Improving the selectivity of acyclic nucleoside analogues as inhibitors of human mitochondrial thymidine kinase: replacement of a triphenylmethoxy moiety with substituted amines and carboxamides.
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.
Hernández
Ana-Isabel
AI
Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
Balzarini
Jan
J
Rodríguez-Barrios
Fátima
F
San-Félix
Ana
A
Karlsson
Anna
A
Gago
Federico
F
Camarasa
María-José
MJ
Pérez-Pérez
María Jesús
MJ
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*
D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D013937:Thymidine Kinase; D013936:Thymidine