Xiong Shang-Shang
Departments of Pharmacology, School of Pharmacy, Qingdao University Medical College, Shandong, People's Republic of China.
J Hepatocell Carcinoma. 2025 Jan 25;12:149-167. doi: 10.2147/JHC.S490445. eCollection 2025.
Artesunate can inhibit the proliferation of various tumor cells and has practical value in developing anti-tumor drugs. However, its biological activity against hepatocellular carcinoma is weak. The efficacy of its anti-tumor effect needs to be improved.
11 compounds of three types were designed and synthesized. Their antitumor activity was detected by MTT assay in vitro and subcutaneous xenograft model in vivo. Then, DCFH-DA probe detection and NAC intervention experiments were used to detect ROS levels. The ferroptosis inhibitor (Liproxstatin-1) was used to study the effect of compound 6c in inducing ferroptosis. Western blot was used to observe the expression of apoptosis-related proteins. The ability of 6c to induce apoptosis was detected by Annexin V-FITC/PI double staining and Hoechst 33342 staining experiment. The effect of 6c on cycle arrest was detected by flow cytometry. Molecular simulations of several hybrids with vascular endothelial growth factor receptor 2 () and Transferrin receptor protein 1 () were performed using MOE molecular docking software.
A series of new artemisinin-4-(4-substituted phenoxy) pyridine derivatives were synthesized and their anticancer activities were tested in three lines of hepatocellular carcinoma (HCC) cells. Among the hybrid hits with anticancer activity, a representative 6c compound increased the reactive oxygen species (ROS) level in hepatocellular carcinoma cells and activated mitochondrial apoptosis and ferroptosis, leading to cell cycle arrest at G2/M phase. Molecular docking shows the binding of 6c compound to oncogenic vascular endothelial growth factor receptor 2 () and Transferrin receptor protein 1 () that are overexpressed in malignant epithelial tumors.
Taken together, our identification of the promising compound 6c may hold developmental potential for therapy of hepatocellular carcinoma.
青蒿琥酯可抑制多种肿瘤细胞的增殖，在开发抗肿瘤药物方面具有实用价值。然而，其对肝癌的生物活性较弱。其抗肿瘤作用的疗效有待提高。
设计并合成了三种类型的11种化合物。通过体外MTT法和体内皮下异种移植模型检测其抗肿瘤活性。然后，采用DCFH-DA探针检测和NAC干预实验检测活性氧水平。使用铁死亡抑制剂（Liproxstatin-1）研究化合物6c诱导铁死亡的作用。采用蛋白质免疫印迹法观察凋亡相关蛋白的表达。通过Annexin V-FITC/PI双染和Hoechst 33342染色实验检测6c诱导凋亡的能力。通过流式细胞术检测6c对细胞周期阻滞的影响。使用MOE分子对接软件对几种与血管内皮生长因子受体2（）和转铁蛋白受体蛋白1（）的杂合物进行分子模拟。
合成了一系列新型青蒿素-4-（4-取代苯氧基）吡啶衍生物，并在三株肝癌（HCC）细胞系中测试了它们的抗癌活性。在具有抗癌活性的杂合命中物中，代表性化合物6c增加了肝癌细胞中的活性氧（ROS）水平，并激活了线粒体凋亡和铁死亡，导致细胞周期阻滞在G2/M期。分子对接显示化合物6c与在恶性上皮肿瘤中过表达的致癌血管内皮生长因子受体2（）和转铁蛋白受体蛋白1（）结合。
综上所述，我们鉴定出的有前景的化合物6c可能在肝癌治疗方面具有开发潜力。
