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Discovery of a potent and selective human AC2 inhibitor based on 7-deazapurine analogues of adefovir
P. Kraina, M. Česnek, E. Tloušťová, H. Mertlíková-Kaiserová, CJ. Fulton, EK. Davidson, BP. Smith, VJ. Watts, Z. Janeba
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
R01 NS119917
NINDS NIH HHS - United States
- MeSH
- adenylátcyklasový toxin MeSH
- adenylátcyklasy * MeSH
- HEK293 buňky MeSH
- lidé MeSH
- nukleosidy chemie MeSH
- organofosfonáty * farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Adefovir based acyclic nucleoside phosphonates were previously shown to modulate bacterial and, to a certain extent, human adenylate cyclases (mACs). In this work, a series of 24 novel 7-substituted 7-deazaadefovir analogues were synthesized in the form of prodrugs. Twelve analogues were single-digit micromolar inhibitors of Bordetella pertussis adenylate cyclase toxin with no cytotoxicity to J774A.1 macrophages. In HEK293 cell-based assays, compound 14 was identified as a potent (IC50 = 4.45 μM), non-toxic, and selective mAC2 inhibitor (vs. mAC1 and mAC5). Such a compound represents a valuable addition to a limited number of small-molecule probes to study the biological functions of individual endogenous mAC isoforms.
Citace poskytuje Crossref.org
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