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

(2010) JOURNAL OF MEDICINAL CHEMISTRY. 53(7). p.2902-2912
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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.
Keywords
ALKYNE 1, DERIVATIVES, 3-DIPOLAR CYCLOADDITION, CLICK-CHEMISTRY, DEOXYRIBONUCLEOSIDE KINASE, TERMINAL ALKYNES, ANTIVIRAL DRUGS, AZIDES, DNA, NUCLEOSIDE, FUNCTIONALIZATION

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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.
@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},
}

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