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.
|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|
|Chanda, Prem B; Boyle, Kristopher E; Brody, Daniel M et al. (2016) Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate (CImI) alkylation subunit. Bioorg Med Chem :|
|Glinkerman, Christopher M; Boger, Dale L (2016) Catalysis of Heterocyclic Azadiene Cycloaddition Reactions by Solvent Hydrogen Bonding: Concise Total Synthesis of Methoxatin. J Am Chem Soc 138:12408-13|
|Morin, Matthew D; Wang, Ying; Jones, Brian T et al. (2016) Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists. J Med Chem 59:4812-30|
|Allemann, Oliver; Brutsch, Manuela; Lukesh 3rd, John C et al. (2016) Synthesis of a Potent Vinblastine: Rationally Designed Added Benign Complexity. J Am Chem Soc 138:8376-9|
|Sears, Justin E; Boger, Dale L (2016) Tandem Intramolecular Diels-Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Initial Scope and Applications. Acc Chem Res 49:241-51|
|Carney, Daniel W; Lukesh 3rd, John C; Brody, Daniel M et al. (2016) Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface. Proc Natl Acad Sci U S A 113:9691-8|
|Lee, Kiyoun; Boger, Dale L (2015) Total synthesis of (-)-kopsinine and ent-(+)-kopsinine. Tetrahedron 71:3741-3746|
|Sears, Justin E; Boger, Dale L (2015) Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties. Acc Chem Res 48:653-62|
|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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