Novel Pyrrole-derivatized Diamino Polyamides and Their Impact on DNA Sequence Recognition
Dr. Kimberly Brien, Hope College
Dr. Vijay Satam, Hope College
Dr. Moses Lee, Hope College
Polyamides that contain imidazole and pyrrole heterocycles are known to target the minor groove of DNA in sequence specific interactions. Such molecules have the ability to alter gene expression. Analogs of the naturally occurring product distamycin have been developed and shown to bind in stacked anti-parallel dimers with their target DNA sequences. Various triamides containing imidazole and pyrrole moieties have been synthesized, and it was found that f-ImPyIm has better affinity and specificity in targeting its cognate DNA sequence, 5’-ACGCGT-3’ than the binding of distamycin to its cognate sequence 5’-AAATTT-3’. With the addition of a second amine group, derivatives of f-ImPyIm have been synthesized in an attempt to increase solubility in aqueous media. In order to track polyamides in cells by means of fluorescence, novel Hx-moieties that are analogs of Hoechst 33258 were introduce in polyamide backbone. These molecules showed excellent binding affinity (K) and sequence specificity to their respective cognate DNA sequences, 5’-ACGCGT-3’ and 5’-ATCGAT-3’ while exhibiting strong fluorescence that allows tracking of these molecules in cells. The focus of this research is directed towards the development of diamino Hx-containing polyamides and testing the effects of the additional NH2 linker on DNA binding properties in comparison to their monoamino counterparts.
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