Abstract

A series of 1,2,3-benzoxathiazine-2,2-dioxides possessing various substituents in the 5, 7, or 8 position was obtained from corresponding 2-hydroxybenzaldehydes in their reaction with sulfamoyl chloride. 5-, 7-, and 8-aryl substituted 1,2,3-benzoxathiazine-2,2-dioxides were prepared from aryl substituted 2-hydroxybenzaldehydes obtained from 3-, 4-, or 6-bromo-2-hydroxybenzaldehydes via two-step protocol. 1,2,3-Benzoxathiazine-2,2-dioxides were investigated for the inhibition of four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, cytosolic hCA I and II and tumour-associated transmembrane hCA IX and XII. Twenty four derivatives of 1,2,3-benzoxathiazine 2,2-dioxide were obtained. Most of them act as nanomolar inhibitors of hCA IX and XII. Almost all compounds except 2d and 5a-e also express nanomolar inhibitory activity for hCA II. hCA I is poorly inhibited or not inhibited by 1,2,3-benzoxathiazine 2,2-dioxides. Some of the new derivatives exhibit promising selectivity towards CA IX/XII over hCA I, although none of the compounds are selective towards CA IX/XII over both hCA I and II.

摘要

一系列在 5、7 或 8 位具有不同取代基的 1,2,3-苯并恶噻嗪-2,2-二氧化物是由相应的 2-羟基苯甲醛与氨磺酰氯反应得到的。5-、7- 和 8-芳基取代的 1,2,3-苯并恶噻嗪-2,2-二氧化物是从 3-、4- 或 6-溴-2-羟基苯甲醛获得的芳基取代的 2-羟基苯甲醛通过两种方法制备的步协议。研究了 1,2,3-Benzoxathiazine-2,2-dioxides 对四种人碳酸酐酶 (hCA, EC 4.2.1.1) 亚型、胞质 hCA I 和 II 以及肿瘤相关跨膜 hCA IX 和 XII 的抑制作用。获得了 1,2,3-苯并恶噻嗪 2,2-二氧化物的 24 个衍生物。它们中的大多数充当 hCA IX 和 XII 的纳摩尔抑制剂。几乎所有的化合物除了2d和5a-e还表达了对 hCA II 的纳摩尔抑制活性。hCA I 很少被 1,2,3-苯并恶噻嗪 2,2-二氧化物抑制或不被抑制。一些新的衍生物对 CA IX/XII 的选择性优于 hCA I，尽管没有一种化合物对 CA IX/XII 的选择性优于 hCA I 和 II。