Abstract

Studies on the diastereoselective, asymmetric total synthesis of vindoline and the clinically important antitumor drug vinblastine are detailed based on the implementation of a tandem [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles, and a recently developed single step Fe(III)-promoted biomimetic coupling and subsequent oxidation reaction of vindoline with catharanthine. Extensions of these studies to the synthesis and evaluation of vinblastine analogues containing previously inaccessible deep-seated structural changes will be pursued, new insights into the mechanism of the biomimetic Fe(III)-promoted coupling of vindoline with catharanthine will be established further expanding access to unique vinblastine analogues, two new alternatives to existing coupling methods will be examined and developed expanding the range of synthetically accessible vinblastine analogues available for examination, and key insights into the structural features of vinblastine and vincristine integral to their binding to tubulin, inhibition of microtubulin formation, and inhibition of cell mitosis and tumor cell growth will be established. Not only will a fundamental understanding of the structure-function relationships of vinblastine's antitumor properties emerge from the studies, but drugs with improved potency, selectivity, efficacy, and/or tumor resistance profiles can be expected to continue to emerge from the studies.

Public Health Relevance

Fundamentally new approaches to the synthesis of vinblastine and vincristine, clinically employed antitumor drugs, will be developed, unique insights into the mechanism of a key biosynthetic (biomimetic) coupling reaction will emerge from the studies, a fundamental understanding of the interaction of vinblastine/vincristine with its biological target (tubulin) will be defined, and new drugs that further improve on the potency, selectivity, and efficacy of the clinically used natural products will be discovered including those that are active against vinblastine-resistant and multidrug-resistant (MDR) tumors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115526-09
Application #
8676683
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fu, Yali
Project Start
2005-07-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
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

Showing the most recent 10 out of 25 publications