Discovery of a potent and selective human AC2 inhibitor based on 7-deazapurine analogues of adefovir

0577921 - ÚOCHB 2024 RIV GB eng J - Journal Article
Kraina, Pavel - Česnek, Michal - Tloušťová, Eva - Mertlíková-Kaiserová, Helena - Fulton, C. J. - Davidson, E. K. - Smith, B. P. - Watts, V. J. - Janeba, Zlatko
Discovery of a potent and selective human AC2 inhibitor based on 7-deazapurine analogues of adefovir.
Bioorganic & Medicinal Chemistry. Roč. 95, November (2023), č. článku 117508. ISSN 0968-0896. E-ISSN 1464-3391
R&D Projects: GA MŠMT LTAUSA18086
Institutional support: RVO:61388963
Keywords : acyclic nucleoside phosphonates * adefovir * 7-deazapurine * prodrugs * adenylate cyclase
OECD category: Organic chemistry
Impact factor: 3.5, year: 2022
Method of publishing: Limited access
https://doi.org/10.1016/j.bmc.2023.117508

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.
Permanent Link: https://hdl.handle.net/11104/0346999