3′-[4-Aryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidine Analogues as Potent and Selective Inhibitors of Human Mitochondrial Thymidine Kinase

被引:28
|
作者
Van Poecke, Sara [1 ]
Negri, Ana [2 ]
Gago, Federico [2 ]
Van Daele, Ineke [1 ]
Solaroli, Nicola [3 ]
Karlsson, Anna [3 ]
Balzarini, Jan [4 ]
Van Calenbergh, Serge [1 ]
机构
[1] Univ Ghent, Lab Med Chem FFW, B-9000 Ghent, Belgium
[2] Univ Alcala, Dept Farmacol, E-28871 Madrid, Spain
[3] Karolinska Inst, S-14157 Stockholm, Sweden
[4] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium
关键词
CLICK CHEMISTRY; 1,3-DIPOLAR CYCLOADDITION; NUCLEOSIDE; DERIVATIVES; FUNCTIONALIZATION; OLIGONUCLEOTIDES; TOXICITY; LIGATION; ALKYNES; AZIDES;
D O I
10.1021/jm901532h
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:2902 / 2912
页数:11
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