ORGN 688 |
| The N-terminus formamido-moiety (f-) of distamycin plays a crucial role in the binding of this naturally occurring polyamide in the minor groove of DNA: The f-group promotes a staggered dimeric binding motif, influences orientation specificity, and enhances the binding affinity. To further understand the function of the f-group, a series of polyamides with alternative N-terminus moieties [acetamido-(CH3-), amino- (NH2-) and trifluoroacetamido- (CF3-)] were synthesized. All compounds contained a heterocyclic core comprising of imidazole-pyrrole-imidazole (IPI). The binding characteristics of the above polyamides were evaluated using DNaseI footprinting and biophysical techniques. DNaseI footprinting of CH3-IPI demonstrated a clear selectivity for the cognate sequence (5'-ACGCGT-3' vs. 5'-AAATTT-3', 5'-ACCGGT-3' and 5'-A[T]A[G]T-3', where bases in square brackets denote a T/G mismatched base pair) and indicated that the acetamido N-terminus maintained orientation specificity in the 5' to 3' direction. Circular Dichroism demonstrated that CH3-IPI and NH2-IPI bound selectively to the cognate 5'-ACGCGT-3' sequence via the minor groove. SPR and ITC studies confirmed cognate selectivity and SPR provided a binding constant of 2.1 x 10(6) M-1 for CH3-IPI binding to 5'-ACGCGT-3, and studies are currently underway for NH2-IPI and CF3-IPI to further probe the selection of the f-group in nature. |
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Asymmetric Reactions, Combinatorial Chemistry, Molecular Recognition and Self-Assembly, Proteins, Peptides, Amino Acids and Enzyme Inhibitors
8:00 PM-10:00 PM, Wednesday, March 28, 2007 Hyatt Regency Chicago -- Riverside Center, Poster
Division of Organic Chemistry |