To design compounds that can selectively target DNA and induce specific biological responses is a key goal of chemical biology. It offers many advantages such as specific control of cellular gene expression, development of new types of drugs, and agents for biotechnology. Most common minor groove binders from the natural products, netropsin and distamycin, to synthetic compounds, Hoechst 33258, pentamidine and related compounds, bind specifically to AT base pairs but weakly to GC sites. Based on extensive experience with minor groove agents for AT recognition, we have incorporated GC recognition motifs into compounds designed for mixed-base-pair recognition. A novel series of heterocyclic cations containing an azabenzimidazole ring has been synthesized in order to investigate both their sequence specificity and binding mode.The binding of the compounds was investigated by thermal melting, circular dichroism (CD), biosensor surface plasmon resonance (SPR) and molecular modeling studies. Compounds, bearing one or two azabenzimidazole-OCH2-phenyl-amidine motifs, which could recognize a G base in a GC base pairs in an AT context, stand out as the most promising compounds. They bind strongly and selectively with the AAAGTTT and AAGAAATTGAA sequences, respectively. More importantly, this study opens new methods for the mixed-base-pair DNA sequences recognition. (supported by NIH grant AI064200)

Design and synthesis of novel heterocyclic diamidines for specific DNA recognition: From AT-rich to mixed-base-pair DNA sequences

247th National Meeting (2014)

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