ORGN 349 |
| Jyoti R. Patel1, Linda Lynch, Robert G. Gentles2, George Sheppard3, Jieyi Wang3, and Chang Park4. (1) Medicinal Chemistry Technologies, Abbott Laboratories, 100 Abbott Park Road, D-R4CP, Bldg-AP10, Room-101, Abbott Park, IL 60064, (2) Bristol Meyers Squibb, (3) Cancer Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, (4) Structural Biology, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064 |
| MetAP-2 (methionine aminopeptidase-2) is a metallo-protease that is capable of N-terminal methionine removal from proteins in eukaryotic cells. MetAP-2 seems to be essential for endothelial cell proliferation. Fumagillin and its derivative TNP-470 show anti-angiogenic activity by irreversible inhibition of MetAP-2. Our efforts sought a reversible inhibitor of the enzyme. We have used solid-phase chemistry to synthesize analogs of the bestatin lead. The crystal structure of the bestatin series shows that the amino group is closely coordinated with one of the two Mn+2 metals in the active site. However, there is the potential that mono-substitution of the amine could access the water pocket adjacent to the amine binding site. To retain the basic properties of the nitrogen, a library of 90 compounds with two sites of diversity was synthesized using Fukuyama chemistry. The compounds were screened against MetAP-2 and MetAP-1. A secondary cell-based anti-proliferation assay was done on selected compounds. |
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Physical Organic, Combinatorial, Materials, Molecular Recognition
8:00 PM-10:00 PM, Tuesday, March 30, 2004 Anaheim Convention Center -- Hall A, Poster
Division of Organic Chemistry |