Synthesis, antiproliferative evaluation and <i>in silico</i> studies of new quinazoline derivatives as VEGFR-2 inhibitors

New quinazoline derivatives were designed and synthesized to target VEGFR-2, aiming to identify potential anticancer agents. The synthesized compounds underwent <i>in</i> <i>vitro</i> screening to evaluate their cytotoxic effects across 60 cancer cells following the NCI protocol. The most promising derivatives, <b>3i</b> and <b>3j</b>, underwent further evaluation <i>via</i> a five-dose test to assess broad-spectrum anticancer activity. Their VEGFR-2 inhibitory potential was compared to sorafenib. Cell cycle analyses, annexin V-FITC, and apoptotic markers were used to examine HT-29 colon cancer cells after treatment with <b>3j</b> for cell cycle arrest and apoptosis induction. Molecular docking and MD simulations explored binding interactions, while ADMET studies assessed pharmacokinetics. Compounds <b>3i</b> and <b>3j</b> exhibited potent to moderate cytotoxic activity, with compound <b>3j</b> showing the highest activity against colon cancer cell lines (GI₅₀ = 3.29 μM). Both compounds demonstrated promising VEGFR-2 inhibitory activity (IC₅₀ = 0.120 and 0.197 µM, respectively), comparable to sorafenib (IC₅₀ = 0.088 µM). Cell cycle analysis displayed G1 phase arrest and pro-apoptotic effects. Docking studies confirmed favorable VEGFR-2 binding affinity (−7.57 and −7.83 kcal/mol). ADMET profiling indicated promising drug-like properties. Compounds <b>3i</b> and <b>3j</b> exhibit promising VEGFR-2 inhibitory properties and significant anticancer activity, warranting further investigation.本研究设计并合成了以血管内皮生长因子受体2（VEGFR-2）为靶点的新型喹唑啉（quinazoline）衍生物，旨在筛选潜在抗癌候选药物。所合成的化合物依照美国国家癌症研究所（National Cancer Institute, NCI）方案开展体外（in vitro）筛选，以评估其对60株癌细胞的细胞毒活性。其中最具开发潜力的衍生物3i与3j进一步通过五剂量试验评估其广谱抗癌活性，并将二者的VEGFR-2抑制活性与索拉非尼（sorafenib）进行对比。针对经3j处理的HT-29结肠癌细胞，采用细胞周期分析、膜联蛋白V-FITC（annexin V-FITC）染色及凋亡标志物检测，探究其细胞周期阻滞与凋亡诱导作用。分子对接与分子动力学（MD）模拟用于探究结合相互作用，ADMET（吸收、分布、代谢、排泄、毒性）研究则评估其药代动力学特性。结果显示，化合物3i与3j表现出从强效至中等强度的细胞毒活性，其中3j对结肠癌细胞系的活性最高，半数生长抑制浓度（GI₅₀）为3.29 μM。二者均展现出良好的VEGFR-2抑制活性，半数抑制浓度（IC₅₀）分别为0.120 μM与0.197 μM，与索拉非尼（IC₅₀=0.088 μM）的活性相当。细胞周期分析结果显示其可诱导G1期细胞周期阻滞，并发挥促凋亡作用。分子对接研究证实二者对VEGFR-2具有良好的结合亲和力，结合能分别为-7.57与-7.83 kcal/mol。ADMET属性分析显示其具备良好的类药特性。综上，化合物3i与3j具备优异的VEGFR-2抑制活性与显著的抗癌活性，值得开展进一步研究。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于新型喹唑啉衍生物作为VEGFR-2抑制剂的开发与评估，旨在发现抗癌药物。研究通过合成化合物3i和3j，并进行了全面的体外和计算机模拟分析，包括细胞毒性测试、VEGFR-2抑制活性比较（IC50值分别为0.120和0.197 µM，接近索拉非尼的0.088 µM）、细胞周期阻滞和凋亡诱导实验。结果表明，这些化合物具有显著的抗癌潜力，特别是对结肠癌细胞系，且ADMET分析显示良好的药物性质，为后续研究提供了基础。