Design and synthesis of thiourea compounds that inhibit transmembrane anchored carbonic anhydrases

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• 作者：Janina Moeker^a ; Kanae Teruya^a ; Sabine Rossit^a ; Brendan L. Wilkinson^a ; Marie Lopez^a ; Laurent F. Bornaghi^a ; Alessio Innocenti^b ; Claudiu T. Supuran^b ; ^{claudiu.supuran@unifi.it} ; Sally-Ann Poulsen^a ; ^{s.poulsen@griffith.edu.au}
• 关键词：CA ; carbonic anhydrase ; AZA ; acetazolamide ; DIPEA ; N ; N-diisopropylethylamine ; HSQC ; heteronuclear single quantum coherence ; HRMS ; high resolution mass spectrometry
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 April, 2012
• 卷：20
• 期：7
• 页码：2392-2404
• 文件大小：931 K

摘要

A library of 32 novel glycoconjugate thiourea-bridged benzene sulfonamides have been synthesized from the reaction of glycosyl isothiocyanates with a panel of simple benzene sulfonamides comprising either a free amine or hydrazide. All compounds were investigated for their ability to inhibit the enzymatic activity of five human carbonic anhydrase (hCA) isozymes: hCA I, II and membrane-associated isozymes IX, XII and XIV. A physicochemical feature of the free sugar thioureido glycoconjugates was high water solubility (>20 mg/mL), as well many of these compounds exhibited a desirable potency and CA isozyme selectivity profile. From this library several inhibitors displayed excellent potency-selectivity profiles for transmembrane anchored CAs over off-target CA I and II. These molecules provide potential dual-acting candidates for the development of inhibitors that target the extracellular CAs (IX, XII and XIV)鈥攅ither directly as free sugars (membrane impermeable) or indirectly as acetylated prodrugs, becoming free sugars upon esterase hydrolysis.