Synthesis and evaluation of penta-substituted pyrrole derivatives as Wip 1 phosphatase inhibitors

ORGN 297

Qun Xu, and Daniel Appella. NIDDK, NIDDK, NIH, Bethesda, MD 20892
The phosphatase Wip 1 indirectly suppresses the activity of the tumor suppressor protein p53, inhibition of its enzymatic activity represents a novel and effective anti-cancer approach. We recently reported the design, solid-phase synthesis, and inhibition data of a series of selective Wip 1 inhibitors bearing penta-substituted pyrrole core. To further establish the structure- activity relationships (SARs) and to identify potent inhibitors for crystal structure studies, a new synthetic route amenable for large scale solution phase synthesis was designed. The synthesis is based on Knoevenagel-Stetter-Paal-Knorr sequence, and features stepwise incorporation of substituents. The inhibition of the derivatives against Wip 1 phosphatase and their selectivity were evaluated.

Heterocycles and Aromatics
1:00 PM-5:20 PM, Monday, August 17, 2009 Walter E. Washington Convention Center -- 206, Oral

Division of Organic Chemistry

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009