香豆素-1,3,4-噁二唑杂合体的合成与生物评价作为选择性碳酸酐酶 IX 和 XII 抑制剂。
Synthesis and biological evaluation of coumarin-1,3,4-oxadiazole hybrids as selective carbonic anhydrase IX and XII inhibitors.
机构信息
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.
出版信息
Bioorg Chem. 2019 Jun;87:765-772. doi: 10.1016/j.bioorg.2019.04.004. Epub 2019 Apr 5.
With an aim to develop novel heterocyclic hybrids as potent anticancer agents, we synthesized a series of coumarin-1,3,4-oxadiazole hybrids (7a-t) and 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 clearly indicated that the coumarin-1,3,4-oxadiazole derivatives (7a-t) exhibited selective inhibition of the tumor associated isoforms, CA IX and CA XII over CA I and II isoforms. Among all, compound 7b, exhibited significant inhibition in lower micromolar potency against hCA XII, with a K of 0.16 µM and compound 7n, exhibited significant inhibition in lower micromolar potency against hCA IX, with a K of 2.34 µM respectively. Therefore, compound 7b and 7n could be the potential leads for development of selective anticancer agents by exhibiting a novel mechanism of action through hCA IX and XII inhibition.
为了开发新型杂环杂合体作为有效的抗癌剂，我们合成了一系列香豆素-1,3,4-恶二唑杂合体（7a-t），并评估了它们对四种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 抑制结果清楚地表明，香豆素-1,3,4-恶二唑衍生物（7a-t）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 同工酶没有抑制作用。在所有化合物中，化合物 7b 对 hCA XII 的抑制活性在较低的微摩尔浓度下表现出显著的抑制作用，K 值为 0.16 µM，化合物 7n 对 hCA IX 的抑制活性在较低的微摩尔浓度下表现出显著的抑制作用，K 值为 2.34 µM。因此，化合物 7b 和 7n 可能是通过抑制 hCA IX 和 XII 来开发选择性抗癌剂的潜在先导化合物，因为它们具有通过抑制 hCA IX 和 XII 来发挥作用的新机制。
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