Drug Design and Synthesis Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi, 110025, India.
University of Florence, NEUROFARBA Department, Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.
Eur J Med Chem. 2022 Dec 5;243:114793. doi: 10.1016/j.ejmech.2022.114793. Epub 2022 Sep 25.
With an aim to develop novel potential antitumor agents, two series of benzene- and benzothiazole-sulfonamide derivatives, acting as effective human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors, have been developed using the tail approach. The synthesized compounds (XS-1 to XS-22) were assayed for the inhibition of physiologically relevant isoforms of hCA, the cytosolic CA I and II, the membrane-bound CA IV and tumor-associated CA IX. It was found the compounds of both series displayed low to medium nanomolar range inhibition against CA I, II and IX, and weak inhibition against CA IV. Some of the derivatives displayed selective inhibition towards tumor-associated CA IX isoform, within the nanomolar range. These potent compounds were also screened for their selective toxicity to evaluate their in vitro anti-proliferative effects on Human Gingival Fibroblasts (HGFs) and breast adenocarcinoma cell line (MCF7). Lastly, molecular docking studies were carried out to explain those structural requirements that were liable for the discrimination among selected human carbonic anhydrase isoforms.
为了开发新型潜在的抗肿瘤药物，我们采用尾部设计方法，开发了两类苯并噻唑磺酰胺衍生物，作为有效的人碳酸酐酶（hCA，EC 4.2.1.1）抑制剂。合成的化合物（XS-1 至 XS-22）被用于抑制生理相关的 hCA 同工酶，包括胞质 CA I 和 II、膜结合 CA IV 和肿瘤相关的 CA IX。结果发现，这两个系列的化合物对 CA I、II 和 IX 均表现出低至中等纳摩尔范围的抑制作用，对 CA IV 的抑制作用较弱。一些衍生物对肿瘤相关的 CA IX 同工酶表现出选择性抑制作用，抑制范围在纳摩尔范围内。这些强效化合物还被筛选出对选择性毒性，以评估它们对人牙龈成纤维细胞（HGFs）和乳腺癌腺癌细胞系（MCF7）的体外增殖抑制作用。最后，进行了分子对接研究，以解释那些易于区分所选人碳酸酐酶同工酶的结构要求。
