Hypoxia-Targeting Carbonic Anhydrase IX Inhibitors by a New Series of Nitroimidazole-Sulfonamides/Sulfamides/Sulfamates

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• 作者：Marouan Rami ; Ludwig Dubois ; Nanda-Kumar Parvathaneni ; Vincenzo Alterio ; Simon J. A. van Kuijk ; Simona Maria Monti ; Philippe Lambin ; Giuseppina De Simone ; Claudiu T. Supuran ; Jean-Yves Winum
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8512-8520
• 全文大小：367K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on the complex of hCA II with the lead sulfamide derivative of this series clarified the binding mode of this type of inhibitors in the enzyme active site cavity. Some of the best nitroimidazole CA IX inhibitors showed significant activity in vitro by reducing hypoxia-induced extracellular acidosis in HT-29 and HeLa cell lines. In vivo testing of the lead molecule in the sulfamide series, in cotreatment with doxorubicin, demonstrated a chemosensitization of CA IX containing tumors. Such CA inhibitors, specifically targeting the tumor-associated isoforms, are candidates for novel treatment strategies against hypoxic tumors overexpressing extracellular CA isozymes.