Design and Mechanism Study of 6c, a Novel Artesunate Derivatives, for Anti-Hepatocellular Carcinoma
Shang-Shang Xiong Departments of Pharmacology, School of Pharmacy, Qingdao University Medical College, Shandong, People’s Republic of ChinaCorrespondence: Shang-Shang Xiong, Email 17355138325@163.comObjective: Artesunate can inhibit the proliferation of various tumor cells and has practical value in...
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Dove Medical Press
2025-01-01
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| Series: | Journal of Hepatocellular Carcinoma |
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| Online Access: | https://www.dovepress.com/design-and-mechanism-study-of-6c-a-novel-artesunate-derivatives-for-an-peer-reviewed-fulltext-article-JHC |
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| author | Xiong SS |
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| description | Shang-Shang Xiong Departments of Pharmacology, School of Pharmacy, Qingdao University Medical College, Shandong, People’s Republic of ChinaCorrespondence: Shang-Shang Xiong, Email 17355138325@163.comObjective: 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.Methods: 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 (VEGFR-2) and Transferrin receptor protein 1 (TFR1) were performed using MOE molecular docking software.Results: 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 (VEGFR-2) and Transferrin receptor protein 1 (TFR1) that are overexpressed in malignant epithelial tumors.Conclusion: Taken together, our identification of the promising compound 6c may hold developmental potential for therapy of hepatocellular carcinoma. Keywords: hepatocellular carcinoma, artesunate, phenoxy-pyridine, hybridization, reactive oxygen species, apoptosis, docking |
| format | Article |
| id | doaj-art-504c2b16501f4e21a6398f95026456c2 |
| institution | Kabale University |
| issn | 2253-5969 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Journal of Hepatocellular Carcinoma |
| spelling | doaj-art-504c2b16501f4e21a6398f95026456c22025-01-27T18:05:34ZengDove Medical PressJournal of Hepatocellular Carcinoma2253-59692025-01-01Volume 1214916799574Design and Mechanism Study of 6c, a Novel Artesunate Derivatives, for Anti-Hepatocellular CarcinomaXiong SSShang-Shang Xiong Departments of Pharmacology, School of Pharmacy, Qingdao University Medical College, Shandong, People’s Republic of ChinaCorrespondence: Shang-Shang Xiong, Email 17355138325@163.comObjective: 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.Methods: 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 (VEGFR-2) and Transferrin receptor protein 1 (TFR1) were performed using MOE molecular docking software.Results: 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 (VEGFR-2) and Transferrin receptor protein 1 (TFR1) that are overexpressed in malignant epithelial tumors.Conclusion: Taken together, our identification of the promising compound 6c may hold developmental potential for therapy of hepatocellular carcinoma. Keywords: hepatocellular carcinoma, artesunate, phenoxy-pyridine, hybridization, reactive oxygen species, apoptosis, dockinghttps://www.dovepress.com/design-and-mechanism-study-of-6c-a-novel-artesunate-derivatives-for-an-peer-reviewed-fulltext-article-JHChepatocellular carcinomaartesunatephenoxy-pyridinehybridizationreactive oxygen speciesapoptosisdocking. |
| spellingShingle | Xiong SS Design and Mechanism Study of 6c, a Novel Artesunate Derivatives, for Anti-Hepatocellular Carcinoma Journal of Hepatocellular Carcinoma hepatocellular carcinoma artesunate phenoxy-pyridine hybridization reactive oxygen species apoptosis docking. |
| title | Design and Mechanism Study of 6c, a Novel Artesunate Derivatives, for Anti-Hepatocellular Carcinoma |
| title_full | Design and Mechanism Study of 6c, a Novel Artesunate Derivatives, for Anti-Hepatocellular Carcinoma |
| title_fullStr | Design and Mechanism Study of 6c, a Novel Artesunate Derivatives, for Anti-Hepatocellular Carcinoma |
| title_full_unstemmed | Design and Mechanism Study of 6c, a Novel Artesunate Derivatives, for Anti-Hepatocellular Carcinoma |
| title_short | Design and Mechanism Study of 6c, a Novel Artesunate Derivatives, for Anti-Hepatocellular Carcinoma |
| title_sort | design and mechanism study of 6c a novel artesunate derivatives for anti hepatocellular carcinoma |
| topic | hepatocellular carcinoma artesunate phenoxy-pyridine hybridization reactive oxygen species apoptosis docking. |
| url | https://www.dovepress.com/design-and-mechanism-study-of-6c-a-novel-artesunate-derivatives-for-an-peer-reviewed-fulltext-article-JHC |
| work_keys_str_mv | AT xiongss designandmechanismstudyof6canovelartesunatederivativesforantihepatocellularcarcinoma |