Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation.
Medicinal Chemistry Center, Togliatti State University, Togliatti, 445020, Russian Federation.
Eur J Med Chem. 2021 Jun 5;218:113352. doi: 10.1016/j.ejmech.2021.113352. Epub 2021 Mar 16.
Herein we report the synthesis of a set of thirty-four primary sulfonamides generated via formal N-H-insertion of metal carbenes into anilinic amino group of sulfanilamide and its meta-substituted analog. Obtained compounds were tested in vitro as inhibitors of four physiologically significant isoforms of the metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1). Many of the synthesized sulfonamides displayed low nanomolar K values against therapeutically relevant hCA II, IX, and XII, whereas they did not potently inhibit hCA I. Provided the promising activity profiles of the substances towards tumor-associated hCA IX and XII isozymes, single-concentration MTT test was performed for the entire set. Disappointingly, most of the discovered hCA inhibitors did not significantly suppress the growth of cancer cells either in normoxia or CoCl induced hypoxic conditions. The only two compounds exerting profound antiproliferative effect turned out to be modest hCA inhibitors. Their out of the range activity in cells is likely attributive to the presence of Michael acceptor substructure which can potentially act either through the inhibition of Thioredoxin reductases (TrxRs, EC 1.8.1.9) or nonspecific covalent binding to cell proteins.
在此，我们报告了一组三十四个通过金属卡宾对磺胺基苯胺中氨基的形式 N-H 插入合成的伯磺酰胺及其间位取代类似物。所得化合物在体外作为四种生理相关的金属酶人碳酸酐酶（hCA，EC 4.2.1.1）同工酶的抑制剂进行了测试。许多合成的磺酰胺对治疗上相关的 hCA II、IX 和 XII 具有低纳摩尔 K 值，而对 hCA I 没有强烈抑制作用。鉴于这些物质对肿瘤相关 hCA IX 和 XII 同工酶的有希望的活性谱，对整个系列进行了单浓度 MTT 测试。令人失望的是，大多数发现的 hCA 抑制剂无论是在常氧还是 CoCl 诱导的缺氧条件下，都不能显著抑制癌细胞的生长。仅两种化合物表现出明显的抗增殖作用，结果被证明是适度的 hCA 抑制剂。它们在细胞中的活性范围之外可能归因于 Michael 受体亚结构的存在，该结构可以通过抑制硫氧还蛋白还原酶（TrxRs，EC 1.8.1.9）或与细胞蛋白的非特异性共价结合而发挥作用。
