RT Journal Article SR Electronic T1 Non-Nucleoside Inhibitors of Mitochondrial Thymidine Kinase (TK-2) Differentially Inhibit the Closely Related Herpes Simplex Virus Type 1 TK and Drosophila melanogaster Multifunctional Deoxynucleoside Kinase JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 263 OP 270 DO 10.1124/mol.63.2.263 VO 63 IS 2 A1 Jan Balzarini A1 Ana-Isabel Hernández A1 Philippe Roche A1 Robert Esnouf A1 Anna Karlsson A1 Maria-José Camarasa A1 Maria-Jesus Pérez-Pérez YR 2003 UL http://molpharm.aspetjournals.org/content/63/2/263.abstract AB 5′-O-Trityl derivatives of thymidine (dThd), (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU), and their acyclic analogs 1-[(Z)-4-triphenylmethoxy-2-butenyl]thymine (KIN-12) and (E)-5-(2-bromovinyl)-1-[(Z)-4-triphenylmethoxy-2-butenyl]uracil (KIN-52) have been synthesized and evaluated for their inhibitory activity against the amino acid sequence related mitochondrial dThd kinase (TK-2), herpes simplex virus type 1 (HSV-1) TK, andDrosophila melanogaster multifunctional 2′-deoxynucleoside kinase (Dm-dNK). Several compounds proved markedly inhibitory to these enzymes and represent a new generation of nucleoside kinase inhibitors. KIN-52 was the most potent and selective inhibitor of TK-2 (IC50, 1.3 μM;Ki, 0.50 μM;Ki/Km, 0.37) but was not inhibitory against HSV-1 TK and Dm-dNK at 100 μM. As found for the alternative substrate BVDU, the tritylated compounds competitively inhibited the three enzymes with respect to dThd. However, whereas BVDU behaved as a noncompetitive inhibitor (alternative substrate) of TK-2 and HSV-1 TK with respect to ATP as the varying substrate, the novel tritylated enzyme inhibitors emerged as reversible purely uncompetitive inhibitors of these enzymes. Computer-assisted modeling studies are in agreement with these findings. The tritylated compounds do not act as alternative substrates and they showed a type of kinetics against the nucleoside kinases different from that of BVDU. KIN-12, and particularly KIN-52, are the very first non-nucleoside specific inhibitors of TK-2 reported and may be useful for studying the physiological role of the mitochondrial TK-2 enzyme. The American Society for Pharmacology and Experimental Therapeutics