作为世界范围内第六最常诊断的癌症和第四导致癌症相关死亡的原因，肝癌被认为是一种严重疾病，其患病率高且预后较差。当前用于肝癌的抗癌药物存在一些缺陷，如在疾病后期疗效有限、对健康细胞产生毒性以及潜在的药物耐药性。大量证据表明，基于香豆素的化合物是有效的抗癌剂，目前有许多类似物正在临床前和临床研究中进行调查。本研究旨在探索一类新型的8-甲氧基香豆素-3-羧酸酰胺对肝癌的抗肿瘤效力。为了实现这一目标，我们设计、合成和表征了一组新的N-(取代苯基)-8-甲氧基香豆素-3-羧酰胺类似物。抗肿瘤活性评估显示，合成的化合物类对Hep-G2细胞具有显著的细胞毒性，而对正常细胞影响不明显。在合成的化合物中，化合物7对Hep-G2细胞表现出最强的细胞毒作用，其IC50为0.75微米，比staurosporine药物(IC50 = 8.37微米)更强。对化合物7抗增值活性的机制研究表明，其干扰DNA复制并诱导DNA损伤，导致细胞周期停滞，如细胞量在G1和G2/M期的百分比明显降低，而在S期的百分比增加。流式细胞术分析进一步揭示，化合物7具有触发HepG-2细胞坏死和凋亡的能力。进一步的机制研究表明，化合物7对细胞色素P450和血管内皮生长因子受体-2(VEGFR-2)蛋白具有强烈的双重抑制活性，而与索拉非尼药物相比具有更强的相结合亲和力。进一步详细的计算研究表明，化合物7对VEGFR2和CYP450蛋白的结合腔具有较高的亲和力。总的来说，我们的发现表明，新合成的化合物类，尤其是化合物7，有望成为开发高效抗肿瘤药物治疗肝癌的有希望的支架。Copyright © 2023 Radwan, Abo-Elabass, Abd El-Baky, Alshwyeh, Almaimani, Almaimani, Ibrahim, Albogami, Jaremko, Alshawwa and Saied.

Being the sixth most diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide, liver cancer is considered as a serious disease with a high prevalence and poor prognosis. Current anticancer drugs for liver cancer have drawbacks, such as limited efficacy in later stages of the disease, toxicity to healthy cells, and the potential for drug resistance. There is ample evidence that coumarin-based compounds are potent anticancer agents, with numerous analogues currently being investigated in preclinical and clinical studies. The current study aimed to explore the antitumor potency of a new class of 8-methoxycoumarin-3-carboxamides against liver cancer. Toward this aim, we have designed, synthesized, and characterized a new set of N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamide analogues. The assessment of antitumor activity revealed that the synthesized class of compounds possesses substantial cytotoxicity toward Hep-G2 cells when compared to staurosporine, without significant impact on normal cells. Out of the synthesized compounds, compound 7 demonstrated the most potent cytotoxic effect against Hep-G2 cells with an IC50 of 0.75 µM, which was more potent than the drug staurosporine (IC50 = 8.37 µM). The investigation into the mechanism behind the antiproliferative activity of compound 7 revealed that it interferes with DNA replication and induces DNA damage, leading to cell cycle arrest as demonstrated by a significant decrease in the percentage of cells in the G1 and G2/M phases, along with an increase in the percentage of cells in the S phase. Flow cytometric analysis further revealed that compound 7 has the ability to trigger programmed cell death by inducing necrosis and apoptosis in HepG-2 cells. Further explorations into the mechanism of action demonstrated that compound 7 displays a potent dual-inhibitory activity toward cytochrome P450 and vascular endothelial growth factor receptor-2 (VEGFR-2) proteins, as compared to sorafenib drug. Further, detailed computational studies revealed that compound 7 displays a considerable binding affinity toward the binding cavity of VEGFR2 and CYP450 proteins. Taken together, our findings indicate that the newly synthesized class of compounds, particularly compound 7, could serve as a promising scaffold for the development of highly effective anticancer agents against liver cancer.Copyright © 2023 Radwan, Abo-Elabass, Abd El-Baky, Alshwyeh, Almaimani, Almaimani, Ibrahim, Albogami, Jaremko, Alshawwa and Saied.