Sulfonamides incorporating 1,3,5-triazine moieties selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms I and II: Solution and X-ray crystallographic studies
Sulfonamides incorporating 1,3,5-triazine moieties selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms I and II: Solution and X-ray crystallographic studies
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DOI：
10.1016/j.bmc.2011.04.005
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发表时间：
2011-05-15
影响因子：
3.5
通讯作者：
Supuran, Claudiu T.
中科院分区：
文献类型：
--
作者：
Carta, Fabrizio;Garaj, Vladimir;Supuran, Claudiu T.
三聚氯氰与D，L-氨基酸和氨基醇反应，合成了一系列新的三嗪基取代的苯磺酰胺类化合物。报道了用这些化合物对生理学相关的人碳酸酐酶（CA，EC 4.2.1.1）同种型如CA I、II、IX、XII和XIV的抑制研究。它们显示出对胞质、脱靶同工酶CA I和II的中等-弱抑制，但其中许多是跨膜、肿瘤相关CA IX和XII（以及CA XIV）的低纳摩尔抑制剂。这些化合物与CA II的加合物中的两个的X-射线晶体结构使我们能够理解与这种强抑制特性相关的特征，并且可能还有它们的选择性。还研究了这些化合物中的两种对其他人类同种型（即hCA IV、VA、VB、VI、VII和XIII）的抑制作用，以及真菌病原性CA Nce 103（白色念珠菌）和Can 2（新型隐球菌）的抑制剂，显示出令人感兴趣的活性。因此，1，3，5-三嗪基取代的苯磺酰胺构成一类具有获得靶向α类哺乳动物、肿瘤相关和β类病原生物CA的抑制剂的巨大潜力的化合物。(C)2011爱思唯尔有限公司保留所有权利。
Reaction of cyanuryl chloride with D, L-amino acids and amino alcohols afforded a new series of triazinyl-substituted benzenesulfonamides incorporating amino acyl/hydroxyalkyl-amino moieties. Inhibition studies of physiologically relevant human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA I, II, IX, XII and XIV with these compounds are reported. They showed moderate-weak inhibition of the cytosolic, offtarget isozymes CA I and II, but many of them were low nanomolar inhibitors of the transmembrane, tumor-associated CA IX and XII (and also of CA XIV). The X-ray crystal structure of two of these compounds in adduct with CA II allowed us to understand the features associated with this strong inhibitory properties and possibly also their selectivity. Two of these compounds were also investigated for the inhibition of other human isoforms, that is, hCA IV, VA, VB, VI, VII and XIII, as well as inhibitors of the fungal pathogenic CAs Nce103 (Candida albicans) and Can2 (Cryptococcus neoformans), showing interesting activity. The 1,3,5-triazinyl-substituted benzenesulfonamides constitute thus a class of compounds with great potential for obtaining inhibitors targeting both alpha-class mammalian, tumor-associated, and beta-class from pathogenic organisms CAs. (C) 2011 Elsevier Ltd. All rights reserved.