Mechanism-Based Inhibitors of Deoxythymidine Monophosphate Synthesis as Antineoplastic Agents

INTRODUCTION 5-Fluorouracil and methotrexate are antimetabolites widely used in the treatment of neoplastic disease. They act by inactivating the two enzymes involved in the biosynthesis of the pyrimidine nucleotide 2’-deoxythymidine 5’-monophosphate, namely thymidylate synthase and dihydrofolate reductase. The three dimensional structure of each enzyme is known and the mechanisms of the reactions they catalyze are well understood. This allows the medicinal chemistry professor the opportunity to engage students in a mechanism-based discussion of how the structure of each antimetabolite permits selective enzyme targeting and inhibition. This article will provide an overview of the structure and function of the thymidylate synthase and dihydrofolate reductase enzymes, take a mechanistic look at the structureactivity relationships of 5-fluorouracil, methotrexate and their clinically important analogs, and highlight some of the newer pyrimidine antagonist molecules recently reported in