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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

Sara Van Poecke UGent, Ana Negri , Jolien Janssens UGent, Nicola Solaroli, Anna Karlsson, Federico Gago, Jan Balzarinii and Serge Van Calenbergh UGent (2011) ORGANIC & BIOMOLECULAR CHEMISTRY. 9(3). p.892-901
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
DEOXYRIBONUCLEOSIDE KINASES, ANALOGS, IDENTIFICATION
journal title
ORGANIC & BIOMOLECULAR CHEMISTRY
Org. Biomol. Chem.
volume
9
issue
3
pages
892 - 901
Web of Science type
Article
Web of Science id
000286431500038
JCR category
CHEMISTRY, ORGANIC
JCR impact factor
3.696 (2011)
JCR rank
11/56 (2011)
JCR quartile
1 (2011)
ISSN
1477-0520
DOI
10.1039/c0ob00591f
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2007915
handle
http://hdl.handle.net/1854/LU-2007915
date created
2012-01-30 15:23:12
date last changed
2016-12-19 15:45:09
@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},
}

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.