4-甲基-1,2,3-苯并恶噻嗪 2,2-二氧化物衍生物作为人碳酸酐酶 IX 和 XII 的选择性抑制剂，对胞质同工酶 I 和 II 具有选择性。
Derivatives of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxide as selective inhibitors of human carbonic anhydrases IX and XII over the cytosolic isoforms I and II.
机构信息
Latvian Institute of Organic Synthesis, Riga, Latvia.
Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Riga, Latvia.
出版信息
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2170370. doi: 10.1080/14756366.2023.2170370.
A series of 4-methyl-1,2,3-benzoxathiazine-2,2-dioxides with various substituents in 5, 6 or 7 positions was obtained from corresponding 2'-hydroxyacetophenones in their reaction with sulphamoyl chloride. 6- and 7-aryl substituted 4-methyl-1,2,3-benzoxathiazine-2,2-dioxides were obtained from aryl substituted 2'-hydroxyacetophenonesprepared from 4- or 5-bromo-2'-hydroxyacetophenones via two-step protocol. 4-Methyl-1,2,3-benzoxathiazine-2,2-dioxides were investigated as inhibitors of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, off-target cytosolic hCA I and II, and target transmembrane, tumour-associated hCA IX and XII. Twenty derivatives of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxide were obtained. With one exception (compound), they mostly act as nanomolar inhibitors of target hCA IX and XII. Basically, all screened compounds express none or low inhibitory properties towards off-target hCA I. hCA II is inhibited in micromolar range. Overwhelming majority of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxides express excellent selectivity towards CA IX/XII over hCA I as well as very good selectivity towards CA IX/XII over hCA II.
一系列 5、6 或 7 位取代的 4-甲基-1,2,3-苯并恶噻嗪-2,2-二氧化物是由相应的 2'-羟基苯乙酮与磺酰氯反应得到的。6-和 7-芳基取代的 4-甲基-1,2,3-苯并恶噻嗪-2,2-二氧化物是由通过两步法从 4-或 5-溴-2'-羟基苯乙酮制备得到的芳基取代的 2'-羟基苯乙酮得到的。4-甲基-1,2,3-苯并恶噻嗪-2,2-二氧化物被用作四种人源（h）碳酸酐酶（hCA，EC 4.2.1.1）同工酶、非靶标胞质 hCA I 和 II 以及靶标跨膜、肿瘤相关 hCA IX 和 XII 的抑制剂。获得了 20 种 4-甲基-1,2,3-苯并恶噻嗪 2,2-二氧化物衍生物。除了一种（化合物）之外，它们主要作为纳摩尔级的靶标 hCA IX 和 XII 的抑制剂。基本上，所有筛选的化合物对非靶标 hCA I 没有或仅有低抑制活性。hCA II 被抑制在微摩尔范围内。绝大多数 4-甲基-1,2,3-苯并恶噻嗪 2,2-二氧化物对 CA IX/XII 表现出极好的选择性，对 CA IX/XII 也具有非常好的选择性，对 hCA II 则选择性较低。
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