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Exploring Heteroaryl-pyrazole Carboxylic Acids as Human Carbonic Anhydrase XII Inhibitors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-08-03 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00229 Roberta Cadoni 1 , Nicolino Pala 1 , Carrie Lomelino 2 , Brian P. Mahon 2 , Robert McKenna 2 , Roberto Dallocchio 3 , Alessandro Dessì 3 , Mauro Carcelli 4 , Dominga Rogolino 4 , Vanna Sanna 1 , Mauro Rassu 5 , Ciro Iaccarino 5 , Daniela Vullo 6 , Claudiu T. Supuran 6 , Mario Sechi 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-08-03 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00229 Roberta Cadoni 1 , Nicolino Pala 1 , Carrie Lomelino 2 , Brian P. Mahon 2 , Robert McKenna 2 , Roberto Dallocchio 3 , Alessandro Dessì 3 , Mauro Carcelli 4 , Dominga Rogolino 4 , Vanna Sanna 1 , Mauro Rassu 5 , Ciro Iaccarino 5 , Daniela Vullo 6 , Claudiu T. Supuran 6 , Mario Sechi 1
Affiliation
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We report the synthesis, biological evaluation, and structural study of a series of substituted heteroaryl-pyrazole carboxylic acid derivatives. These compounds have been developed as inhibitors of specific isoforms of carbonic anhydrase (CA), with potential as prototypes of a new class of chemotherapeutics. Both X-ray crystallography and computational modeling provide insights into the CA inhibition mechanism. Results indicate that this chemotype produces an indirect interference with the zinc ion, thus behaving differently from other related nonclassical inhibitors. Among the tested compounds, 2c with Ki = 0.21 μM toward hCA XII demonstrated significant antiproliferative activity against hypoxic tumor cell lines. Taken together, the results thus provide the basis of structural determinants for the development of novel anticancer agents.
中文翻译：
探索杂芳基-吡唑羧酸作为人类碳酸酐酶XII抑制剂
我们报告了一系列取代的杂芳基-吡唑羧酸衍生物的合成，生物学评估和结构研究。已开发出这些化合物作为碳酸酐酶（CA）特定同工型的抑制剂，并有可能作为新型化学疗法的原型。X射线晶体学和计算模型都提供了对CA抑制机制的见解。结果表明，该化学型对锌离子产生间接干扰，因此其行为与其他相关的非经典抑制剂不同。在供试化合物，2C与ķ我= 0.21μM朝向ħCA XII对缺氧肿瘤细胞系表现出显着的抗增殖活性。综上所述，结果为开发新型抗癌药提供了结构决定因素的基础。
更新日期：2017-08-04
中文翻译：
探索杂芳基-吡唑羧酸作为人类碳酸酐酶XII抑制剂
我们报告了一系列取代的杂芳基-吡唑羧酸衍生物的合成，生物学评估和结构研究。已开发出这些化合物作为碳酸酐酶（CA）特定同工型的抑制剂，并有可能作为新型化学疗法的原型。X射线晶体学和计算模型都提供了对CA抑制机制的见解。结果表明，该化学型对锌离子产生间接干扰，因此其行为与其他相关的非经典抑制剂不同。在供试化合物，2C与ķ我= 0.21μM朝向ħCA XII对缺氧肿瘤细胞系表现出显着的抗增殖活性。综上所述，结果为开发新型抗癌药提供了结构决定因素的基础。
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