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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA042056-31
Application #
8686550
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Misra, Raj N
Project Start
1986-02-01
Project End
2019-03-31
Budget Start
2014-04-11
Budget End
2015-03-31
Support Year
31
Fiscal Year
2014
Total Cost
$439,424
Indirect Cost
$207,538
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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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