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艾尔德计算机辅助发现了针对循环氧基酶-2的新型布洛芬-胺抗瘤化合物

Fengxu Wu^1,2, Tianshuai Wang^1,2, Xiaoyu Tang^1,2

¹School of Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hubei University of Medicine, Shiyan 442000, China.

|October 7, 2024

概括

研究人员设计了由ibuprofen-coumarin衍生的新型循环氧化酶-2 (COX-2) 抑制剂. 化合物6c和7g对宫癌细胞具有强烈活性,对COX-2比COX-1具有选择性.

科学领域:

药用化学医学化学
计算化学计算化学
药理学药理学是指药理学的学科.

背景情况:

循环氧化酶-2 (COX-2) 是抗炎和抗癌疗法的关键标.
布洛芬-库马林混合物代表了药物发现的有希望的支架.
开发选择性COX-2抑制剂至关重要,以尽量减少与非选择性NSAID相关的副作用.

研究的目的:

使用计算方法设计和合成新的COX-2抑制剂.
评估合成化合物的体外酶抑制活性和抗癌潜力.
研究化合物的结构-活性关系和选择性.

主要方法:

在化合物设计中采用了自动在体配体导向进化 (AILDE) 方法.
合成了基于ibuprofen-coumarin支架的18种衍生化合物.
评估了对COX-2的酶抑制活性和宫癌细胞系 (HeLa) 中的细胞毒性.
进行了分子模拟,以了解与COX-2和COX-1的结合相互作用.

主要成果:

六种化合物表现出对COX-2的微分子抑制活性.
16种化合物表现出对宫癌细胞的抑制活性.
化合物6c (IC50 = 0.606 μM) 和7g (IC50 = 0.783 μM) 在HeLa细胞中显示出优异的抗癌活性,超过了gefitinib.
分子模拟显示,化合物6c和7g上的素原子与COX-2形成关键的素键,增强活性.
化合物6c和7g对COX-2比COX-1具有选择性 (选择性指数分别为6倍和5倍).
化合物6c和7g在HEK293正常细胞中显示了可接受的安全性.

结论:

化合物6c和7g是强效和选择性的COX-2抑制剂,对宫癌细胞具有显著的抗癌活性.
观察到的活性归因于与COX-2的特定素结合相互作用.
这些化合物代表了癌症治疗进一步发展的有希望的领先候选人.

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