COMBINATORIAL APPROACHES TO DNA AND TUBULIN BINDING MOLECULES

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This grant application describes a program directed at the development of DNA sequence specific molecules by combinatorial molecular imprinting techniques. Appropriately functionalized calicheamicin oligosaccharides with olefinic appendages of various sizes will be allowed to bind into the minor grove of duplex DNA containing two (or more) binding sites, and those who fit will be ligated via the olefin metathesis reaction. Through this and related strategies we hope to develop a series of sequence specific oligosaccharides for certain DNA sequences that can be used as vehicles for specific DNA cleavage and cross-linking as well as for modulating gene expression and suppression as a means to cancer chemotherapy. A second project will involve the construction of an apothilone B library using a combination of solution and solid phase chemistry techniques. The synthesized library will be screened in tubulin polymerization and cytotoxicity assays. Potential anticancer agents are expected to be identified from these studies.