We designed and synthesized thirty novel quinoxaline aryl ethers as anticancer agents, and the structures of final compounds were confirmed with various analytical techniques like Mass, 1H NMR, 13C NMR, FTIR, and elemental analyses. The compounds were tested against three cancer cell lines: colon cancer (HCT‐116), breast cancer (MDA‐MB‐231), prostate cancer (DU‐145), and one normal cell line: human embryonic kidney cell line (HEK‐293). The obtained results indicate that two compounds, FQ and MQ, with IC50 values < 16 μM, were the most active compounds. Molecular docking studies revealed the binding of FQ and MQ molecules in the active site of the c‐Met kinase (PDB ID: 3F66, 1.40 Å). Furthermore, QikProp ADME prediction and the MDS analysis preserved those critical docking data of both compounds, FQ and MQ. Western blotting was used to confirm the impact of the compounds FQ and MQ on the inhibition of the c‐Met kinase receptor. The apoptosis assays were performed to investigate the mechanism of cell death for the most active compounds, FQ and MQ. The Annexin V/7‐AAD assay indicated apoptosis in MDA‐MB‐231 cells treated with FQ and MQ, with FQ (21.4%) showing a higher efficacy in killing MDA‐MB‐231 cells than MQ (14.25%). The Caspase 3/7 7‐AAD assay further supported these findings, revealing higher percentages of apoptotic cells for FQ‐treated MDA‐MB‐231 cells (41.8%). The results obtained from the apoptosis assay conclude that FQ exhibits better anticancer activity against MDA‐MB‐231 cells than MQ.

中文翻译：

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新型喹喔啉芳基醚类抗癌药物的设计、合成和生物学评价

我们设计并合成了三十种新型喹喔啉芳基醚作为抗癌剂，并通过各种分析技术（如质谱、1核磁共振氢谱,1313C NMR、FTIR 和元素分析。这些化合物针对三种癌细胞系进行了测试：结肠癌（HCT-116）、乳腺癌（MDA-MB-231）、前列腺癌（DU-145）和一种正常细胞系：人胚胎肾细胞系（HEK- 293）。所得结果表明，两种化合物 FQ 和 MQ 具有 IC50值 < 16 μM 是最活跃的化合物。分子对接研究揭示了 FQ 和 MQ 分子在 c-Met 激酶活性位点的结合（PDB ID：3F66，1.40 Å）。此外，QikProp ADME 预测和 MDS 分析保留了 FQ 和 MQ 两种化合物的关键对接数据。使用蛋白质印迹法证实化合物 FQ 和 MQ 对 c-Met 激酶受体抑制的影响。进行细胞凋亡测定以研究最活跃的化合物 FQ 和 MQ 的细胞死亡机制。膜联蛋白 V/7-AAD 检测表明，用 FQ 和 MQ 处理的 MDA-MB-231 细胞发生凋亡，FQ (21.4%) 比 MQ (14.25%) 具有更高的杀伤 MDA-MB-231 细胞的功效。Caspase 3/7 7-AAD 测定进一步支持了这些发现，显示 FQ 处理的 MDA-MB-231 细胞的凋亡细胞百分比更高（41.8%）。细胞凋亡测定结果得出结论，FQ 对 MDA-MB-231 细胞表现出比 MQ 更好的抗癌活性。