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Title: Novel selective human mitochondrial kinase inhibitors: design, synthesis and enzymatic activity
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 #
Issue Date: Apr-2007
Publisher: Pergamon
Series Title: Bioorganic & Medicinal Chemistry vol:15 issue:8 pages:3065-3081
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.
URI: 
ISSN: 0968-0896
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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