Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality. Telomerase inhibitors (i.e., azidothymidine) can represent promising antitumor agents, although showing high toxicity when administered alone. Better outcomes were observed within a multipharmacological approach instead. In this context, we exploited the validated antitumor targets carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII to attain the first proof of concept on CA–telomerase dual-hybrid inhibitors. Compounds 1b, 7b, 8b, and 11b showed good in vitro inhibition potency against the CAs IX and XII, with K_I values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC₅₀ values ranging from 5.2 to 9.1 μM). High-resolution X-ray crystallography on selected derivatives in the adduct with hCA II as a model study allowed to determine their binding modes and thus to set the structural determinants necessary for further development of compounds selectively targeting the tumoral cells.

中文翻译：

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叠氮胸苷“点击”成1,2,3-三唑：关于碳酸酐酶-端粒酶双杂交抑制剂的首次报道。

癌细胞依靠酶端粒酶（EC 2.7.7.49）促进细胞永生。端粒酶抑制剂（即叠氮胸苷）可以代表有希望的抗肿瘤药，尽管单独给药时显示出高毒性。相反，在多药理学方法中观察到更好的结果。在这种情况下，我们利用经过验证的抗肿瘤靶标碳酸酐酶（CAs; EC 4.2.1.1）IX和XII获得了CA-端粒酶双杂交抑制剂的第一个概念证明。化合物1b，7b，8b和11b对CAs IX和XII表现出良好的体外抑制能力，K _I值在低纳摩尔范围内，并且在PC-3和HT-29细胞中具有很强的抗端粒酶活性（IC_50个值，范围从5.2到9.1μM。对加合物中选定衍生物的高分辨率X射线晶体学分析（以hCA II为模型研究）可以确定其结合模式，从而确定进一步开发选择性靶向肿瘤细胞的化合物所必需的结构决定因素。