MECHANISM-BASED ENZYME INHIBITORS: NOVEL ANTIFOLATES

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The proposed project is part of a long range research effort aimed at the development of new approaches to the chemotherapy of proliferative diseases. The main objective of this research is to apply mechanistic considerations to the design and subsequent study of novel antifolates capable of interferring with the formation and the hydrolysis of the poly-Gamma-glutamyl chain of folic acid derivatives catalyzed by folylpolyglutamate synthetase and conjugase, respectively. The chemical part of the project involves the rational design, synthesis and characterization of new antifolates and is followed by biochemical studies aimed at the evaluation of the enzyme inhibitory activities of the newly synthesized compounds. These studies employ intact and reversibly permeabilized L1210 leukemic cells and isolated enzyme systems. The cytotoxicity of the compounds is determined in vitro by measuring the extent of growth inhibition of L1210 leukemia cells in suspension cultures. The synthesis of active compounds will be scaled up for biological testing in a variety of animal tumor systems in vivo. It is a major goal of the project to correlate cellular and cell-free enzyme inhibitory activity with in vitro cytotoxicity and in vivo biological activity data and use the results of this study as a guideline to formulate future research plans concerning the possibilities of therapeutic applications.