Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 16610, Prague 6, Czech Republic.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN, 47907, USA.
ChemMedChem. 2018 Sep 6;13(17):1779-1796. doi: 10.1002/cmdc.201800332. Epub 2018 Jul 31.
A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC values ranging from 4.1 to 5.6 μm in HEK293 cell-based assays.
我们制备了一系列 13 种非环核苷膦酸（ANPs）作为双酰胺前药。在 J774A.1 巨噬细胞细胞测定中，发现其中 5 种化合物对百日咳博德特氏菌腺苷酸环化酶毒素（ACT）无细胞毒性且具有选择性抑制作用。阿德福韦的 8-氮杂-7-脱氮嘌呤衍生物（PMEA）是该系列中最有效的 ACT 抑制剂（IC =16 nm），对哺乳动物腺苷酸环化酶（mACs）具有显著的选择性。通过在无细胞测定中直接评估相应的膦酸二膦酸盐，对最有效的类似物的 AC 抑制特性进行了确认，发现它们对炭疽杆菌的 ACT 和水肿因子（EF）均具有很强的抑制作用（IC 值范围为 0.5 至 21 nm）。此外，还发现 PMEA 的 7-卤代-7-脱氮嘌呤类似物是有效的选择性哺乳动物 AC1 抑制剂（对 AC2 和 AC5 没有抑制作用），在基于 HEK293 细胞的测定中，IC 值范围为 4.1 至 5.6 μm。
