Thymidylate Synthase Inhibition of Modified Quinazoline Antifolates

Abstract

Thymidylate synthase (T.S.) is a pivotal enzyme in pyrimidine biosynthesis. The enzyme catalyses the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) and represents the only de novo source of this nucleotide required for DNA synthesis. The co-factor 5, 10-methylenetetrahydrofolate (I) supplies the one-carbon fragment required for the reaction and also acts as a reducing agent. Regeneration of the co-factor is achieved in a cycle of reactions catalysed by the enzymes dihydrofolate reductase (DHFR) and serine hydroxymethyl transferase (SHMT) (Figure 1). Whilst SHMT has received little attention, many antifolate approaches to cancer chemotherapy have been based upon the inhibition of DHFR (1). In turning our attention to T.S. as a target for antifolate chemotherapy we anticipated several potential advantages over inhibition of DHFR. Principal among these was that inhibition of T.S. should not affect purine biosynthesis, protein synthesis or RNA synthesis and in this respect may avoid some of the side effects associated with DHFR inhibitors such as methotrexate (2,3).