Nicholas Pinkin, Chemistry
"Synthesis of Potential Inhibitors of Thymidylate Synthase Based on Quinazoline Structural Skeleton"
Faculty Mentor: Dr.Ramachandra Hosmane
Expected Graduation Date: Spring 2010
Cancer is a group of diseases that causes about 13 percent of all deaths in the world, estimated at 7.6 million in 2007 alone. My research aims to create a set of drugs to inhibit an enzyme in the body fundamental to the out-of-control growth that cancer cells exhibit. This enzyme, Thymidylate Synthase (TS), catalyzes the conversion of Uracil Monophosphate to Thymidine Monophosphate using N5,N10-methylenetetrahydrofolate (THF) as a methyl donor. Cancerous cells need Thymidine to replicate, and therefore proliferate quickly in a TS rich environment. The compounds we propose are potential competitive inhibitor analogs of THF. Already, the necessary intermediates to the final six different THF analogs have been synthesized by condensation of commercially available carboxaldehydes and 1-ethoxy-3-methyl malonate to give UMR-150 (a-f) in 51 percent yield. Subsequent dehydration and decarboxylation of UMR-150 (a-f) with sodium ethoxide in ethanol formed the mono-ester product NP-001 in 63 percent yield. Both compounds have been verified through the use of 1H and 13C nuclear magnetic resonance spectroscopy. This initial progress in synthesizing these drugs makes us confident that the final proposed analogues can be synthesized in a timely fashion. Once synthesized, we plan to carry out enzyme assays to determine their inhibitory properties.