血管内皮生长因子受体 2 是多种癌症治疗的重要靶点。本研究旨在利用 MTT 法探讨 17 种新型喹喔啉-3-丙酰胺对结肠癌 (HCT-116) 和乳腺癌 (MCF-7) 的细胞毒活性。结果显示，化合物 8、9 和 14 比参比药物阿霉素 (DOX) 和索拉非尼具有更高的细胞毒性。有趣的是，与 DOX（SI HCT-116 0.72 和 MCF-7 0.9）相比，它们对 HCT-116（SI 11.98-19.97）和 MCF-7（SI 12.44-23.87）更具选择性。这些化合物有效降低血管内皮生长因子受体2；其中，化合物14表现出与索拉非尼相似的VEGFR-2抑制活性（IC50 0.076 M）。与对照相比，14抑制血管生成的能力通过VEGF-A水平的降低得到证实。此外，与对照实验相比，它诱导前 G1 期细胞百分比显着增加近 1.38 倍（这可能表明细胞凋亡），G2/M 期细胞百分比显着增加 3.59 倍。流式细胞术分析表明，化合物 14 通过程序性细胞死亡和坏死途径引发细胞凋亡。此外，它还导致凋亡标志物，即 caspase-3 p53 和 BAX 显着增加。与对照相比，MCF-7 细胞中 caspase-3 的表达水平显着增加，从 47.88 增加到 423.10，p53 的表达水平从 22.19 pg/ml 显着增加到 345.83 pg/ml。此外，它还使促凋亡蛋白 BAX 增加了 4.3 倍，同时使抗凋亡标记物 BCL2 降低了 0.45 倍。对接研究进一步支持了该机制，其中化合物 14 显示出与 VEGFR-2 活性位点的必需氨基酸良好的结合。药代动力学特性显示了这些药物相对于舒尼替尼的优势：它们不是 P-gp 蛋白的底物；这表明它们流出细胞、发挥最大作用的机会较小；此外，它们不允许渗透到 BBB。该期刊版权所有 © 英国皇家化学学会。

Vascular endothelial growth factor receptor-2 is a vital target for therapeutic mediation in various types of cancer. This study was aimed at exploring the cytotoxic activity of seventeen novel quinoxaline-3-propanamides against colon cancer (HCT-116) and breast cancer (MCF-7) using MTT assay. Results revealed that compounds 8, 9, and 14 elicited higher cytotoxicity than the reference drugs, doxorubicin (DOX) and sorafenib. Interestingly, they are more selective for HCT-116 (SI 11.98-19.97) and MCF-7 (SI 12.44-23.87) compared to DOX (SI HCT-116 0.72 and MCF-7 0.9). These compounds effectively reduced vascular endothelial growth factor receptor-2; among them, compound 14 displayed similar VEGFR-2 inhibitory activity to sorafenib (IC50 0.076 M). The ability of 14 to inhibit angiogenesis was demonstrated by a reduction in VEGF-A level compared to control. Furthermore, it induced a significant increase in the percentage of cells at pre-G1 phase by almost 1.38 folds (which could be indicative of apoptosis) and an increase in G2/M by 3.59 folds compared to the control experiment. A flow cytometry assay revealed that compound 14 triggered apoptosis via the programmed cell death and necrotic pathways. Besides, it caused a remarkable increase in apoptotic markers, i.e., caspase-3 p53 and BAX. When compared to the control, significant increase in the expression levels of caspase-3 from 47.88 to 423.10 and p53 from 22.19 to 345.83 pg per ml in MCF-7 cells. As well, it increased the proapoptotic protein BAX by 4.3 times while lowering the antiapoptotic marker BCL2 by 0.45 fold. Docking studies further supported the mechanism, where compound 14 showed good binding to the essential amino acids in the active site of VEGFR-2. Pharmacokinetic properties showed the privilege of these hits over sunitinib: they are not substrates of P-gp protein; this suggests that they have less chance to efflux out of the cell, committing maximum effect; and in addition, they do not allow permeation to the BBB.This journal is © The Royal Society of Chemistry.