The long range objective of this research proposal is to develop anticancer drugs in the antifolate series that are very selective with low host toxicity. To achieve this objective, we propose to synthesize a series of antifolates that are: a) Synthetic substrates of dihydrofolate reductase (DHFR) that can be enzymatically activated to inhibitors of other folate based enzymes; b) Specific inhibitors of thymidylate synthase (TS), glycinamide- ribonucleotide formyltransferase (GARFTase), amino imidazole carboxamide ribonucleotide formyltransferase (AICARFTase), folylpolyglutamate synthetase (FPGS), and the nonpolyglutamatable counterparts of each of these enzyme inhibitors that are capable of facile transport to mammalian cells. Preferential accumulation of cytotoxic antifolate polyglutamates in tumors as a strategy for achieving selective toxicity in cancer chemotherapy will be investigated by exploiting the differential folylpolyglutamate hydrolase activity in tumor versus normal proliferative tissues. For this purpose, we propose to develop the required chemistry to deliver antifolate polyglutamates intact to mammalian cells via conjugation with macromolecules to cell cytosol subsequent to endocytosis. A Mass Spectral facility for the quantitative and qualitative analysis of folate and antifolate metabolites will be established at the University of South Alabama. All potential drugs will be evaluated thoroughly for their anticancer activity by our biological and industrial collaborators, using the appropriate biochemical and pharmacological test systems. Promising compounds will be evaluated in vivo for their antitumor activity in tumor bearing animals.
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