Structural Variations on the Turn Unit of DNA-Binding Hairpin Py-Im Polyamides

Modulation of gene expression by small molecules is a challenge in the field of chemical biology. Hairpin pyrrole-imidazole polyamides are a class of programmable small molecules that bind to the minor groove of DNA, and have been shown to inhibit gene expression by interfering with transcription factor-DNA interfaces. When considering the biological implications of these molecules, improvement of sequence-specificities and binding affinities is of great interest. The work described herein focuses on modifications to the turn sub-unit of hairpin polyamides, and subsequent effects on the biophysical and biological characteristics of these molecules. The substitution of a gamma-2,4-diaminobutyric acid with an &agr;-2,4-diaminobutyric acid hairpin turn moiety resulted in greater selectivity, and diminished reactivity for polyamide-alkylator conjugates. These molecules have been utilized in generating site-specific damage in histone H4 genes in cancer cells. Employment of 3,4-diaminobutyric acid in the turn unit has resulted in increased DNA affinities for polyamides targeting particular sequences. These molecules are also promising in their abilities to tolerate modifications that improve cellular uptake but would otherwise severely diminish binding.