An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition, and Protein X-ray Structures of Psammaplin C

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• 作者：Prashant Mujumdar ; Kanae Teruya ; Kathryn F. Tonissen ; Daniela Vullo ; Claudiu T. Supuran ; Thomas S. Peat ; Sally-Ann Poulsen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：59
• 期：11
• 页码：5462-5470
• 全文大小：633K
• 年卷期：0
• ISSN：1520-4804

文摘

Psammaplin C is one of only two described natural product primary sulfonamides. Here we report the synthesis of psammaplin C and evaluate the inhibition profile against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes. The compound exhibited unprecedented inhibition of an important cancer-associated isozyme, hCA XII, with a K_i of 0.79 nM. The compound also displayed good isoform selectivity for hCA XII over other CAs. We present the first reported protein X-ray crystal structures of psammaplin C in complex with human CAs. We engineered the easily crystallized hCA II enzyme to mimic both the hCA IX and hCA XII binding sites and then utilized protein X-ray crystallography to determine the binding pose of psammaplin C within the hCA II, hCA IX, and hCA XII mimic active sites, all to high resolution. This is the first time a natural product primary sulfonamide inhibitor has been assessed for inhibition and binding to CAs.