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Discovery of New Sulfonamide Carbonic Anhydrase IX Inhibitors Incorporating Nitrogenous Bases
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-11-27 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00399 Alessio Nocentini 1 , Silvia Bua 1 , Carrie L. Lomelino 2 , Robert McKenna 2 , Marta Menicatti 1 , Gianluca Bartolucci 1 , Barbara Tenci 3 , Lorenzo Di Cesare Mannelli 3 , Carla Ghelardini 3 , Paola Gratteri 1 , Claudiu T. Supuran 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-11-27 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00399 Alessio Nocentini 1 , Silvia Bua 1 , Carrie L. Lomelino 2 , Robert McKenna 2 , Marta Menicatti 1 , Gianluca Bartolucci 1 , Barbara Tenci 3 , Lorenzo Di Cesare Mannelli 3 , Carla Ghelardini 3 , Paola Gratteri 1 , Claudiu T. Supuran 1
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Incorporation of the purine/pyrimidine moieties as tails to classical benzenesulfonamide scaffolds afforded two series of human (h) carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The compounds were designed according to the molecular hybridization approach, in order to modulate the interaction with different CA isozymes and exploit the antitumor effect of uracil and adenine derivatives in parallel and synergic mode to the inhibition of the tumor-associated hCA IX. The sulfonamides were investigated as inhibitors of four isoforms, cytosolic hCA I/II and transmembrane hCA IV/IX. The inhibitory profiles were dependent on the length and positioning of the spacer connecting the two pharmacophores. X-ray crystallography demonstrated the binding mode of an inhibitor to hCA II and hCA IX-mimic. Compounds endowed with the best hCA IX inhibitory efficacy were evaluated for antiproliferative activity against HT-29 colon cancer cell lines. The in vitro results suggest multiple mechanisms of action are responsible for the compounds’ cytotoxic efficacy.
中文翻译：
新型含氮碱的磺酰胺碳酸酐酶IX抑制剂的发现
将嘌呤/嘧啶部分作为尾部掺入经典的苯磺酰胺支架中，可提供两个系列的人（h）碳酸酐酶（CA，EC 4.2.1.1）抑制剂。根据分子杂交方法设计化合物，以调节与不同CA同工酶的相互作用，并以平行和协同模式利用尿嘧啶和腺嘌呤衍生物的抗肿瘤作用来抑制与肿瘤相关的hCA IX。研究了磺酰胺作为四种同工型的抑制剂，即胞质hCA I / II和跨膜hCA IV / IX。抑制曲线取决于连接两个药效基团的间隔子的长度和位置。X射线晶体学证实了抑制剂与hCA II和hCA IX模拟物的结合模式。评估具有最佳hCA IX抑制功效的化合物对HT-29结肠癌细胞系的抗增殖活性。这体外结果表明，多种作用机制是该化合物的细胞毒性功效的原因。
更新日期：2017-11-27
中文翻译：
新型含氮碱的磺酰胺碳酸酐酶IX抑制剂的发现
将嘌呤/嘧啶部分作为尾部掺入经典的苯磺酰胺支架中，可提供两个系列的人（h）碳酸酐酶（CA，EC 4.2.1.1）抑制剂。根据分子杂交方法设计化合物，以调节与不同CA同工酶的相互作用，并以平行和协同模式利用尿嘧啶和腺嘌呤衍生物的抗肿瘤作用来抑制与肿瘤相关的hCA IX。研究了磺酰胺作为四种同工型的抑制剂，即胞质hCA I / II和跨膜hCA IV / IX。抑制曲线取决于连接两个药效基团的间隔子的长度和位置。X射线晶体学证实了抑制剂与hCA II和hCA IX模拟物的结合模式。评估具有最佳hCA IX抑制功效的化合物对HT-29结肠癌细胞系的抗增殖活性。这体外结果表明，多种作用机制是该化合物的细胞毒性功效的原因。
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