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