A pyrimidine-based "flexible" bisubstrate analogue inhibitor of human thymidylate synthase |
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| Authors: | I Y Yang R M Slusher A D Broom T Ueda Y C Cheng |
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| Affiliation: | Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City 84112. |
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| 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. |
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