ORGN 703 |
| Polyamides containing pyrrole (P) and imidazole (I) have the potential to be utilized as gene control agents via their ability to target specific DNA sequences. To improve upon the binding affinity of monomeric polyamides such as distamycin, a series of dimeric H-pin polyamides were synthesized, incorporating two f-IPI units tethered via alkyl linkers of length C6-C9. Molecular modeling demonstrated that the C8 linker was the optimum length, showing the least strain after energetic minimization. All biophysical studies confirmed binding in a staggered motif. Thermal denaturation experiments with ACGCGT corroborated this result as C8 and C9 yielded the greatest deltaTm (both 19 degrees C) and also indicated superior binding affinity when compared to the parent monomer f-IPI (1 degree C). Data from Circular Dichroism studies suggest binding in the minor groove. DNaseI footprinting determined the C8 linker to be the strongest binder with a footprint beginning at 0.005 microM, a 10-fold improvement on the monomer species (0.05 microM). A detailed discussion on the results will be presented. H-Pin polyamides designed to bind to the minor groove in a staggered configuration provides a renewed opportunity for the development of agents with the potential of controlling gene expression. Previously reported H-Pin polyamides have focused mainly on binding to DNA in a fully overlapped motif. |
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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 |