Xanthates and Trithiocarbonates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Effects in Vivo
Xanthates and Trithiocarbonates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Effects in Vivo
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DOI：
10.1021/jm400414j
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发表时间：
2013-06-13
影响因子：
7.3
通讯作者：
Supuran, Claudiu T.
中科院分区：
文献类型：
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作者：
Carta, Fabrizio;Akdemir, Atilla;Supuran, Claudiu T.
二硫代氨基甲酸盐 (DTC) 最近被发现可作为碳酸酐酶 (CA、EC 4.2.1.1) 抑制剂。在碱存在下，通过醇/硫醇与二硫化碳反应制备了一系列结构与 DTC 相关的黄原酸盐和三硫代碳酸盐。测试了这些化合物对四种人 (h) 同工型 hCA I、II、a 和 XII 的抑制作用，这些亚型涉及青光眼（CA II 和 XII）或癌症 (CA IX) 等病理学。检测到了几种针对这些 CM 的低纳摩尔黄原酸盐/三硫代碳酸盐抑制剂。对 CA II 活性位点内一些黄原酸盐的对接研究表明，这些化合物以类似的方式与二硫代氨基甲酸盐结合，与酶活性位点的 Zn(II) 离子单齿配位。通过局部给药，几种黄药在两种青光眼动物模型中显示出有效的降低眼内压的活性。黄原酸盐和硫代黄原酸盐代表了两类新型、有前景的 CA 抑制剂。
Dithiocarbamates (DTCs) were recently discovered as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. A series of xanthates and a trithiocarbonate, structurally related to the DTCs, were prepared by reaction of alcohols/thiols with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms, hCA I, II, a, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar xanthate/trithiocarbonate inhibitors targeting these CM were detected. A docking study of some xanthates within the CA II active site showed that these compounds bind in a similar manner with the dithiocarbamates, coordinating monodentately to the Zn(II) ion from the enzyme active site. Several xanthates showed potent intraocular pressure lowering activity in two animal models of glaucoma via the topical administration. Xanthates and thioxanthates represent two novel, promising classes of CA inhibitors.