title: Improving the selectivity of acyclic nucleoside analogues as inhibitors of human mitochondrial thymidine kinase: replacement of a triphenylmethoxy moiety with substituted amines and carboxamides.
abstract: Two series of analogues of the novel human mitochondrial thymidine kinase inhibitor 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine were synthesized by replacing the triphenylmethoxy moiety by a variety of substituted amines and carboxamides. In all the cases, the selectivity against the mitochondrial enzyme was either maintained or improved, and several derivatives were almost as potent as the parent compound. A molecular model was built that can account for the observed selectivities.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Ana-Isabel
authors.initials: AI
authors.lastname: Hernández
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Fátima
authors.initials: F
authors.lastname: Rodríguez-Barrios
authors.forename: Ana
authors.initials: A
authors.lastname: San-Félix
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D013937:Thymidine Kinase; D013936:Thymidine