Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy.

中文翻译：

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[1,4]二恶英[2,3-f]喹唑啉衍生物作为c-Met和VEGFR-2的双重抑制剂的合成及其抗肿瘤活性。

c-Met和VEGFR-2都是癌症治疗的重要靶标。为了开发可逆的和非共价的c-Met和VEGFR-2双重抑制剂，设计并合成了一系列[1,4]二恶英[2,3-f]喹唑啉衍生物。酶分析表明，大多数目标化合物对c-Met和VEGFR-2均具有抑制作用，IC50值在纳摩尔范围内，尤其是化合物7m和7k。基于进一步的体外细胞增殖测定，化合物7k在体内对肝细胞癌（MHCC97H细胞）异种移植小鼠模型具有明显的抗肿瘤活性。我们将化合物7m与c-Met和VEGFR-2激酶对接，并解释了这些类似物的SAR。所有结果表明目标化合物是c-Met和VEGFR-2激酶的双重抑制剂，在癌症治疗中具有广阔的发展前景。