Synthesis of Pyrrole Derivatives for Selective Inhibition of Wip-1 Phosphatase

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NIDDK	CHEM-3

Authors

• P. Gupta
• D. H. Appella

Abstract

The enzyme Wip-1 is a serine/threonine phosphatase with oncogenic properties. Over expression of Wip-1 has been observed in several cancers, including breast cancer, neuroblastoma, and ovarian clear cell adenocarcinoma. The phosphatase Wip-1 indirectly suppresses the activity of protein p53, a protein that functions as a tumor suppressor and is frequently described as the “guardian of the genome.” Targeting Wip-1 with small molecule inhibitors represents a novel approach to restore tumor suppressor function and subsequent cancer cell arrest/apoptosis. We recently reported the design, solid-phase synthesis, and inhibition data of a series of selective Wip-1 inhibitors bearing a penta-substituted pyrrole core. To further establish the structure-activity relationships (SARs) and to identify potent inhibitors for crystal structure studies, a 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 data against Wip-1 phosphatase will be described along with an analysis of the selectivity of the molecules for Wip-1 over other phosphatases.

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