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Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors.
ACS Omega ( IF 3.7 ) Pub Date : 2020-06-29 , DOI: 10.1021/acsomega.0c00838 Qian Zhang 1 , Xiaobo Liu 1 , Wenhui Gan 1 , Jinjin Wu 1 , Hualan Zhou 1 , Zunhua Yang 2 , Yiling Zhang 2 , Min Liao 1 , Ping Yuan 1 , Shan Xu 1 , Pengwu Zheng 1 , Wufu Zhu 1
ACS Omega ( IF 3.7 ) Pub Date : 2020-06-29 , DOI: 10.1021/acsomega.0c00838 Qian Zhang 1 , Xiaobo Liu 1 , Wenhui Gan 1 , Jinjin Wu 1 , Hualan Zhou 1 , Zunhua Yang 2 , Yiling Zhang 2 , Min Liao 1 , Ping Yuan 1 , Shan Xu 1 , Pengwu Zheng 1 , Wufu Zhu 1
Affiliation
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Two series of novel triazolo-pyridazine/-pyrimidine derivatives were designed, synthesized, and evaluated for their inhibitory activity against c-Met kinase, as well as three c-Met overexpressed cancer cell lines (A549, MCF-7, and HeLa) and one normal human hepatocytes cell line LO2 in vitro. The pharmacological data indicated that most of the tested compounds showed moderate cytotoxicity, and the most promising compound 12e exhibited significant cytotoxicity against A549, MCF-7, and HeLa cell lines with IC50 values of 1.06 ± 0.16, 1.23 ± 0.18, and 2.73 ± 0.33 μM, respectively. Moreover, the inhibitory activity of compound 12e against c-Met kinase (IC50 = 0.090 μM) was equal to that of Foretinib (IC50 = 0.019 μM). The result of the acridine orange (AO) single staining test demonstrated that compound 12e could remarkably induce apoptosis of A549 cells. The results of apoptosis and cycle distribution of cells showed that compound 12e could induce late apoptosis of A549 cells and stimulate A549 cells arresting in the G0/G1 phase. Structure–activity relationships (SARs), pharmacological results, and docking studies indicated that the introduction of 5-methylthiazole fragment to the five-atom moiety was beneficial for the activity. So far, the existing data indicated that compound 12e may become a potential class II c-Met inhibitor.
中文翻译：
发现带有芳族（杂环）偶联的唑类作为II类c-Met抑制剂的Triazolo-哒嗪/嘧啶衍生物。
设计，合成并评估了两个系列的新三唑并哒嗪/嘧啶衍生物对c-Met激酶的抑制活性以及三个c-Met过表达的癌细胞系（A549，MCF-7和HeLa）和一种正常的人肝细胞LO2细胞体外培养。药理学数据表明，大多数测试化合物显示出中等的细胞毒性，而最有前途的化合物12e对A549，MCF-7和HeLa细胞系显示出明显的细胞毒性，IC 50值为1.06±0.16、1.23±0.18和2.73±分别为0.33μM。此外，化合物12e对c-Met激酶的抑制活性（IC 50 = 0.090μM）与Foretinib（IC50 = 0.019μM）。cr啶橙（AO）单一染色的结果表明，化合物12e可以明显诱导A549细胞凋亡。细胞凋亡和细胞周期分布的结果表明，化合物12e可以诱导A549细胞晚期凋亡，并刺激A549细胞停滞在G0 / G1期。结构-活性关系（SARs），药理结果和对接研究表明，将5-甲基噻唑片段引入五原子部分对于该活性是有益的。到目前为止，现有数据表明化合物12e可能成为潜在的II类c-Met抑制剂。
更新日期：2020-07-14
中文翻译：
发现带有芳族（杂环）偶联的唑类作为II类c-Met抑制剂的Triazolo-哒嗪/嘧啶衍生物。
设计，合成并评估了两个系列的新三唑并哒嗪/嘧啶衍生物对c-Met激酶的抑制活性以及三个c-Met过表达的癌细胞系（A549，MCF-7和HeLa）和一种正常的人肝细胞LO2细胞体外培养。药理学数据表明，大多数测试化合物显示出中等的细胞毒性，而最有前途的化合物12e对A549，MCF-7和HeLa细胞系显示出明显的细胞毒性，IC 50值为1.06±0.16、1.23±0.18和2.73±分别为0.33μM。此外，化合物12e对c-Met激酶的抑制活性（IC 50 = 0.090μM）与Foretinib（IC50 = 0.019μM）。cr啶橙（AO）单一染色的结果表明，化合物12e可以明显诱导A549细胞凋亡。细胞凋亡和细胞周期分布的结果表明，化合物12e可以诱导A549细胞晚期凋亡，并刺激A549细胞停滞在G0 / G1期。结构-活性关系（SARs），药理结果和对接研究表明，将5-甲基噻唑片段引入五原子部分对于该活性是有益的。到目前为止，现有数据表明化合物12e可能成为潜在的II类c-Met抑制剂。
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