Studies towards the synthesis of the p53-MDM2 inhibitor chlorofusin

ORGN 449

Andrew R. Germain, germain@bu.edu1, John A. Porco Jr., porco@bu.edu1, Mark Searcey, mark.searcey@pharmacy.ac.uk2, and Esther C. Y. Woon, esther.woon@pharmacy.ac.uk2. (1) Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, 24 Cummington Street, Boston, MA 02215, (2) Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom
The p53-MDM2 interaction has recently become a significant target for cancer treatment. The tumor suppressor p53 plays a crucial role in preventing cancer by inducing G1 arrest and apoptosis. As a result of screening microbial extracts of Fusarium sp., the azaoxaspiranechlorofusin was found to inhibit the p53-MDM2 interaction (IC50 = 4.6 μM). The relative stereochemistry of the azaphilone chromophore has been determined, but the absolute stereochemistry relative to the cyclopeptide portion was not assigned. Herein, we outline our approach towards the synthesis of chlorofusin featuring enantioselective oxidative dearomatization and further oxidative modification of the azaphilone core.

 

Total Synthesis of Complex Molecules
8:00 AM-12:00 PM, Wednesday, 29 March 2006 Georgia World Congress Center -- C301, Oral

Division of Organic Chemistry

The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006