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

Nunzia Ciliberti; Stefano Manfredini; Angela Angusti; Elisa Durini; Nicola Solaroli; Silvia Vertuani; Lisa Buzzoni; Maria Cruz Bonache; Efrat Ben-Shalom; Anna Karlsson; Ann Saada; Jan Balzarini

doi:10.1016/j.bmc.2007.01.049

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

Bioorg Med Chem. 2007 Apr 15;15(8):3065-81. doi: 10.1016/j.bmc.2007.01.049. Epub 2007 Feb 2.

Authors

Nunzia Ciliberti¹, Stefano Manfredini, Angela Angusti, Elisa Durini, Nicola Solaroli, Silvia Vertuani, Lisa Buzzoni, Maria Cruz Bonache, Efrat Ben-Shalom, Anna Karlsson, Ann Saada, Jan Balzarini

Affiliation

¹ Department of Pharmaceutical Sciences, University of Ferrara, Italy.

PMID: 17324575
DOI: 10.1016/j.bmc.2007.01.049

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / pharmacology
Arabinonucleosides / chemistry
Arabinonucleosides / pharmacology
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Fibroblasts / drug effects
Fibroblasts / enzymology
Humans
Indicators and Reagents
Magnetic Resonance Spectroscopy
Mitochondria / enzymology*
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
Thymidine Kinase / antagonists & inhibitors
Viruses / drug effects
Viruses / enzymology

Substances

Antiviral Agents
Arabinonucleosides
Enzyme Inhibitors
Indicators and Reagents
9-arabinofuranosylguanine
Phosphotransferases
Phosphotransferases (Alcohol Group Acceptor)
deoxyribonucleoside kinases
Thymidine Kinase
Protein-Tyrosine Kinases