Synthesis and antitumor activities of novel 3-(6-aminopyridin-3-yl)benzamide derivatives: Inducing cell cycle arrest and apoptosis via AURKB transcription inhibition,Bioorganic Chemistry

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Synthesis and antitumor activities of novel 3-(6-aminopyridin-3-yl)benzamide derivatives: Inducing cell cycle arrest and apoptosis via AURKB transcription inhibition
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2024-05-12 , DOI: 10.1016/j.bioorg.2024.107450
Xinran Zhao ₁ , Rongtao Wang ₁ , Feng Zhang ₁ , Fang Luo ₁ , Ting Zhong ₁ , Ailing Linghu ₁ , Liang Xiong ₁ , Huiyin Yang ₁ , Yanhua Fan ₁

Affiliation

Here, a series of 3-(6-aminopyridin-3-yl) benzamide derivatives were designed and synthesized. Cell viability assay indicated that most compounds exhibited potent antiproliferative activity against all the tested cancer cells. Among them, compound displayed the best antiproliferative activity particularly in A549 cells, with an IC value of 0.04 ± 0.01 μM. RNA-seq analysis was employed to explore the potential pathways related to the antiproliferative activity of compound . The data revealed that exerted antiproliferative activity mainly by regulating cell cycle, DNA replication and p53 signaling pathway. Indeed, compound induced G2/M phase arrest by AURKB transcription inhibition and resulted in cell apoptosis via p53 signaling pathway. Most importantly, compound demonstrated potent antitumor activity in A549 xenograft tumor model. Collectively, might be a promising lead compound for the development of new therapeutic agents for AURKB overexpressed or mutated cancers.

中文翻译：

新型3-(6-氨基吡啶-3-基)苯甲酰胺衍生物的合成和抗肿瘤活性：通过AURKB转录抑制诱导细胞周期停滞和凋亡

在此，设计并合成了一系列3-(6-氨基吡啶-3-基)苯甲酰胺衍生物。细胞活力测定表明，大多数化合物对所有测试的癌细胞都表现出有效的抗增殖活性。其中，化合物尤其对A549细胞表现出最好的抗增殖活性，IC50值为0.04±0.01μM。采用RNA-seq分析来探索与化合物的抗增殖活性相关的潜在途径。数据显示其主要通过调节细胞周期、DNA复制和p53信号通路发挥抗增殖活性。事实上，化合物通过 AURKB 转录抑制诱导 G2/M 期停滞，并通过 p53 信号通路导致细胞凋亡。最重要的是，化合物在 A549 异种移植肿瘤模型中表现出有效的抗肿瘤活性。总的来说，它可能是一种有前景的先导化合物，可用于开发 AURKB 过度表达或突变癌症的新治疗药物。

更新日期：2024-05-12

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