title: Structure-activity relationship of 2,4,5-trioxoimidazolidines as inhibitors of thymidine phosphorylase.
abstract: Novel non-nucleobase-derived inhibitors of the angiogenic enzyme, thymidine phosphorylase, have been identified using molecular modelling, synthesis and biological evaluation. These inhibitors are 2,4,5-trioxoimidazolidines bearing N-(substituted)phenylalkyl groups, together with, in most cases, N'-(CH(2))(n)-carboxylic acid, ester or amide side chains. The best compound from this series is 3-(2,4,5-trioxo-3-phenylethyl-imidazolodin-1-yl)propionamide, with an IC(50) of 40 μM against Escherichia coli TP. Molecular modelling suggests that this ligand, when complexed with closed-cleft human TP, would have the phenylalkyl group in the active site region normally occupied by a thymine-containing structure.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Rajabi
authors.forename: David
authors.initials: D
authors.lastname: Mansell
authors.forename: Sally
authors.initials: S
authors.lastname: Freeman
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
mesh_terms: D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006827:Hydantoins / Q000737:chemistry; D048289:Imidazolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D006827:Hydantoins; D048289:Imidazolidines; D013939:Thymidine Phosphorylase