Abstract

Studies on the development of a diastereoselective and enantioselective total synthesis of vindoline and the clinically important antitumor drug vinblastine are detailed based on implementation of a unique tandem Diels-Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles. In addition to defining the scope of such tandem cycloaddition cascades, applications in the total synthesis of (1) vindorosine, (2) minovine, (3) aspidospermidine, (4) (-)-vindoline, (5) (+)-vinblastine and (+)-vincristine, (6) and an extensive series of (+)-vinblastine analogues are detailed. The proposed studies include the examination of antitumor compounds that mediate their cellular effects through tubulin binding and provide a well-defined problem on the design, preparation, and evaluation of synthetic, mechanism-based analogues in which fundamental studies of the structural features responsible for tubulin binding affinity and selectivity may be addressed. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115526-02
Application #
7220646
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2006-04-10
Project End
2011-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$320,404
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Lukesh 3rd, John C; Carney, Daniel W; Dong, Huijun et al. (2017) Vinblastine 20' Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance. J Med Chem 60:7591-7604
Yang, Shouliang; Sankar, Kuppusamy; Skepper, Colin K et al. (2017) Total synthesis of a key series of vinblastines modified at C4 that define the importance and surprising trends in activity. Chem Sci 8:1560-1569
Allemann, Oliver; Cross, R Matthew; Brütsch, Manuela M et al. (2017) Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20' ethyl substituent. Bioorg Med Chem Lett 27:3055-3059
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
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
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; 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
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
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
Campbell, Erica L; Skepper, Colin K; Sankar, Kuppusamy et al. (2013) Transannular Diels-Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles: total synthesis of a unique set of vinblastine analogues. Org Lett 15:5306-9

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