Carbonic anhydrase inhibitors: 2-Substituted-1,3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes VA and VB over the cytosolic and membrane-associated carbonic anhydrases I, II and IV

被引：27

作者：

Smaine, Fatma-Zohra ^{[1
]}

Pacchiano, Fabio ^{[2
]}

Rami, Marouan ^{[1
]}

Barragan-Montero, Veronique ^{[1
]}

Vullo, Daniela ^{[2
]}

Scozzafava, Andrea ^{[2
]}

Winum, Jean-Yves ^{[1
]}

Supuran, Claudiu T. ^{[2
]}

机构：

[1] Ecole Natl Super Chim Montpellier, CNRS, UM1, UM2,UMR 5247,IBMM, F-34296 Montpellier, France

[2] Univ Florence, Lab Chim Bioinorgan, I-50019 Florence, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 24期

关键词：

Carbonic anhydrase; Sulfamide; Isozyme VA and VB; Mitochondria; Isozyme-selective inhibitor;

D O I：

10.1016/j.bmcl.2008.10.093

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 2-substituted-1,3,4-thiadiazole-5-sulfamides was prepared and assayed as inhibitors of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, the membrane-associated CA IV and the mitochondrial CA VA and VB. The new compounds showed weak inhibitory activity against hCA I (K(I)s of 102 nM-7.42 mu M), hCA II (K(I)s of 0.54-7.42 mu M) and hCA IV (K(I)s of 4.32-10.05 mu M) but were low nanomolar inhibitors of hCA VA and hCA VB, with inhibition constants in the range of 4.2-32 nM and 1.3-74 nM, respectively. Furthermore, the selectivity ratios for inhibiting the mitochondrial enzymes over CA II were in the range of 67.5-415, making these sulfamides the first selective CA VA/VB inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6332 / 6335

页数：4

共 36 条

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