Discovery of [1,2,4]triazolo[4,3-a]pyrazine derivatives bearing a 4-oxo-pyridazinone moiety as potential c-Met kinase inhibitors,New Journal of Chemistry

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Discovery of [1,2,4]triazolo[4,3-a]pyrazine derivatives bearing a 4-oxo-pyridazinone moiety as potential c-Met kinase inhibitors
New Journal of Chemistry ( IF 2.7 ) Pub Date : 2020-05-05 , DOI: 10.1039/d0nj00575d
Binliang Zhang _{1,

2,

3,

4,

5} , Xiaobo Liu _{1,

2,

3,

4,

5} , Hehua Xiong _{1,

2,

3,

4,

5} , Qian Zhang _{1,

2,

3,

4,

5} , Xin Sun _{1,

2,

3,

4,

5} , Zunhua Yang _{4,

5,

6,

7} , Shan Xu _{1,

2,

3,

4,

5} , Pengwu Zheng _{1,

2,

3,

4,

5} , Wufu Zhu _{1,

2,

3,

4,

5}

Affiliation

Two series of [1,2,4]triazolo[4,3-a]pyrazine derivatives bearing 4-oxo-pyridazinone moieties (compounds 21a–l and 22a–l) were designed and their IC₅₀ values were evaluated against three cancer cell lines (A549, MCF-7 and HeLa) and c-Met kinase. Among them, the compound with most potential, 22i, exhibited excellent anti-tumor activity against A549, MCF-7 and HeLa cancer cell lines with IC₅₀ values of 0.83 ± 0.07 μM, 0.15 ± 0.08 μM and 2.85 ± 0.74 μM, respectively, and it also possessed superior c-Met kinase inhibition ability at the nanomolar level (IC₅₀ = 48 nM). Moreover, dose-dependent experiments, AO fluorescence staining, cell cycle assay, Annexin V-FITC/PI staining and docking studies were carried out in this study. The results demonstrated that compound 22i could be a potential c-Met kinase inhibitor.

中文翻译：

发现带有4-氧代-哒嗪酮部分的[1,2,4]三唑并[4,3-a]吡嗪衍生物作为潜在的c-Met激酶抑制剂

设计了两个带有4-氧代-哒嗪酮部分的化合物[1,2,4]三唑并[4,3- a ]吡嗪衍生物系列（化合物21a-1和22a-1），并针对三种癌细胞评估了它们的IC ₅₀值系（A549，MCF-7和HeLa）和c-Met激酶。其中，最具潜力的化合物22i对A549，MCF-7和HeLa癌细胞系表现出优异的抗肿瘤活性，IC ₅₀值分别为0.83±0.07μM，0.15±0.08μM和2.85±0.74μM，并且在纳摩尔水平上也具有出色的c-Met激酶抑制能力（IC ₅₀= 48 nM）。此外，在这项研究中进行了剂量依赖性实验，AO荧光染色，细胞周期测定，膜联蛋白V-FITC / PI染色和对接研究。结果表明化合物22i可能是潜在的c-Met激酶抑制剂。

更新日期：2020-05-05

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