Synthesis, Structure鈥揂ctivity Relationship Studies, and X-ray Crystallographic Analysis of Arylsulfonamides as Potent Carbonic Anhydrase Inhibitors

详细信息    查看全文

• 作者：Rosaria Gitto ; Francesca M. Damiano ; Pavel Mader ; Laura De Luca ; Stefania Ferro ; Claudiu T. Supuran ; Daniela Vullo ; Ji艡铆 Brynda ; Pavl铆na 艠ez谩膷ov谩 ; Alba Chimirri
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3891-3899
• 全文大小：458K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

A series of arylsulfonamides has been synthesized and investigated for the inhibition of some selected human carbonic anhydrase isoforms. The studied compounds showed significant inhibitory effects in the nanomolar range toward druggable isoforms (hCA VII, hCA IX, and hCA XIV) (K_i values from 4.8 to 61.7 nM), whereas they generally exhibited significant selectivity over hCA I and hCA II, that are ubiquitous and considered off-target isoforms. On the basis of biochemical data, we herein discussed structure鈥揳ffinity relationships for this series of arylsulfonamides, suggesting a key role for alkoxy substituents in CA inhibition. Furthermore, X-ray crystal structures of complexes of two active inhibitors (I and 2a) with hCA II allowed us to elucidate the main interactions between the inhibitor and specific amino acid residues within the catalytic site.