) Chemical synthesis of natural products with promising biological properties is often the first step to understanding what a molecule interacts with in the Cell. Moreover, flexible synthetic plans provide an opportunity for the synthesis of analogs that may not be available in Nature. The proposed total synthesis of ambewelamide A and its congeners (structural analogs) that bear different acyl sidechains is an important step toward understanding the origin of its potent anticancer properties. Ambewelamide contains a unique epidithiadiketopiperazine core structure that presents a challenge for its synthesis. In addition, its epoxide functionality is thought to play a critical role in its anticancer properties. This molecule is available in very limited quantities from Nature. A new chemical method for the synthesis of part of the natural product will be developed and employed in the synthesis of ambewelamide A. Crucial to understanding how the natural product inhibits cancer cell growth, the molecules prepared in the proposed investigation will be evaluated against cancer cell lines. This is a first step to identifying promising chemotherapeutics and developing a more detailed understanding of the interaction of ambewelamide with cellular targets. In this proposal there are four specific aims: (1) To develop a new tandem enyne-ring closing metathesis to synthesize six membered rings from alkynes and 1,5 dienes and to develop the reaction's scope; (2) to employ tandem metathesis to synthesize the natural product ambewelamide A; (3) to test the importance of the epoxide functionality in the natural product through congener synthesis coupled with direct assay of the compounds ability to inhibit cancer cell growth; (4) to develop a new solid phase synthesis approach to making simple epidithiadiketopiperazines in order to evaluate their antitumor/anticancer properties.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA090603-01
Application #
6320672
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$227,989
Indirect Cost
Name
State University of New York at Buffalo
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
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