This proposal presents a plan for an enantioselective total synthesis of the natural product kopsimaline A and its structural analogues. Kopsimaline A has been found to be effective at reversing multidrug resistance in vincristine-resistant human cancer KB cells. Due to structural similarities between kopsimaline A and vincristine, efflux transporter proteins may preferentially bind kopsimaline A instead of vincristine, effectively inhibiting the export of vincristine out of cancer cells, reversing multidrug resistance. The synthetic plan involves a 22 step synthetic route from commercially available materials. Key steps include a [4 + 2]/[3 + 2] intramolecular cycloaddition cascade, a double conjugate addition of an enamine onto a vinyl sulfone and a ring expansion via a modified von Braun reaction. The proposed route is conducive to the creation of a library of synthetic analogues that will help identify key structural features responsible for the biological activity of the compound. Kopsimaline A will also be tested in concert with a number of vinblastine analogues that have already been synthesized by the Boger laboratory in search of an effective combination for use in chemotherapy.
Every year over a million people are diagnosed with cancer. Chemotherapy remains the most effective way currently to treat cancer;however, multidrug resistance to chemotherapies has become an increasing problem today. This proposal outlines a plan for the total synthesis of a small molecule that has been found to effectively reverse multidrug resistance in human cancer cells.
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| Leggans, Erick K; Duncan, Katharine K; Barker, Timothy J et al. (2013) A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives. J Med Chem 56:628-39 |
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| Leggans, Erick K; Barker, Timothy J; Duncan, Katharine K et al. (2012) Iron(III)/NaBH4-mediated additions to unactivated alkenes: synthesis of novel 20'-vinblastine analogues. Org Lett 14:1428-31 |
