Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation
AbstractThe colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum in vitro antitumour activity. In this study, s...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2155815 |
| _version_ | 1797400923302002688 |
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| author | Wei Liu Youyou He Zhongjie Guo Miaomiao Wang Xiaodong Han Hairui Jia Jin He Shanshan Miao Shengzheng Wang |
| author_facet | Wei Liu Youyou He Zhongjie Guo Miaomiao Wang Xiaodong Han Hairui Jia Jin He Shanshan Miao Shengzheng Wang |
| author_sort | Wei Liu |
| collection | DOAJ |
| description | AbstractThe colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum in vitro antitumour activity. In this study, structure based rational design and systematic structural optimisation were performed to obtain analogues C1∼J2 bearing diverse substituents and scaffolds. Among them, analogue G13 bearing a hydroxymethyl group displayed good tubulin polymerisation inhibitory activity (IC50 = 13.5 μM) and potent antiproliferative activity (IC50 values: 0.65 μM∼0.90 μM). G13 potently inhibited the migration and invasion of MDA-MB-231 cells, and displayed potent antiangiogenic activity. It efficiently increased intracellular ROS level and decreased MMP in cancer cells, and obviously induced the fragmentation and disassembly of the microtubules network. More importantly, G13 exhibited good in vivo antitumour efficacy in MDA-MB-231 xenograft model (TGI = 38.2%; i.p., 30 mg/kg). |
| first_indexed | 2024-03-09T02:02:29Z |
| format | Article |
| id | doaj.art-1ee17a3b8c554a94a78f1efbb7b57ebb |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-03-09T02:02:29Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-1ee17a3b8c554a94a78f1efbb7b57ebb2023-12-08T03:24:22ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742023-12-0138110.1080/14756366.2022.2155815Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluationWei Liu0Youyou He1Zhongjie Guo2Miaomiao Wang3Xiaodong Han4Hairui Jia5Jin He6Shanshan Miao7Shengzheng Wang8Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an, ChinaFaculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an, ChinaDepartment of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi’an, ChinaFaculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an, ChinaDepartment of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi’an, ChinaFaculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an, ChinaDepartment of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi’an, ChinaDepartment of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi’an, ChinaDepartment of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi’an, ChinaAbstractThe colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum in vitro antitumour activity. In this study, structure based rational design and systematic structural optimisation were performed to obtain analogues C1∼J2 bearing diverse substituents and scaffolds. Among them, analogue G13 bearing a hydroxymethyl group displayed good tubulin polymerisation inhibitory activity (IC50 = 13.5 μM) and potent antiproliferative activity (IC50 values: 0.65 μM∼0.90 μM). G13 potently inhibited the migration and invasion of MDA-MB-231 cells, and displayed potent antiangiogenic activity. It efficiently increased intracellular ROS level and decreased MMP in cancer cells, and obviously induced the fragmentation and disassembly of the microtubules network. More importantly, G13 exhibited good in vivo antitumour efficacy in MDA-MB-231 xenograft model (TGI = 38.2%; i.p., 30 mg/kg).https://www.tandfonline.com/doi/10.1080/14756366.2022.2155815Tubulin inhibitorscolchicine binding sitestructural optimisationantitumour activity |
| spellingShingle | Wei Liu Youyou He Zhongjie Guo Miaomiao Wang Xiaodong Han Hairui Jia Jin He Shanshan Miao Shengzheng Wang Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation Journal of Enzyme Inhibition and Medicinal Chemistry Tubulin inhibitors colchicine binding site structural optimisation antitumour activity |
| title | Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation |
| title_full | Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation |
| title_fullStr | Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation |
| title_full_unstemmed | Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation |
| title_short | Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation |
| title_sort | discovery of potent tubulin inhibitors targeting the colchicine binding site via structure based lead optimization and antitumor evaluation |
| topic | Tubulin inhibitors colchicine binding site structural optimisation antitumour activity |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2155815 |
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