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Synthesis and Biological Evaluation of 4‐Sulfamoylphenyl/Sulfocoumarin Carboxamides as Selective Inhibitors of Carbonic Anhydrase Isoforms hCA II, IX, and XII
ChemMedChem ( IF 3.6 ) Pub Date : 2018-05-22 , DOI: 10.1002/cmdc.201800180 Srinivas Angapelly 1 , Andrea Angeli 2 , Arbaj Jabbar Khan 1 , P. V. Sri Ramya 1 , Claudiu T. Supuran 2 , Mohammed Arifuddin 1
ChemMedChem ( IF 3.6 ) Pub Date : 2018-05-22 , DOI: 10.1002/cmdc.201800180 Srinivas Angapelly 1 , Andrea Angeli 2 , Arbaj Jabbar Khan 1 , P. V. Sri Ramya 1 , Claudiu T. Supuran 2 , Mohammed Arifuddin 1
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With the aim to develop potent and selective human carbonic anhydrase inhibitors (hCAIs), we synthesized 4‐sulfamoylphenyl/sulfocoumarin benzamides (series 5 a–r and series 7 a–q) and evaluated their inhibition profiles against five isoforms of the zinc‐containing human carbonic anhydrase (hCA, EC 4.2.1.1): cytosolic hCA I and II, and the transmembrane isozymes hCA IV, IX, and XII. Compounds 5 a–r were found to selectively inhibit hCA II in the nanomolar range, while being less effective against the other hCA isoforms. As noted from the literature, sulfocoumarin (1,2‐benzoxathiine 2,2‐dioxide) acts as a “prodrug” inhibitor and is hydrolyzed by the esterase activity of hCA to form 2‐hydroxyphenylvinylsulfonic acid, which thereafter binds to the enzyme in a manner similar to that of coumarins and sulfoxocoumarins. All these sulfocoumarins (compounds 7 a–q) were found to be very weak or ineffective as inhibitors of the housekeeping off‐target hCA isoforms I and II, and effectively inhibited the transmembrane tumor‐associated isoforms IX and XII in the high nanomolar to micromolar ranges. Further structural modifications of these molecules could be useful for the development of effective hCA inhibitors used for the treatment of glaucoma, epilepsy, and cancer.
中文翻译：
作为碳酸酐酶同工型hCA II，IX和XII的选择性抑制剂的4-氨基磺酰基苯基/磺基香豆素羧酰胺的合成和生物学评估
为了开发有效的和选择性的人类碳酸酐酶抑制剂（hCAIs），我们合成了4-氨磺酰基苯基/磺基香豆素苯甲酰胺（系列5 a – r和系列7 a – q），并评估了它们对含锌的五种同工型的抑制谱。人碳酸酐酶（hCA，EC 4.2.1.1）：胞质hCA I和II，以及跨膜同工酶hCA IV，IX和XII。化合物5 a – r据发现，它们在纳摩尔范围内选择性抑制hCA II，而对其他hCA亚型的抑制作用较弱。从文献中可以看出，磺基香豆素（1,2-苯并氧杂氨酸2,2-二氧化物）充当“前药”抑制剂，并通过hCA的酯酶活性水解形成2-羟基苯基乙烯基磺酸，然后与酶结合。类似于香豆素和磺氧香豆素的方式。所有这些磺基香豆素（化合物7 a – q）被发现作为管家脱靶hCA异构体I和II的抑制剂非常弱或无效，并在高纳摩尔至微摩尔范围内有效抑制跨膜肿瘤相关的亚型IX和XII。这些分子的进一步结构修饰可用于开发用于治疗青光眼，癫痫和癌症的有效hCA抑制剂。
更新日期：2018-05-22
中文翻译：
作为碳酸酐酶同工型hCA II，IX和XII的选择性抑制剂的4-氨基磺酰基苯基/磺基香豆素羧酰胺的合成和生物学评估
为了开发有效的和选择性的人类碳酸酐酶抑制剂（hCAIs），我们合成了4-氨磺酰基苯基/磺基香豆素苯甲酰胺（系列5 a – r和系列7 a – q），并评估了它们对含锌的五种同工型的抑制谱。人碳酸酐酶（hCA，EC 4.2.1.1）：胞质hCA I和II，以及跨膜同工酶hCA IV，IX和XII。化合物5 a – r据发现，它们在纳摩尔范围内选择性抑制hCA II，而对其他hCA亚型的抑制作用较弱。从文献中可以看出，磺基香豆素（1,2-苯并氧杂氨酸2,2-二氧化物）充当“前药”抑制剂，并通过hCA的酯酶活性水解形成2-羟基苯基乙烯基磺酸，然后与酶结合。类似于香豆素和磺氧香豆素的方式。所有这些磺基香豆素（化合物7 a – q）被发现作为管家脱靶hCA异构体I和II的抑制剂非常弱或无效，并在高纳摩尔至微摩尔范围内有效抑制跨膜肿瘤相关的亚型IX和XII。这些分子的进一步结构修饰可用于开发用于治疗青光眼，癫痫和癌症的有效hCA抑制剂。
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