Ghent University Academic Bibliography

Advanced

3'-[4-Aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogues as potent and selective inhibitors of human mitochondrial thymidine kinase

Sara Van Poecke UGent, Ana Negri, Federico Gago, Ineke Van Daele, Nicola Solaroli, Anna Karlsson, Jan Balzarini and Serge Van Calenbergh UGent (2010) JOURNAL OF MEDICINAL CHEMISTRY. 53(7). p.2902-2912
abstract
In an effort to increase the potency and selectivity of earlier identified substrate-based inhibitors of mitochondrial thymidine kinase 2 (TK-2), we now describe the synthesis of new thymidine analogues containing a 4- or 5-substituted 1,2,3-triazol-1-yl substituent at the 3'-position of the 2'-deoxyribofuranosyl ring. These analogues were prepared by Cu- and Ru-catalyzed cycloadditions of 3'-azido-3'-deoxythymidine and the appropriate alkynes, which produced the 1,4- and 1,5-triazoles, respectively. Selected analogues showed nanomolar inhibitory activity for TK-2, while virtually not affecting the TK-1 counterpart. Enzyme kinetics indicated a competitive and uncompetitive inhibition profile against thymidine and the cosubstrate ATP, respectively. This behavior is rationalized by suggesting that the inhibitors occupy the substrate-binding site in a TK-2 ATP complex that maintains the enzyme's active site in a closed conformation through the stabilization of a small lid domain.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ALKYNE 1, DERIVATIVES, 3-DIPOLAR CYCLOADDITION, CLICK-CHEMISTRY, DEOXYRIBONUCLEOSIDE KINASE, TERMINAL ALKYNES, ANTIVIRAL DRUGS, AZIDES, DNA, NUCLEOSIDE, FUNCTIONALIZATION
journal title
JOURNAL OF MEDICINAL CHEMISTRY
J. Med. Chem.
volume
53
issue
7
pages
2902 - 2912
Web of Science type
Article
Web of Science id
000276096300019
JCR category
CHEMISTRY, MEDICINAL
JCR impact factor
5.207 (2010)
JCR rank
3/50 (2010)
JCR quartile
1 (2010)
ISSN
0022-2623
DOI
10.1021/jm901532h
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1141175
handle
http://hdl.handle.net/1854/LU-1141175
date created
2011-02-07 13:47:45
date last changed
2016-12-19 15:45:26
@article{1141175,
  abstract     = {In an effort to increase the potency and selectivity of earlier identified substrate-based inhibitors of mitochondrial thymidine kinase 2 (TK-2), we now describe the synthesis of new thymidine analogues containing a 4- or 5-substituted 1,2,3-triazol-1-yl substituent at the 3'-position of the 2'-deoxyribofuranosyl ring. These analogues were prepared by Cu- and Ru-catalyzed cycloadditions of 3'-azido-3'-deoxythymidine and the appropriate alkynes, which produced the 1,4- and 1,5-triazoles, respectively. Selected analogues showed nanomolar inhibitory activity for TK-2, while virtually not affecting the TK-1 counterpart. Enzyme kinetics indicated a competitive and uncompetitive inhibition profile against thymidine and the cosubstrate ATP, respectively. This behavior is rationalized by suggesting that the inhibitors occupy the substrate-binding site in a TK-2 ATP complex that maintains the enzyme's active site in a closed conformation through the stabilization of a small lid domain.},
  author       = {Van Poecke, Sara and Negri, Ana and Gago, Federico and Van Daele, Ineke and Solaroli, Nicola and Karlsson, Anna and Balzarini, Jan and Van Calenbergh, Serge},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keyword      = {ALKYNE 1,DERIVATIVES,3-DIPOLAR CYCLOADDITION,CLICK-CHEMISTRY,DEOXYRIBONUCLEOSIDE KINASE,TERMINAL ALKYNES,ANTIVIRAL DRUGS,AZIDES,DNA,NUCLEOSIDE,FUNCTIONALIZATION},
  language     = {eng},
  number       = {7},
  pages        = {2902--2912},
  title        = {3'-[4-Aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogues as potent and selective inhibitors of human mitochondrial thymidine kinase},
  url          = {http://dx.doi.org/10.1021/jm901532h},
  volume       = {53},
  year         = {2010},
}

Chicago
Van Poecke, Sara, Ana Negri, Federico Gago, Ineke Van Daele, Nicola Solaroli, Anna Karlsson, Jan Balzarini, and Serge Van Calenbergh. 2010. “3’-[4-Aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine Analogues as Potent and Selective Inhibitors of Human Mitochondrial Thymidine Kinase.” Journal of Medicinal Chemistry 53 (7): 2902–2912.
APA
Van Poecke, S., Negri, A., Gago, F., Van Daele, I., Solaroli, N., Karlsson, A., Balzarini, J., et al. (2010). 3’-[4-Aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogues as potent and selective inhibitors of human mitochondrial thymidine kinase. JOURNAL OF MEDICINAL CHEMISTRY, 53(7), 2902–2912.
Vancouver
1.
Van Poecke S, Negri A, Gago F, Van Daele I, Solaroli N, Karlsson A, et al. 3’-[4-Aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogues as potent and selective inhibitors of human mitochondrial thymidine kinase. JOURNAL OF MEDICINAL CHEMISTRY. 2010;53(7):2902–12.
MLA
Van Poecke, Sara, Ana Negri, Federico Gago, et al. “3’-[4-Aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine Analogues as Potent and Selective Inhibitors of Human Mitochondrial Thymidine Kinase.” JOURNAL OF MEDICINAL CHEMISTRY 53.7 (2010): 2902–2912. Print.