Eukaryotic parasitic diseases, such as sleeping sickness, are caused by ancient, unusual and quite deadly microorganisms. Dicationic diamidines such as furamidine, berenil, and pentamidine that target the DNA minor groove at extended AT sequences have significant activity against these diseases. The thousands of DNA minicircles with A/T rich sequence tracts in the parasite kinetoplast provide a large array of potential binding sites and may be the biological target of the dications. Our strategy to capitalize on these observations and intrinsic features of the heterocycles involves design and development of new compounds targeted to A/T sequences in the DNA minor groove in a variety of complexes that have limited toxicity and good cell uptake properties in parasites. Classical minor groove binding compounds are unfused heterocyclic cations and it has been proposed that there are strict limits on their structures for DNA complex formation. Rules for compound design have been derived based on a stringent set of compound curvature and functional group positioning criteria. Recent observations on compounds developed in our laboratories, however, have led us to question whether such design limitations are required. We have found compounds, for example, that do not have classical minor groove shapes but that bind exceptionally strongly to the minor groove. Structural and thermodynamic results that help to explain the unusual binding affinity will be presented. Supported by NIH, The Gates Foundation,The Georgia Research Alliance, and Cancer Research UK
Back to Frontiers in Nucleic Acid Chemistry II
Back to The 57th Southeast/61st Southwest Regional Meeting (November 1-4, 2005)