Novel selective human mitochondrial kinase inhibitors: Design, synthesis and enzymatic activity

• Published in: Bioorganic & medicinal chemistry 2007-04, Vol.15 (8), p.3065-3081
• Main Authors: Ciliberti, Nunzia, Manfredini, Stefano, Angusti, Angela, Durini, Elisa, Solaroli, Nicola, Vertuani, Silvia, Buzzoni, Lisa, Bonache, Maria Cruz, Ben-Shalom, Efrat, Karlsson, Anna, Saada, Ann, Balzarini, Jan
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Arabinonucleosides - chemistry; Arabinonucleosides - pharmacology; Biological and medical sciences; Design; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Fibroblasts - drug effects; Fibroblasts - enzymology; Human TK2 inhibitors; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Medical sciences; Medicin och hälsovetenskap; Miscellaneous; Mitochondria - enzymology; Nucleoside analogs; Pharmacology. Drug treatments; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases - antagonists & inhibitors; Protein-Tyrosine Kinases - antagonists & inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure-Activity Relationship; Synthesis; Thymidine Kinase - antagonists & inhibitors; Viruses - drug effects; Viruses - enzymology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.01.049

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 μM, 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 μM). 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.