Design, synthesis, and primary activity assays of baicalein derivatives as cyclin-dependent kinase 1 inhibitors,Chemical Biology & Drug Design

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Design, synthesis, and primary activity assays of baicalein derivatives as cyclin-dependent kinase 1 inhibitors
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2021-07-07 , DOI: 10.1111/cbdd.13917
Jiajia Mou ₁ , Shuang Qiu ₁ , Danghui Chen ₁ , Yanru Deng ₁ , Teka Tekleab ₂

Affiliation

Malignant tumor is a disease with high mortality. Traditional treatment methods have many disadvantages, such as side-effects, drug resistance. Because cyclin-dependent kinase 1 (CDK1) plays an indispensable role in cell cycle regulation, it became an attractive target in rational anti-cancer drug discovery. Herein, we reported a series of baicalein derivatives, which remarkably repressed the proliferation of MCF-7 tumor cells and the activity of CDK1/cyclin B kinase. Among them, compound 4a displayed better inhibition rate than flavopiridol against MCF-7 proliferation at the concentration of 50 μg/ml, comparable to compound CGP74514A, while compound 3o possessed the best activity against CDK1/cyclin B kinase (IC₅₀ = 1.26 μM). The inhibitory activities toward the kinase well correlated with anti-proliferative activities. Molecular docking results suggested that compound 3o can interact with the key amino acid residues, E81, L83, and D146, of CDK1 through hydrogen bond just like flavopiridol does. And it can also form an extra hydrogen bond with D146 by its introduced 7-acrylate group, which flavopiridol does not have. These findings proved that baicalein derivatives can be used as CDK1 inhibitors fighting against cancer.

中文翻译：

作为细胞周期蛋白依赖性激酶 1 抑制剂的黄芩素衍生物的设计、合成和主要活性测定

恶性肿瘤是一种死亡率很高的疾病。传统的治疗方法存在副作用、耐药性等诸多弊端。由于细胞周期蛋白依赖性激酶 1 (CDK1) 在细胞周期调节中起着不可或缺的作用，因此它成为合理抗癌药物发现的一个有吸引力的目标。在此，我们报道了一系列黄芩素衍生物，它们显着抑制 MCF-7 肿瘤细胞的增殖和 CDK1/细胞周期蛋白 B 激酶的活性。其中，化合物4a在 50 μg/ml 浓度下对 MCF-7 增殖的抑制率优于黄酮醇，与化合物 CGP74514A 相当，而化合物3o对 CDK1/cyclin B 激酶的活性最好（IC ₅₀ = 1.26 μM）。对激酶的抑制活性与抗增殖活性密切相关。分子对接结果表明，化合物3o可以通过氢键与CDK1的关键氨基酸残基E81、L83和D146相互作用，就像flavopiridol一样。并且它还可以通过其引入的7-丙烯酸酯基团与D146形成额外的氢键，这是flavopiridol所没有的。这些发现证明黄芩素衍生物可以作为CDK1抑制剂来对抗癌症。

更新日期：2021-09-15

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