Alternative zinc-binding groups in synthesis of matrix metalloproteinase inhibtors

INOR 130

Arpita Agrawal, aagrawal@ucsd.edu, Jana A. Lewis, janal@ucsd.edu, Jay Stork, jstork@ucsd.edu, and Seth M. Cohen, scohen@ucsd.edu. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0358
Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes capable of degrading extracellular matrix. In normal physiology, MMPs regulate tissue remodeling, development, angiogenesis, cell adhesion, and proliferation. If left uninhibited, MMPs can cause diseases such as arthritis, neuronal demyelination, and cancer. MMPs have a characteristic and highly conserved tris(histidine) coordinated Zn2+ ion in the active site. MMP inhibitors (MPIs) are designed to bind the active site zinc ion and inhibit activity. Most MPIs designed thus far contain an acetohydroxamic acid (AHA) zinc-binding group (ZBG). However, alternative ZBGs with different peptidomimetic backbones have been synthesized and tested as potential MPIs using commercially available fluorescent assay kits. These ZBGs include hydroxypyridinones and pyrones, and have been shown to be more potent than AHA in MMP inhibition. Current research focuses on the structure-activity-relationship (SAR) of different ZBGs with biphenyl and terphenyl peptidomimetic backbones and their effect on MMP inhibition. Future research involves thionation of pyrone ZBGs, measurement of IC50 values, and in vitro cytotoxicity assays.
 

Bioinorganic Chemistry
7:00 PM-10:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Inorganic Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006