title: Novel ribofuranosylnucleoside lead compounds for potent and selective inhibitors of mitochondrial thymidine kinase-2.
abstract: The ribonucleoside analogues (E)-5-(2-bromovinyl)uridine (5-BV-Urd) and 3'-spiro-(4'-amino-1',2'-oxathiole-2',2'-dioxide)-5-methyluridine (3'-AOD-5-MeUrd) emerged as potent and selective competitive inhibitors of mitochondrial thymidine kinase (TK)-2 with respect to thymidine (K(i)/K(m) values of 9.0 and 1.2 respectively). Cytosolic TK-1 did not show measurable affinity for these compounds. [(32)P]Phosphate transfer studies from [gamma-(32)P]ATP to 5-BV-Urd and 3'-AOD-5-MeUrd revealed extremely poor substrate activity but potent inhibitory potential of the compounds. It was concluded that the ribonucleosides 5-BV-Urd and 3'-AOD-5-MeUrd represent two new lead compounds for potent and selective inhibitors of mitochondrial TK-2.
authors.affiliation: Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Jan.Balzarini@rega.kuleuven.ac.be
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: C
authors.initials: C
authors.lastname: Zhu
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: M J
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.forename: C
authors.initials: C
authors.lastname: Chamorro
authors.forename: M J
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: A
authors.initials: A
authors.lastname: Karlsson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C424164:3'-spiro-(4'-amino-1',2'-oxathiole-2',2'-dioxide)-5-methyluridine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C047764:5-(2-bromovinyl)uridine; D000255:Adenosine Triphosphate; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D014529:Uridine