. Studies on the total synthesis of antitumor antibiotics are detailed, including vinblastine, vincristine, related Vinca alkaloids and their analogs. Fundamental studies on the discovery, investigation, development, and application of: (1) heterocyclic and acyclic azadiene cycloaddition reactions including the recently explored 1,2,3-triazines and presently unknown 1,2,3,4-tetrazines and 1,2,3,5-tetrazines, (2) the tandem Diels?Alder/1,3- dipolar cycloaddition cascade reactions of 1,3,4-oxadiazoles, and (2) the thermal cycloadditions of cyclopropenone ketals including those of reversibly generated ?-delocalized singlet vinylcarbenes will be conducted and provide the opportunity for the introduction of new powerful synthetic methodology. We will further examine (4) Fe(III)?NaBH4 hydrogen atom transfer (HAT) olefin functionalization reactions, (5) single-electron transfer Fe(III)-promoted indole coupling reactions, (6) a PIFA-promoted aromatic substitution reaction that we introduced, as well as explore (7) two new BAHA-promoted single-electron oxidative coupling reactions that we have discovered since the grant was last reviewed. The studies target antitumor compounds that act through selective protein (e.g., tubulin) or sequence selective DNA binding and provide well-defined challenges for the design, synthesis, and evaluation of synthetic, mechanism-based analogs in which the structural features responsible for their target binding affinity, selectivity, and functional reactivity will be identified, addressed, optimized, and exploited. Efforts will provide synthetic vinblastine analogs that clarify their interaction with their biological target, help delineate their mechanism of action, and address clinical limitations of the natural product drug. Studies have provided synthetic vinblastine analogs now available in 3-steps from commercial materials that are as much as 100-fold more potent than the natural product and/or that directly overcome the basis of clinical resistance derived from Pgp overexpression and drug efflux (aka MDR). Analogs with improved potency, selectivity, and/or such improved tumor resistance profiles can be expected to emerge from the studies that could provide the basis for transformative new oncology drugs, representing compounds that not only could serve as vinblastine replacements in clinic, but also offer new and effective treatment options in instances of other multidrug resistant tumors (overexpression of Pgp) refractory to nearly all other front-line drugs.
Fundamental new synthetic approaches and new synthetic methodology and their use in the discovery of new therapeutics for the treatment of cancer will emerge from the studies, and a fundamental understanding of the mechanism of action and the interaction of biologically active natural products with their biological target will be developed. New approaches to the synthesis of vinblastine and related new drugs that improve on the potency, selectivity, and efficacy of clinically used natural products (vinblastine and vincristine) will be discovered, including those that are active against vinblastine-resistant and multidrug-resistant (MDR) tumors.
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