Carbonic anhydrase inhibitors.: Inhibition of the transmembrane isozyme XII with sulfonamides -: a new target for the design of antitumor and antiglaucoma drugs?

被引:215
作者
Vullo, D
Innocenti, A
Nishimori, I
Pastorek, J
Scozzafava, A
Pastoreková, S
Supuran, CT
机构
[1] Univ Florence, Lab Chim Bioinorgan, I-50019 Florence, Italy
[2] Kochi Med Sch, Dept Internal Med 1, Nanko Ku, Kochi 7838505, Japan
[3] Slovak Acad Sci, Inst Virol, Ctr Mol Med, Bratislava 84505, Slovakia
关键词
D O I
10.1016/j.bmcl.2004.12.053
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
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页码:963 / 969
页数:7
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