title: 5-propynylpyrimidine nucleoside derivatives: rationally designed mechanism-based inactivators of thymidylate synthase.
abstract: A novel series of 5-propynyl-dUMP derivatives, with a variety of leaving groups on the side-chain, was designed as potential mechanism-based inhibitors of thymidylate synthase (TS), and synthesized from 5-iodo-2'-deoxyuridine by Pd(0)-catalyzed coupling, followed by direct phosphorylation with POCl3. All members of the series inhibited TS competitively with Ki-values of 0.015-18 microM. Analogs with fluorine or imidazole-based leaving groups caused rapid, irreversible inactivation of TS.
authors.affiliation: Department of Chemistry, University at Buffalo, State University of New York, 457 Cooke Hall, Buffalo, New York 14260, USA.
authors.forename: T I
authors.initials: TI
authors.lastname: Kalman
authors.forename: Z
authors.initials: Z
authors.lastname: Nie
authors.forename: A
authors.initials: A
authors.lastname: Kamat
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000480:Alkynes; D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors; C022030:methylacetylene; C007267:2'-deoxyuridylic acid; D013940:Thymidylate Synthase