Studies on the total synthesis and evaluation of antitumor antibiotics including (1) kopsifoline, (2) lycorine, (3) pancratistatin, (4) vindoline an vinca alkaloids, (5) pyrimidoblamic acid and bleomycin analogs, (6) P-3A, (7) indolocarbazoles including rebeccamycin, and (8) cordytropolone are detailed. In the studies, the investigation, development, and use of: (1) heterocyclic and acyclic azadiene Diels-Alder reactions, (2) the thermal cycloaddition reactions of cyclopropenone ketals including those of reversibly generated -delocalized singlet vinylcarbenes, and (3) the tandem Diels-Alder/1,3-dipolar cycloaddition reactions of 1,3,4- oxadiazoles will be pursued and provide the opportunity for the discovery and development of new powerful synthetic methodology. The studies target antitumor compounds that express their effects through selective protein (e.g., tubulin, PKC, EF1A elongation factor) or sequence selective DNA binding and provide well-defined problems on the design, synthesis, and evaluation of synthetic, mechanism-based analogs in which the structural features responsible for their protein or DNA binding affinity, selectivity, and functional reactivity will e addressed, identified, optimized, and exploited.
Fundamental new synthetic approaches and 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.
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|Duerfeldt, Adam S; Boger, Dale L (2014) Total syntheses of (-)-pyrimidoblamic acid and P-3A. J Am Chem Soc 136:2119-25|
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|Uematsu, Mika; Boger, Dale L (2014) Asymmetric synthesis of a CBI-based cyclic N-acyl O-amino phenol duocarmycin prodrug. J Org Chem 79:9699-703|
|Wolfe, Amanda L; Duncan, Katharine K; Lajiness, James P et al. (2013) A fundamental relationship between hydrophobic properties and biological activity for the duocarmycin class of DNA-alkylating antitumor drugs: hydrophobic-binding-driven bonding. J Med Chem 56:6845-57|
|Xie, Jian; Wolfe, Amanda L; Boger, Dale L (2013) Total synthesis of kopsinine. Org Lett 15:868-70|
|Turner, Travis C; Shibayama, Kotaro; Boger, Dale L (2013) Hypervalent iodine(III)-promoted intermolecular C-C coupling of vindoline with ýý-ketoesters and related substrates. Org Lett 15:1100-3|
|Barker, Timothy J; Duncan, Katharine K; Otrubova, Katerina et al. (2013) Potent Vinblastine C20' Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line. ACS Med Chem Lett 4:|
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