title: Synthetic inhibitors of Escherichia coli, calf thymus, and Ehrlich ascites tumor thymidylate synthetase.
abstract: In a study of active site binding the inhibition of thymidylate synthetase derived from Escherichia coli, calf thymus, and Ehrlich ascites tumor was examined using eight inhibitors. 5-Substituted 2'-deoxyuridine 5'-phosphate analogues used in this study are the hydroxymethyl, methoxymethyl, benzyloxymethyl, formyl, acetyl, allyl, and two potential active site alkylating substituents: 2,3-oxypropyl and the azidomethyl analogues. All compounds were competitive with the substrate, 2'-deoxyuridine 5'-phosphate; the most potent inhibitor was 5-formyl-dUMP (Ki = 0.1, 0.09, and 0.08 muM for the respective enzyme). The 5-hydroxymethyl, 5-benzyloxymethyl, and 5-azidomethyl derivatives of dUMP showed some differential inhibition; these compounds were two to three times more active against the ascites tumor enzyme than against the thymus enzyme.
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002286:Carcinoma, Ehrlich Tumor / Q000201:enzymology*; D004926:Escherichia coli / Q000201:enzymology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D013056:Spectrophotometry, Ultraviolet; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D013950:Thymus Gland / Q000201:enzymology*; D014500:Uracil Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D014500:Uracil Nucleotides; D008780:Methyltransferases; D013940:Thymidylate Synthase