The DNA minor groove continues to be an important biological target in the development of anticancer, antiviral, and antimicrobial compounds. Among agents that target the minor groove, studies of benzimidazole-based DNA binders such as Hoechst 33258 have made it clear that the benzimidazole-amidine portion of these molecules promotes an efficient, site-selective DNA association. Building on the beneficial attributes of existing benzimidazole-based DNA binding agents, we have synthesized a series of benzimidazole-amino acid conjugates to permit investigation of their DNA recognition and binding properties. In this series of compounds, the benzimidazole-amidine moiety is being utilized as the core DNA �anchoring� element accompanied by different amino acids to provide structural diversity that may influence DNA binding affinity and site-selectivity. Accordingly, single amino acid conjugates of benzimidazole-amidines were synthesized with all 20 naturally-occurring amino acids, as well as dipeptide conjugates of the general form R-Gly-Xaa (where R is the benzimidazole-amidine and Xaa is any amino acid). All conjugates were synthesized through a solid-phase synthetic route. Building from a resin-bound amino acid (or dipeptide): (1) 4-formyl benzoic acid was coupled to the resin-bound amino acid (via N,N�-diisopropylcarbodiimide and hydroxybenzotriazole) followed by (2) introduction of a 3,4-diamino-N'-hydroxybenzimidamide (in the presence of 1,4-benzoquinone) to construct the benzimidazole ring; and, finally, (3) the resin-bound amidoxime functionality was reduced to an amidine via 1M SnCl2�2H2O in DMF before resin cleavage. As will be reported, the DNA binding activities of these compounds were analyzed and compared using a fluorescent intercalator displacement (FID) assay.

Design, synthesis, and study of DNA-targeted benzimidazole-amino acid conjugates

246th National Meeting (2013)

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