Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India.
Bioorg Chem. 2019 May;86:386-392. doi: 10.1016/j.bioorg.2019.02.004. Epub 2019 Feb 5.
A series of novel 7-hydroxycoumarin-3-carboxamides was synthesized by the reaction of 7-hydroxy-2-oxo-2H-chromene-3-carboxylic acid with various substituted aromatic amines. The newly synthesized compounds were evaluated for their inhibitory activity against the four physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms CA I, CA II, CA IX and CA XII. The CA inhibition results show that the newly synthesized 7-hydroxycoumarin-3-carboxamides (4a-n) exhibited selective inhibition of the tumor associated isoforms, CA IX and CA XII over CA I and II isoforms. The inhibition constants ranged from sub micromolar to low micromolar. Amongst all the compounds tested, compound 4m was the most effective inhibitor exhibiting sub micromolar potency against both hCA IX and hCA XII, with a K of 0.2 µM. Therefore, it can be anticipated that compound 4m can serve as a lead for development of anticancer therapy by exhibiting a novel mechanism of action. The binding modes of the most potent compounds within hCA IX and XII catalytic clefts were investigated by docking studies.
合成了一系列新型的 7-羟基香豆素-3-甲酰胺，方法是将 7-羟基-2-氧代-2H-色烯-3-羧酸与各种取代的芳族胺反应得到。新合成的化合物被评估为对四个生理相关的人碳酸酐酶（hCA，EC 4.2.1.1）同工酶 CA I、CA II、CA IX 和 CA XII 的抑制活性。CA 抑制结果表明，新合成的 7-羟基香豆素-3-甲酰胺（4a-n）对肿瘤相关同工酶 CA IX 和 CA XII 表现出选择性抑制，而对 CA I 和 II 同工酶则没有抑制作用。抑制常数范围从亚微摩尔到低微摩尔。在所测试的所有化合物中，化合物 4m 是最有效的抑制剂，对 hCA IX 和 hCA XII 的抑制作用均达到亚微摩尔水平，K 值为 0.2µM。因此，可以预期化合物 4m 可以通过表现出新型作用机制，作为开发抗癌疗法的先导物。通过对接研究研究了最有效化合物在 hCA IX 和 XII 催化裂缝中的结合模式。
