanti-opportunistic infections agents (Bell, C. A.; Dykstra, C. C.;Naiman, N. A. I.; Cory, M.;Fairley, T. A.; Tidwell, R. R.Antimicrob. AgentsChemother. 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 onbenzimidazole−receptor complexes, the syntheses and DNA interactions of series ofsymmetric benzimidazolecations, linked by alkyl or alkenyl groups, have been evaluated.Biophysical techniques, thermaldenaturation measurement (ΔTm), kinetics, andcircular dichroism (CD) have been used inconjunction with NMR and molecular modeling to evaluate the affinities,binding mode, andstructure of complexes formed between these compounds and DNA. Allof the compounds bindstrongly to DNA samples with four or more consecutive AT base pairs,and they bind negligiblyto GC rich DNA or to RNA. Spectral and kinetics characteristics ofthe benzimidazole complexesindicate that the compounds bind in the DNA minor groove at ATsequences. NMR andmolecular modeling of the complex formed between an ethylene-linkedbenzimidazole derivative,5, and the self-complementary oligomer d(GCGAATTCGC) havebeen used to establishstructural details for the minor groove complex. These resultshave been used as a startingpoint for molecular mechanics calculations to refine the model of theminor groove−benzimidazole complex and to draw conclusions regarding the molecularbasis for the effectsof substituent changes on benzimidazole−DNA affinities.
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