title: Novel selective human mitochondrial kinase inhibitors: design, synthesis and enzymatic activity.
abstract: Selective and effective TK2 inhibitors can be obtained by introduction of bulky lipophilic chains (acyl or alkyl entities) at the 2' position of araT and BVaraU, nucleoside analogues naturally endowed with a low TK2 affinity. These derivatives showed a competitive inhibitory activity against TK2 in micromolar range. BVaraU nucleoside analogues, modified on the 2'-O-acyl chain with a terminal N-Boc amino-group, conserved or increased the inhibitory activity against TK2 (7l and 7m IC(50): 6.4 and 3.8 microM, respectively). The substitution of an ester for a carboxamide moiety at the 2' position of araT afforded a consistent reduction of the inhibitory activity (25, IC(50): 480 microM). On the contrary, modifications at 2'-OH position of araC and araG, have provided inactive derivatives against TK2 and dGK, respectively. The biological activity of a representative compound, 2'-O-decanoyl-BVaraU, was also investigated in normal human fibroblasts and was found to impair mitochondrial function due to TK2 inhibition.
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, Italy.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Ciliberti
authors.forename: Stefano
authors.initials: S
authors.lastname: Manfredini
authors.forename: Angela
authors.initials: A
authors.lastname: Angusti
authors.forename: Elisa
authors.initials: E
authors.lastname: Durini
authors.forename: Nicola
authors.initials: N
authors.lastname: Solaroli
authors.forename: Silvia
authors.initials: S
authors.lastname: Vertuani
authors.forename: Lisa
authors.initials: L
authors.lastname: Buzzoni
authors.forename: Maria Cruz
authors.initials: MC
authors.lastname: Bonache
authors.forename: Efrat
authors.initials: E
authors.lastname: Ben-Shalom
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001087:Arabinonucleosides / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000201:enzymology*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D014780:Viruses / Q000187:drug effects / Q000201:enzymology
chemical_list: D000998:Antiviral Agents; D001087:Arabinonucleosides; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; C028771:9-arabinofuranosylguanine; D010770:Phosphotransferases; D017853:Phosphotransferases (Alcohol Group Acceptor); C020018:deoxyribonucleoside kinases; D013937:Thymidine Kinase; D011505:Protein-Tyrosine Kinases