Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma
The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2021.700956/full |
| _version_ | 1818988235766890496 |
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| author | Yuting Wang Mingyao He Xiang Li Xiang Li Jinlong Chai Qinglin Jiang Cheng Peng Gu He Wei Huang |
| author_facet | Yuting Wang Mingyao He Xiang Li Xiang Li Jinlong Chai Qinglin Jiang Cheng Peng Gu He Wei Huang |
| author_sort | Yuting Wang |
| collection | DOAJ |
| description | The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical assay results indicated that compounds 4k–4r suppressed RalA/B binding capacities to their substrates. Cellular proliferation assays indicated that these RalA inhibitors potently inhibited the proliferation of HCC cell lines, including HepG2, SMMC-7721, Hep3B, and Huh-7 cells. Among the evaluated compounds, 4p displayed good inhibitory capacities on RalA (IC50 = 0.22 μM) and HepG2 cells (IC50 = 2.28 μM). Overall, our results suggested that a novel small-molecule RalA inhibitor with a 6-sulfonylamide-pyrano [2, 3-c]-pyrazole scaffold suppressed autophagy and cell proliferation in hepatocellular carcinoma, and that it has potential for HCC-targeted therapy. |
| first_indexed | 2024-12-20T19:19:22Z |
| format | Article |
| id | doaj.art-53775f1024e345398dc94efc031c4ca8 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-20T19:19:22Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-53775f1024e345398dc94efc031c4ca82022-12-21T19:29:03ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462021-11-01910.3389/fchem.2021.700956700956Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular CarcinomaYuting Wang0Mingyao He1Xiang Li2Xiang Li3Jinlong Chai4Qinglin Jiang5Cheng Peng6Gu He7Wei Huang8State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaState Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaState Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, ChinaSchool of Pharmacy and Sichuan Province College Key Laboratory of Structure-Specific Small Molecule Drugs, Chengdu Medical College, Chengdu, ChinaState Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaThe activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical assay results indicated that compounds 4k–4r suppressed RalA/B binding capacities to their substrates. Cellular proliferation assays indicated that these RalA inhibitors potently inhibited the proliferation of HCC cell lines, including HepG2, SMMC-7721, Hep3B, and Huh-7 cells. Among the evaluated compounds, 4p displayed good inhibitory capacities on RalA (IC50 = 0.22 μM) and HepG2 cells (IC50 = 2.28 μM). Overall, our results suggested that a novel small-molecule RalA inhibitor with a 6-sulfonylamide-pyrano [2, 3-c]-pyrazole scaffold suppressed autophagy and cell proliferation in hepatocellular carcinoma, and that it has potential for HCC-targeted therapy.https://www.frontiersin.org/articles/10.3389/fchem.2021.700956/fullRalA inhibitorspyrano[2;3-c]-pyrazolehepatocellular carcinomasynthesisautophagy |
| spellingShingle | Yuting Wang Mingyao He Xiang Li Xiang Li Jinlong Chai Qinglin Jiang Cheng Peng Gu He Wei Huang Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma Frontiers in Chemistry RalA inhibitors pyrano[2;3-c]-pyrazole hepatocellular carcinoma synthesis autophagy |
| title | Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma |
| title_full | Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma |
| title_fullStr | Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma |
| title_full_unstemmed | Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma |
| title_short | Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma |
| title_sort | design synthesis and biological evaluation of pyrano 2 3 c pyrazole based rala inhibitors against hepatocellular carcinoma |
| topic | RalA inhibitors pyrano[2;3-c]-pyrazole hepatocellular carcinoma synthesis autophagy |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2021.700956/full |
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