Design, synthesis and biological evaluation of 4-phenoxy-pyridine/pyrimidine derivatives as dual VEGFR-2/c-Met inhibitors,New Journal of Chemistry

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Design, synthesis and biological evaluation of 4-phenoxy-pyridine/pyrimidine derivatives as dual VEGFR-2/c-Met inhibitors
New Journal of Chemistry ( IF 2.7 ) Pub Date : 2022-05-31 , DOI: 10.1039/d2nj01561g
Feiyi Yang ₁ , Qian Zhang _{1,

2} , Qiuyan Guo ₁ , Qingshan Pan ₁ , Chunping Wen ₁ , Xinya Lv ₁ , Wufu Zhu ₁ , Pengwu Zheng ₁

Affiliation

A class of 4-phenoxy-pyridine/pyrimidine derivatives (23a–23p and 24a–24h) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors. The in vitro anti-cancer cell proliferative activity of the compounds indicated that compound 23k was regarded as a promising derivative. Compared to the lead compounds Foretinib and Sorafenib, 23k showed excellent inhibitory activity against the A549, MCF-7, HepG2 and Ovcar-3 cell lines with IC₅₀ values of 2.16 ± 0.19 μM, 9.13 ± 0.65 μM, 20.15 ± 2.64 and 9.65 ± 0.51 μM, respectively. In addition, 23k exhibited low toxicity to human normal cells (LO2 cells) with IC₅₀ values above 100 μM. In kinase assays, the most promising compound 23k showed excellent kinase inhibitory activity and selectivity against VEGFR-2 and c-Met with IC₅₀ values of 1.05 and 1.43 μM, respectively. Further activity studies demonstrated that 23k not only induced apoptosis in A549, but also blocked the A549 cell lines in the G0/G1 phase in a dose-dependent manner. Moreover, molecular docking and molecular dynamics simulation studies revealed the binding modes of 23k to VEGFR-2 and c-Met. The binding modes and structure–activity relationship (SAR) investigations of synthetic pyridine/pyrimidine derivatives, as well as a brief mechanism of their anti-VEGFR-2 and c-Met kinase activities, are presented in this paper.

中文翻译：

作为 VEGFR-2/c-Met 双重抑制剂的 4-苯氧基-吡啶/嘧啶衍生物的设计、合成和生物学评价

设计、合成和评估了一类 4-苯氧基-吡啶/嘧啶衍生物（23a-23p和24a-24h ）作为有效的双重 VEGFR-2/c-Met 抑制剂。化合物的体外抗癌细胞增殖活性表明化合物23k被认为是一种有前途的衍生物。与先导化合物 Foretinib 和 Sorafenib 相比，23k对 A549、MCF-7、HepG2 和 Ovcar-3 细胞系表现出优异的抑制活性，IC ₅₀值为 2.16 ± 0.19 μM、9.13 ± 0.65 μM、20.15 ± 2.64 和 9.65 ±分别为 0.51 μM。此外，23k对人类正常细胞（LO2 细胞）表现出低毒性，IC ₅₀值高于 100 μM。在激酶测定中，最有希望的化合物23k显示出优异的激酶抑制活性和对 VEGFR-2 和 c-Met 的选择性，IC ₅₀值分别为 1.05 和 1.43 μM。进一步的活性研究表明，23k不仅诱导 A549 细胞凋亡，而且以剂量依赖性方式阻断 G0/G1 期的 A549 细胞系。此外，分子对接和分子动力学模拟研究揭示了23k与 VEGFR-2 和 c-Met 的结合模式。本文介绍了合成吡啶/嘧啶衍生物的结合模式和构效关系 (SAR) 研究，以及它们抗 VEGFR-2 和 c-Met 激酶活性的简要机制。

更新日期：2022-05-31

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