Abstract

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 (compound2a), 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.

摘要

由相应的2'-羟基苯乙酮与氨磺酰氯反应得到一系列在5、6或7位具有不同取代基的4-甲基-1,2,3-苯并氧噻嗪-2,2-二氧化物。通过两步方案从 4- 或 5-溴-2'-羟基苯乙酮制备的芳基取代的 2'-羟基苯乙酮中获得 6-和 7-芳基取代的 4-甲基-1,2,3-苯并氧噻嗪-2,2-二氧化物。研究了 4-甲基-1,2,3-苯并氧噻嗪-2,2-二氧化物作为四种人 (h) 碳酸酐酶 (hCA, EC 4.2.1.1) 异构体、脱靶胞质 hCA I 和 II 以及靶标的抑制剂跨膜、肿瘤相关的 hCA IX 和 XII。得到20种4-甲基-1,2,3-苯并恶噻嗪2,2-二氧化物衍生物。除一个例外（化合物2a）外，它们主要充当靶标 hCA IX 和 XII 的纳摩尔抑制剂。基本上，所有筛选的化合物对脱靶 hCA I 没有或表现出较低的抑制特性。hCA II 在微摩尔范围内受到抑制。绝大多数 4-甲基-1,2,3-苯并氧噻嗪 2,2-二氧化物对 CA IX/XII 的选择性优于 hCA I，对 CA IX/XII 的选择性优于 hCA II。