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.

Agency
National Institute of Health (NIH)
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
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
Barker, Timothy J; Duncan, Katharine K; Otrubova, Katerina et al. (2013) Potent Vinblastine C20' Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line. ACS Med Chem Lett 4:
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
Leggans, Erick K; Duncan, Katharine K; Barker, Timothy J et al. (2013) A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives. J Med Chem 56:628-39
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Leggans, Erick K; Barker, Timothy J; Duncan, Katharine K et al. (2012) Iron(III)/NaBH4-mediated additions to unactivated alkenes: synthesis of novel 20'-vinblastine analogues. Org Lett 14:1428-31
Gotoh, Hiroaki; Duncan, Katharine K; Robertson, William M et al. (2011) 10'-Fluorovinblastine and 10'-Fluorovincristine: Synthesis of a Key Series of Modified Vinca Alkaloids. ACS Med Chem Lett 2:948-952
Va, Porino; Campbell, Erica L; Robertson, William M et al. (2010) Total synthesis and evaluation of a key series of C5-substituted vinblastine derivatives. J Am Chem Soc 132:8489-95
Tam, Annie; Gotoh, Hiroaki; Robertson, William M et al. (2010) Catharanthine C16 substituent effects on the biomimetic coupling with vindoline: preparation and evaluation of a key series of vinblastine analogues. Bioorg Med Chem Lett 20:6408-10
Kato, Daisuke; Sasaki, Yoshikazu; Boger, Dale L (2010) Asymmetric total synthesis of vindoline. J Am Chem Soc 132:3685-7

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