title: Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase.
abstract: A series of novel imidazolyluracil conjugates were rationally designed and synthesised to probe the active site constraints of the angiogenic enzyme, thymidine phosphorylase (TP, E.C. 2.4.2.4). The lead compound in the series, 15d, showed good binding in the active site of human TP with an inhibition in the low muM range. The absence of a methylene bridge between the uracil and the imidazolyl subunits (series 16) decreased potency (up to 3-fold). Modelling suggested that active site residues Arg202, Ser217 and His116 are important for inhibitor binding.
authors: School of Pharmacy & Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
authors: Virginia A
authors: VA
authors: McNally
authors: Mehdi
authors: M
authors: Rajabi
authors: Abdul
authors: A
authors: Gbaj
authors: Ian J
authors: IJ
authors: Stratford
authors: Philip N
authors: PN
authors: Edwards
authors: Kenneth T
authors: KT
authors: Douglas
authors: Richard A
authors: RA
authors: Bryce
authors: Mohammed
authors: M
authors: Jaffar
authors: Sally
authors: S
authors: Freeman
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014498:Uracil; D013939:Thymidine Phosphorylase