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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Pyrrolo and pyrrolopyrimidine sulfonamides act as cytotoxic agents in hypoxia via inhibition of transmembrane carbonic anhydrases
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Pyrrolo and pyrrolopyrimidine sulfonamides act as cytotoxic agents in hypoxia via inhibition of transmembrane carbonic anhydrases

机译：吡咯醇和吡咯哒嘧啶磺酰胺通过抑制跨膜碳酸酐酶作为缺氧中的细胞毒性剂

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摘要

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound llb potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：合成了一系列含有吡咯和吡咯基嘧啶支架的磺胺胺衍生物，并作为碳酸酐酶抑制剂筛选。将合成化合物的抑制活性与胞质溶胶人碳酸酐酶同种型I和II以及透气性同种型IX和XII评价。几个候选者对IX和XII同种型表明有效的抑制活性。此外，在正常细胞（Wi38）和宫颈癌细胞系（HeLa）下，在正常和缺氧条件下使用乙肼作为参考药物，进行细胞毒性选择性和最有效衍生物的活性的前体内筛选。化合物LLB效力在缺氧比常氧条件高几乎三倍，而化合物11F的缺氧与常氧HeLa细胞的缺氧11F的差异几乎高。所有筛选的衍生物在正常细胞上表现出较少的效力（Wi38）。进行分子对接，以发现同种型CaIX的活性位点内的化合物的可能结合模式。 （c）2019年Elsevier Masson SAS。版权所有。

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