Acyclic nucleoside phosphonates with 2-aminothiazole base as inhibitors of bacterial and mammalian adenylate cyclases.
Acyclic nucleoside phosphonates with 2-aminothiazole base as inhibitors of bacterial and mammalian adenylate cyclases.
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DOI：
10.1016/j.ejmech.2021.113581
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发表时间：
2021-10-15
影响因子：
6.7
通讯作者：
Janeba Z
中科院分区：
文献类型：
--
作者：
Břehová P;Chaloupecká E;Česnek M;Skácel J;Dračínský M;Tloušťová E;Mertlíková-Kaiserová H;Soto-Velasquez MP;Watts VJ;Janeba Z
合成了一系列新型的无环核苷膦(ANPs)作为潜在的腺苷环化酶抑制剂，其中阿德福韦的腺嘌呤核苷酸碱基(PMEA)被5-取代的2-氨基噻唑取代。该设计是基于MB05032的结构，MB05032是一种果糖1，6-二磷酸酶的有效和选择性的抑制剂，也是一种很好的腺苷一磷酸(AMP)的模拟物。其中14个化合物对百日咳杆菌环化酶毒素(ACT)有较强的抑制作用，大部分对J774A.1巨噬细胞无细胞毒性。在酶促试验中，所选择的磷酸二磷酸盐(核苷三磷酸类似物)对ACT(IC50低至37 nM)和炭疽杆菌水肿因子(IC50低至235 nM)具有很强的抑制作用。此外，在基于HEK293细胞的检测中，发现几个ANP是哺乳动物AC1的选择性抑制剂(尽管有一些相关的细胞毒性)，其中一个化合物显示出对哺乳动物AC2的选择性抑制(仅有剩余腺苷环化酶活性的12%)，但没有观察到细胞毒性。哺乳动物AC1抑制剂可能代表着开发治疗人类炎症性和神经病理性疼痛的药物的潜在先导。
A series of novel acyclic nucleoside phosphonates (ANPs) was synthesized as potential adenylate cyclase inhibitors, where the adenine nucleobase of adefovir (PMEA) was replaced with a 5-substituted 2-aminothiazole moiety. The design was based on the structure of MB05032, a potent and selective inhibitor of fructose 1,6-bisphosphatase and a good mimic of adenosine monophosphate (AMP). From the series of eighteen novel ANPs, which were prepared as phosphoroamidate prodrugs, fourteen compounds were potent (single digit micromolar or submicromolar) inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT), mostly without observed cytotoxicity in J774A.1 macrophage cells. Selected phosphono diphosphates (nucleoside triphosphate analogues) were potent inhibitors of ACT (IC50 as low as 37 nM) and B. anthracis edema factor (IC50 as low as 235 nM) in enzymatic assays. Furthermore, several ANPs were found to be selective mammalian AC1 inhibitors in HEK293 cell-based assays (although with some associated cytotoxicity) and one compound exhibited selective inhibition of mammalian AC2 (only 12% of remaining adenylate cyclase activity) but no observed cytotoxicity. The mammalian AC1 inhibitors may represent potential leads in development of agents for treatment of human inflammatory and neuropathic pain.
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影响因子：
3.4
作者：
Brehova, Petra;Smidkova, Marketa;Skacel, Jan;Dracinsky, Martin;Mertlikova-Kaiserova, Helena;Velasquez, Monica P. Soto;Watts, Val J.;Janeba, Zlatko
通讯作者：
Janeba, Zlatko
DOI：
10.1073/pnas.0502983102
发表时间：
2005-05-31
影响因子：
11.1
作者：
Erion, MD;van Poelje, PD;Lipscomb, WN
通讯作者：
Lipscomb, WN
影响因子：
4.8
作者：
Gille, A;Lushington, GH;Seifert, R
通讯作者：
Seifert, R
DOI：
10.1124/jpet.113.207449
发表时间：
2013-11-01
影响因子：
3.5
作者：
Conley, Jason M.;Brand, Cameron S.;Watts, Val J.
通讯作者：
Watts, Val J.
影响因子：
7.3
作者：
McGuigan, Christopher;Madela, Karolina;Chamberlain, Stanley
通讯作者：
Chamberlain, Stanley