This proposal presents a plan for an enantioselective total synthesis of the natural product kopsimaline A and its structural analogues. Kopsimaline A has been found to be effective at reversing multidrug resistance in vincristine-resistant human cancer KB cells. Due to structural similarities between kopsimaline A and vincristine, efflux transporter proteins may preferentially bind kopsimaline A instead of vincristine, effectively inhibiting the export of vincristine out of cancer cells, reversing multidrug resistance. The synthetic plan involves a 22 step synthetic route from commercially available materials. Key steps include a [4 + 2]/[3 + 2] intramolecular cycloaddition cascade, a double conjugate addition of an enamine onto a vinyl sulfone and a ring expansion via a modified von Braun reaction. The proposed route is conducive to the creation of a library of synthetic analogues that will help identify key structural features responsible for the biological activity of the compound. Kopsimaline A will also be tested in concert with a number of vinblastine analogues that have already been synthesized by the Boger laboratory in search of an effective combination for use in chemotherapy.

Public Health Relevance

Every year over a million people are diagnosed with cancer. Chemotherapy remains the most effective way currently to treat cancer;however, multidrug resistance to hemotherapies has become an increasing problem today. This proposal outlines a plan for the total synthesis of a small molecule that has been found to effectively reverse multidrug resistance in human cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA165303-02
Application #
8341016
Study Section
Special Emphasis Panel (ZRG1-F04A-G (20))
Program Officer
Jakowlew, Sonia B
Project Start
2011-09-24
Project End
2013-07-26
Budget Start
2012-09-24
Budget End
2013-07-26
Support Year
2
Fiscal Year
2012
Total Cost
$42,529
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
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