title: Synthesis and evaluation of thymine-derived carboxamides against mitochondrial thymidine kinase (TK-2) and related enzymes.
abstract: Based on the structure of our previously identified mitochondrial thymidine kinase (TK-2) inhibitors, three series of thymine-derived carboxamides have been synthesized and tested against TK-2 and related enzymes. The methodology employed has been a solution-phase parallel synthesis based on the coupling of three thymine-derived acids [4-(thymin-1-yl)butyric acid (I), [4-(thymin-1-yl)-butyrylamino]acetic acid (II) and 6-(thymin-1-yl)hexanoic acid (III)] with different commercially available primary amines that carry cyano and/or phenyl groups. The couplings were performed in good yields (from 60% to 90%), with the exception of those that incorporate the highly crowded triphenylmethylamine (e). From the new synthesized compounds, the N-trityl-6-(thymin-1-yl)hexanamide (IIIe) was the most active TK-2 inhibitor (IC(50)=19+/-2microM).
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Eva-María
authors.initials: EM
authors.lastname: Priego
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*; D013941:Thymine / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D010770:Phosphotransferases; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C021892:nucleoside phosphotransferase; D013941:Thymine