) 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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University of New York at Buffalo
Schools of Arts and Sciences
United States
Zip Code
Diver, Steven T (2007) Ruthenium Vinyl Carbene Intermediates in Enyne Metathesis. Coord Chem Rev 251:671-701
Galan, Brandon R; Giessert, Anthony J; Keister, Jerome B et al. (2005) Studies on the mechanism of intermolecular enyne metathesis: kinetic method and alkyne substituent effects. J Am Chem Soc 127:5762-3
Giessert, Anthony J; Diver, Steven T (2005) Cross enyne metathesis of para-substituted styrenes: a kinetic study of enyne metathesis. Org Lett 7:351-4
Kulkarni, Amol A; Diver, Steven T (2004) Ring synthesis by stereoselective, methylene-free enyne cross metathesis. J Am Chem Soc 126:8110-1
Peppers, Brian P; Diver, Steven T (2004) Tandem cyclopropanation/ring-closing metathesis of dienynes. J Am Chem Soc 126:9524-5
Kulkarni, Amol A; Diver, Steven T (2003) Cycloheptadiene ring synthesis by tandem intermolecular enyne metathesis. Org Lett 5:3463-6
Giessert, Anthony J; Snyder, Lee; Markham, Jordan et al. (2003) Intermolecular enol ether-alkyne metathesis. Org Lett 5:1793-6
Giessert, Anthony J; Brazis, Nicholas J; Diver, Steven T (2003) Ethylene-promoted intermolecular enyne metathesis. Org Lett 5:3819-22