Carbonic anhydrase inhibitors. Diazenylbenzenesulfonamides are potent and selective inhibitors of the tumor-associated isozymes IX and XII over the cytosolic isoforms I and II

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• 作者：Fabrizio Carta ; Alfonso Maresca ; Andrea Scozzafava ; Daniela Vullo ; Claudiu T. Supuran
• 关键词：Carbonic anhydrase ; Tumor-associated isoforms ; CA IX ; CA XII ; Isoform-selective inhibitor ; Diazenylbenzenesulfonamides
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：15 October 2009
• 年：2009
• 卷：17
• 期：20
• 页码：7093-7099
• 全文大小：273 K

文摘

A series of diazenylbenzenesulfonamides, azo-dye derivatives of sulfanilamide or metanilamide incorporating phenol and amine moieties, were tested for inhibition of the tumor-associated isozymes of carbonic anhydrase (CA, EC 4.2.1.1), CA IX and XII. These compounds showed moderate-low inhibitory activities against the cytosolic isoforms CA I and II (offtargets) and excellent, low nanomolar inhibitory activity against the transmembrane CA IX and XII (K_Is in the range of 3.5–63 nM against CA IX and 5.0–69.4 nM against CA XII, respectively). The selectivity ratio for inhibiting the tumor-associated CA IX over the offtarget CA II was in the range of 15–104 for these diazenylbenzenesulfonamides, making them among the most isoform-selective inhibitors targeting tumor-associated CAs (over the ubiquitous CA II). Since CA IX/XII were recently shown to be both therapeutic and diagnostic targets for hypoxic solid tumors overexpressing these proteins, such compounds held promise for the management of hypoxic tumors, which are largely non-responsible to classical chemo- and radio-therapy.