March 6, 2012

Title: Development of methodology for the synthesis of enamides and studies on a chemical probe for epigenetic protein WDR5

Abstract: The first part of the presentation describes a copper-catalyzed coupling of amides with potassium trifluoroborate salts to yield enamides. The enamide linkage represents a fragile structural element that is prominently featured in a wide range of natural products with promising biological activities. The described protocol offers a convenient alternative to the previously developed methods, and should greatly improve the synthetic utility of enamide functionality for natural product syntheses.

The second part focuses on the development of a chemical probe for the epigenetic protein WDR5, which is a subunit of the multiprotein MLL complex. WDR5 is an attractive target due to its involvement in overexpression of certain genes that is observed in acute lymphoblastic leukemia, acute myeloid leukemia and in solid tumors such as prostate carcinoma and primary colorectal tumors. A chemical probe is a small molecule designed to selectively affect the activity of histone proteins that package DNA in chromatin, alter its structure, and will complement genetic knockout and serve as a starting point for drug discovery.