title: A pyrimidine-based "flexible" bisubstrate analogue inhibitor of human thymidylate synthase.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City 84112.
authors.forename: I Y
authors.initials: IY
authors.lastname: Yang
authors.forename: R M
authors.initials: RM
authors.lastname: Slusher
authors.forename: A D
authors.initials: AD
authors.lastname: Broom
authors.forename: T
authors.initials: T
authors.lastname: Ueda
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D001665:Binding Sites; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D013940:Thymidylate Synthase