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
| Autor: | Anna Karlsson, Andrea Negri, Nicola Solaroli, Jan Balzarini, Federico Gago, Sara Van Poecke, Serge Van Calenbergh, Jolien Janssens |
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| Rok vydání: | 2011 |
| Předmět: |
Azoles
Models Molecular Molecular Structure Pyrimidine Kinase Stereochemistry Aryl Organic Chemistry Thymidine Kinase Biochemistry chemistry.chemical_compound Drosophila melanogaster chemistry Thymidine kinase Animals Humans Tetrazole Homology modeling Amines Physical and Theoretical Chemistry Thymidine Nucleoside |
| Zdroj: | Org. Biomol. Chem.. 9:892-901 |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/c0ob00591f |
| Popis: | 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 TK2 versus TK1. Interestingly, for the current series of analogues, a strong correlation was observed between TK2 and Drosophila melanogaster dNK inhibition, further substantiating the phylogenetic relationship between these two nucleoside kinases. ispartof: Organic & Biomolecular Chemistry vol:9 issue:3 pages:892-901 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
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