Synthesis of analogs of 5-[2-(5-amidinobenzimidazoyl)]-2-(4-amidinophenyl)furan hydrochloride to test a DNA minor groove dimer binding model

Organic dications that bind to the DNA minor groove have biological activities that range from effectiveness against opportunistic infections to anticancer properties. They also serve as important models in the study of nucleic acid-small molecule interactions.; Biophysical studies of 2,5-bis(4-amidinophenyl)furan (furamidine) indicate that factors such as electrostatic, hydrogen bonding, and van der Waals interactions as well the radius of curvature of the molecule are important contributors to the minor groove binding affinity of this type of dication. Based on these studies and with the goal to increase the overall efficacy, decrease toxicity, and improve the minor groove affinity, our laboratory synthesized derivatives of furamidine with extended aromatic ring systems.; 5-[2-(5-Amidinobenzimidazoyl)]-2-(4-amidinophenyl)furan hydrochloride (DB293) (where one of the phenyl rings has been replaced by benzimidazole in reference to furamidine) was synthesized and studied. Footprinting experiments identified an unusual mode of interaction of DB293 with GC sequences. NMR and surface plasmon resonance studies indicate that two DB293 molecules bind as a side-by-side antiparallel stacked dimer into the DNA minor groove. Since all other dicationic furan derivatives are known to bind in the minor groove as monomers and recognize AT regions of the DNA, the GC recognition and dimer-binding mode represents an important new interaction mode. In an effort to understand what structural features of DB293 are required for the dimer formation and GC recognition, the synthesis of new analogs of DB293 has been undertaken. This dissertation describes the synthesis and characterization of seven new diamidines, which were designed to probe the structural requirements for dimer formation. Also, some biophysical data of these compounds, which were generated by the Wilson group at Georgia State University are briefly presented and discussed.