Abstract

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC₅₀ of 3.2 nM very close to positive control sorafenib (IC₅₀ = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC₅₀ of 7.7 and 4.5 µM in comparison to sorafenib (IC₅₀ = 3.51 and 2.17 µM). In addition, compounds 28, 30f, 30i, and 31b exhibited excellent VEGFR-2 inhibition activities (IC₅₀ range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a. Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles

摘要

血管内皮生长因子受体-2 (VEGFR-2) 在癌症血管生成中发挥着关键作用。事实证明，抑制 VEGFR-2 活性可有效抑制肿瘤增殖。据此，设计并合成了两个系列的新型3-甲基喹喔啉衍生物作为VEGFR-2抑制剂。体外评估了合成衍生物对 MCF-7 和 HepG2 细胞系的细胞毒活性。此外，还评估了目标化合物的 VEGFR-2 抑制活性，以表明其细胞毒性的潜在机制。在很大程度上，VEGFR-2抑制的结果与细胞毒性的结果高度相关。化合物27a是最有效的VEGFR-2抑制剂，IC ₅₀为3.2 nM，非常接近阳性对照索拉非尼(IC ₅₀ = 3.12 nM)。该化合物对 MCF-7 和 HepG2 表现出强烈的细胞毒作用，与索拉非尼相比，IC ₅₀分别为 7.7 和 4.5 µM（IC ₅₀ = 3.51 和 2.17 µM）。此外，化合物28、30f、30i和31b表现出优异的VEGFR-2抑制活性（IC 50_范围为4.2至6.1 nM）以及有前景的细胞毒活性。对最活跃的成员27a进行了细胞周期进程和细胞凋亡诱导的研究。此外，还确定了27a对caspase-3、caspase-9水平和BAX/Bcl-2比率的影响。进行分子对接研究来解释目标化合物与 VEGFR-2 口袋的结合模式。此外，对合成的化合物进行了毒性和 ADMET 计算，以研究其药代动力学特征