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Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms.
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2020-03-04 , DOI: 10.1021/acsmedchemlett.0c00062
Francesca Mancuso 1 , Anna Di Fiore 2 , Laura De Luca 1 , Andrea Angeli 3 , Simona M Monti 2 , Giuseppina De Simone 2 , Claudiu T Supuran 3 , Rosaria Gitto 1
Affiliation  

We report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides (5a-s) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeutics. X-ray crystallography confirmed that this class of benzenesulfonamides binds CAs through the canonical anchoring of the benzenesulfonamide moiety to the metal ion and a tail-mediated recognition of the middle/top area of the active site cavity. Compound 5e (R = 2-Cl) demonstrated relevant selectivity toward brain-expressed hCA VII. The best balancing in binding affinity and selectivity toward tumor-expressed hCA IX/hCA XII over ubiquitous hCA I/hCA II was found for inhibitor 5o (R = 3-NO2). Notably 5b (R = 2-F) proved to be the most efficacious inhibitor of hCA XII for which computational studies elucidated the CA recognition process.

中文翻译:

展望可药物治疗的人碳酸酐酶同工型的活性位点腔的边缘。

我们报告了一系列的取代的4-(4-芳酰基哌嗪-1-羰基)苯磺酰胺(5a-s)的合成和生化评估,这些药物被开发为可药用的碳酸酐酶(CA)亚型的抑制剂,作为鉴定新疗法的工具。X射线晶体学证实,这类苯磺酰胺通过苯磺酰胺部分对金属离子的典型锚定和活性中心腔中部/顶部区域的尾部介导识别而与CA结合。化合物5e(R = 2-Cl)对脑表达的hCA VII具有相关的选择性。对于抑制剂5o(R = 3-NO2),发现对肿瘤表达的hCA IX / hCA XII的结合亲和力和选择性优于无处不在的hCA I / hCA II的最佳平衡。
更新日期:2020-03-04
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