A pyrimidine-based 'flexible' bisubstrate analogue inhibitor of human thymidylate synthase

Article abstract of DOI:10.1021/jm00119a012

The synthesis and characterization of two 'flexible' bisubstrate analogues of the intermediate in the thymidylate synthase reaction are reported. Steric constraints are minimized and diasteromeric mixtures avoided by using a pyrimidine-based analogue as the folate portion of the inhibitor while retaining all known important binding sites. A preliminary assessment of certain conformational parameters by NMR is presented. The compounds are shown to be potent competitive inhibitors with respect to dUMP or 5,10-CH₂-H₄PteGlu but gave mixed kinetics with respect to 5,10-CH₂-H₄PteGlu₅ for human thymidylate synthase.