期刊
BIOCHEMICAL PHARMACOLOGY
卷 71, 期 12, 页码 1671-1682出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2006.03.006
关键词
adenosine kinase; Mycobacterium tuberculosis; nucleoside analogs; structure-activity relationship; purine salvage; methyl-adenosine
资金
- NIAID NIH HHS [AI43241] Funding Source: Medline
Adenosine kinase (Ado kinase, EC 2.7.1.20) is a purine salvage enzyme that phosphorylates adenosine (Ado) to AMP. Ado kinase from Mycobacterium tuberculosis also catalyzes an essential step in the conversion of 2-methyl-Ado to a compound with selective antimyco-bacterial activity. In order to aid in the design of more potent and selective Ado analogs, eighty nucleoside analogs with modifications to the adenine (Ade) moiety of Ado were evaluated as both substrates and inhibitors of Ado kinase from M. tuberculosis, and a subset was further tested with human Ado kinase for the sake of comparison. The best substrates were 2-aza-Ado, 8-aza-9-deaza-Ado, and 2-fluoro-Ado and the most potent inhibitors were N-1-benzyl-Ado (K-i = 0.19 mu M), 2-fluoro-Ado (K-i = 0.5 mu M), 6-cyclopentyloxy-purine riboside (K-i = 0.15 mu M), and 7-iodo-7-deaza-Ado (K-i = 0.21 mu M). These studies revealed the presence of a hydrophobic pocket near the N-6- and N-1-positions that can accommodate substitutions at least as large as a benzyl group. The ability to fit into this pocket increased the likelihood that a compound would be an inhibitor and not a substrate. The 2-position was able to accommodate exocyclic substitutions as large as a methoxy group, although substrate activity was low. Similarly, the 7-position could bind an exocyclic group as large as a carboxamido moiety. However, all of the compounds tested with modifications at the 7-position were much better inhibitors than substrates. MIC studies performed with selected compounds have yielded several Ado analogs with promising antitubercular activity. Future studies will utilize this information for the design of new analogs that may be selective antitubercular agents. (c) 2006 Elsevier Inc. All rights reserved.
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