ORGN 506 |
| Laxman Nallan1, Wesley C Van Voorhis2, and Michael H Gelb1. (1) Department of chemistry, University of washington, Box; 351700, Seattle, WA 98195-1700, (2) Infectious Diseases, University of Washington, 1959 Pacific Ave. NE, Seattle, WA 98195-1700 |
| Protein prenylation, a novel post translational modification, involves the covalent attachment of either a 15-carbon farnesyl or a 20-carbon geranylgeranyl isoprenoid to the carboxy terminal cystine residue via a thioether bond. The enzymes responsible for isoprenoid addition to proteins are termed protein prenyltransferases and the CaaX prenyltransferases, classified by their lipid substrate and termed protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type I (GGTase I)and protein geranylgeranyltransferase type II (GGTase II). Protein prenylation occurs in protozoan parasites. Gelb et al. reported that protein farnesylation occurs in the trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania mexicana amazonensis. Malaria is one of the most widespread infectious diseases in the tropics. Over 300 million persons are infected each year, resulting in more than one million deaths annually. The fatal cases are generally caused by the most virulent human malaria parasite, Plasmodium falciparum. Current clinical treatment involves the use of inexpensive drugs such as chloroquine. However, resistance has rendered many of these drugs ineffective. Chakrabrti et al.reported that an FTase inhibitor showed inhibition activity against the growth of P. falciparum in human red blood cells. Our specific aim is to synthesize inhibitors of P. falciparum protein farnesyltransferase (Pf-PFT) as drugs against malaria. We have synthesized a variety of PFTIs that have been patented and found that Bristol Myers Squibb (BMS) PFTIs are far superior at killing P. falciparum, with many BMS PFTIs at low nanomolar concentrations.
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Total Synthesis, Asymmetric Reactions and Syntheses, Bioorganic
9:00 AM-11:00 AM, Wednesday, March 31, 2004 Anaheim Convention Center -- Hall C, Poster
Division of Organic Chemistry |