Advanced search
1 file | 332.44 KB

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

Author
Organization
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 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.
Keywords
DEOXYRIBONUCLEOSIDE KINASES, ANALOGS, IDENTIFICATION

Downloads

    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 332.44 KB

Citation

Please use this url to cite or link to this publication:

Chicago
Van Poecke, Sara, Ana Negri , Jolien Janssens, Nicola Solaroli, Anna Karlsson, Federico Gago, Jan Balzarinii, and Serge Van Calenbergh. 2011. “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.” Organic & Biomolecular Chemistry 9 (3): 892–901.
APA
Van Poecke, S., Negri , A., Janssens, J., Solaroli, N., Karlsson, A., Gago, F., Balzarinii, J., et al. (2011). 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. ORGANIC & BIOMOLECULAR CHEMISTRY, 9(3), 892–901.
Vancouver
1.
Van Poecke S, Negri A, Janssens J, Solaroli N, Karlsson A, Gago F, et al. 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. ORGANIC & BIOMOLECULAR CHEMISTRY. 2011;9(3):892–901.
MLA
Van Poecke, Sara, Ana Negri , Jolien Janssens, et al. “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.” ORGANIC & BIOMOLECULAR CHEMISTRY 9.3 (2011): 892–901. Print.
@article{2007915,
  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 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.},
  author       = {Van Poecke, Sara and Negri , Ana  and Janssens, Jolien and Solaroli, Nicola and  Karlsson, Anna and Gago, Federico  and Balzarinii, Jan  and Van Calenbergh, Serge},
  issn         = {1477-0520},
  journal      = {ORGANIC \& BIOMOLECULAR CHEMISTRY},
  keyword      = {DEOXYRIBONUCLEOSIDE KINASES,ANALOGS,IDENTIFICATION},
  language     = {eng},
  number       = {3},
  pages        = {892--901},
  title        = {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},
  url          = {http://dx.doi.org/10.1039/c0ob00591f},
  volume       = {9},
  year         = {2011},
}

Altmetric
View in Altmetric
Web of Science
Times cited: