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Issue 3, 2011
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Synthesis, modeling and evaluation of 3′-(1-aryl-1H-tetrazol-5-ylamino)-substituted 3′-deoxythymidine derivatives as potent and selective human mitochondrial thymidine kinase inhibitors

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Abstract

Based on the presumed binding mode of an earlier identified inhibitor, we herein report new 3′-modified nucleosides as potent and selective inhibitors of mitochondrial thymidine kinase (TK2). A series of thirteen 3′-amino-, 3′-guanidino- and 3′-tetrazole-containing nucleosides were synthesized and evaluated for their TK2 inhibitory activity. Within the tetrazole series, compounds with nanomolar inhibitory activity were identified. A homology model of TK2 allowed to elucidate the observed activities. Introduction of a 2-bromovinyl group on C-5 of the pyrimidine base of the most promising 3′-derivative further improved the inhibitory activity, and caused a significant increase in the selectivity for TK2versusTK1. Interestingly, for the current series of analogues, a strong correlation was observed between TK2 and Drosophila melanogasterdNK inhibition, further substantiating the phylogenetic relationship between these two nucleoside kinases.

Graphical abstract: Synthesis, modeling and evaluation of 3′-(1-aryl-1H-tetrazol-5-ylamino)-substituted 3′-deoxythymidine derivatives as potent and selective human mitochondrial thymidine kinase inhibitors

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Article information


Submitted
17 Aug 2010
Accepted
14 Oct 2010
First published
02 Dec 2010

Org. Biomol. Chem., 2011,9, 892-901
Article type
Paper

Synthesis, modeling and evaluation of 3′-(1-aryl-1H-tetrazol-5-ylamino)-substituted 3′-deoxythymidine derivatives as potent and selective human mitochondrial thymidine kinase inhibitors

S. Van Poecke, A. Negri, J. Janssens, N. Solaroli, A. Karlsson, F. Gago, J. Balzarini and S. Van Calenbergh, Org. Biomol. Chem., 2011, 9, 892
DOI: 10.1039/C0OB00591F

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