Antifolate metabolism and sites of action: implications for the design of new antifolates.

Recently, folate-dependent enzymes in the de novo thymidine and purine biosynthetic pathways have come under scrutiny as potential sites for chemotherapeutic exploitation by antifolates. In this manuscript we report on the progress that has been made in designing inhibitors of these pathways. In addition, a molecular model is proposed for the design of new antifolates directed against thymidylate synthase (TS).