Fluorescent sulfonamide carbonic anhydrase inhibitors incorporating 1,2,3-triazole moieties: Kinetic and X-ray crystallographic studies

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• 作者：Fabrizio Carta^a ; ^b ; Marta Ferraroni^a ; Andrea Scozzafava^a ; Claudiu T. Supuran^a ; ^b ; ^{claudiu.supuran@unifi.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Carbonic anhydrase ; Sulfonamide ; Fluorescence ; Click chemistry ; 1 ; 2 ; 3-Triazole
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：24
• 期：2
• 页码：104-112
• 全文大小：1653 K

文摘

Fluorescent sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) were essential for demonstrating the role played by the tumor-associated isoform CA IX in acidification of tumors, cancer progression towards metastasis and for the development of imaging and therapeutic strategies for the management of hypoxic tumors which overexpress CA IX. However, the presently available such compounds are poorly water soluble which limits their use. Here we report new fluorescent sulfonamides 7, 8 and 10 with increased water solubility. The new derivatives showed poor hCA I inhibitory properties, but were effective inhibitors against the hCA II (K_Is of 366–127 nM), CA IX (K_Is of 8.1–36.9 nM), CA XII (K_Is of 4.1–20.5 nM) and CA XIV (K_Is of 12.8–53.6 nM). A high resolution X-ray crystal structure of one of these compounds bound to hCA II revealed the factors associated with the good inhibitory properties. Furthermore, this compound showed a three-fold increase of water solubility compared to a similar derivative devoid of the triazole moiety, making it an interesting candidate for ex vivo/in vivo studies.