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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Misra, Raj N
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Scripps Research Institute
La Jolla
United States
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Shankar, Sundaresh; Whitby, Landon R; Casquilho-Gray, Hedi E et al. (2016) Small-Molecule Fusion Inhibitors Bind the pH-Sensing Stable Signal Peptide-GP2 Subunit Interface of the Lassa Virus Envelope Glycoprotein. J Virol 90:6799-807
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Sears, Justin E; Barker, Timothy J; Boger, Dale L (2015) Total Synthesis of (-)-Vindoline and (+)-4-epi-Vindoline Based on a 1,3,4-Oxadiazole Tandem Intramolecular [4 + 2]/[3 + 2] Cycloaddition Cascade Initiated by an Allene Dienophile. Org Lett 17:5460-3

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