Carbonic anhydrase inhibitors.: Inhibition of the transmembrane isozyme XII with sulfonamides -: a new target for the design of antitumor and antiglaucoma drugs?
Carbonic anhydrase inhibitors.: Inhibition of the transmembrane isozyme XII with sulfonamides -: a new target for the design of antitumor and antiglaucoma drugs?
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DOI：
10.1016/j.bmcl.2004.12.053
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发表时间：
2005-02-15
影响因子：
2.7
通讯作者：
Supuran, CT
中科院分区：
文献类型：
--
作者：
Vullo, D;Innocenti, A;Supuran, CT
研究了新克隆的人类碳酸酐酶（CA, EC 4.2.1.1）同位酶XII （hCA XII）与一系列磺胺类药物的抑制作用，包括一些临床使用的衍生物（乙酰唑胺、甲基唑胺、乙氧唑胺、二氯苯胺、多唑胺、溴唑胺、苯唑胺、磺胺类药物，或临床开发的抗肿瘤药物吲哚磺胺），以及磺胺类抗癫痫药物托吡酯。一些简单的氨基/联氨/羟基取代芳香族/杂环磺胺也被纳入研究。所有类型的活性都被检测到，几种中等效价抑制剂（K(I)s在34-220 nM范围内），而乙氧唑胺和几种卤代磺胺表现出较强的效价，K(I)s在11-22 nM范围内。临床使用的抗青光眼磺胺类药物，除了二氯苯酰胺是一种中等抑制剂（K-I为50 nM），以及托吡酯、吲哚仑和舒匹利表现为非常有效的hCA XII抑制剂，K(I)s在3.0-5.7 nM范围内。几种亚纳摩尔抑制剂（K(I)s在0.30-0.85 nM范围内）也被检测到。化合物对hcaxii的选择性优于hcaii，其选择性比在177.7 ~ 566.7之间。显然，hCA XII是抗青光眼磺胺类药物的靶标，有效的hCA XII抑制剂可能与其他肿瘤相关同工酶CA IX抑制剂一起被开发/用于治疗缺氧肿瘤。(C) 2004 Elsevier Ltd.版权所有。
The inhibition of a newly cloned human carbonic anhydrase (CA, EC 4.2.1.1), isozyme XII (hCA XII), has been investigated with a series of sulfonamides, including some clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and sulpiride, or indisulam, a compound in clinical development as antitumor drug), as well as the sulfamate antiepileptic drug topiramate. Some simple amino-/hydrazine-/hydroxy-substituted aromatic/heterocyclic sulfonamides have also been included in the study. All types of activity have been detected, with several medium potency inhibitors (K(I)s in the range of 34-220 nM), whereas ethoxzolamide and several halogenated sulfanilamides showed stronger potency, with K(I)s in the range of 11-22 nM. The antiglaucoma sulfonamides used clinically, except dichlorophenamide, which is a moderate inhibitor (K-I of 50 nM), as well as topiramate, indisulam, and sulpiride behave as very potent hCA XII inhibitors, with K(I)s in the range of 3.0-5.7 nM. Several subnanomolar inhibitors (K(I)s in the range of 0.30-0.85 nM) have also been detected. Compounds with excellent selectivity against hCA XII over hCA II have been found, showing selectivity ratios in the range of 177.7-566.7. Apparently, hCA XII is a target of the antiglaucoma sulfonamides, and potent hCA XII inhibitors may be developed/used for the management of hypoxic tumors, together with inhibitors of the other tumor-associated isozyme, CA IX. (C) 2004 Elsevier Ltd. All rights reserved.