Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities
A new series of 1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901,...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2302320 |
| _version_ | 1826919932509552640 |
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| author | Chao Wang Yujing Zhang Shanbo Yang Lingyu Shi Rong Rong Tingting Zhang Yudong Wu Dongming Xing |
| author_facet | Chao Wang Yujing Zhang Shanbo Yang Lingyu Shi Rong Rong Tingting Zhang Yudong Wu Dongming Xing |
| author_sort | Chao Wang |
| collection | DOAJ |
| description | A new series of 1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901, and MCF-7) in vitro. Among them, 10t exhibited the most potent activities against three cancer cell lines with IC50 values ranging from 0.12 to 0.21 μM. Tubulin polymerisation experiments indicated that 10t potently inhibited tubulin polymerisation at concentrations of 3 μM and 5 μM, and immunostaining assays revealed that 10t remarkably disrupted tubulin microtubule dynamics at a concentration of 0.12 μM. Furthermore, cell cycle studies and cell apoptosis analyses demonstrated that 10t at concentrations of 0.12 μM, 0.24 μM, and 0.36 μM significantly caused G2/M phase cell cycle arrest and apoptosis. The results of molecular modelling studies suggested that 10t interacts with tubulin by forming hydrogen bonds with colchicine sites Thrα179 and Asnβ349. In addition, the prediction of physicochemical properties disclosed that 10t conformed well to the Lipinski’s rule of five. |
| first_indexed | 2024-03-08T14:00:37Z |
| format | Article |
| id | doaj.art-f64cf30fe3d14e0bac180712344b0f19 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2025-02-17T13:20:46Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-f64cf30fe3d14e0bac180712344b0f192024-12-26T09:30:43ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2302320Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activitiesChao Wang0Yujing Zhang1Shanbo Yang2Lingyu Shi3Rong Rong4Tingting Zhang5Yudong Wu6Dongming Xing7Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaThe Affiliated Cardiovascular Hospital of Qingdao University, Qingdao University, Qingdao, ChinaCancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaCancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaYantai Key laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, ChinaCancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaCancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaCancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, ChinaA new series of 1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901, and MCF-7) in vitro. Among them, 10t exhibited the most potent activities against three cancer cell lines with IC50 values ranging from 0.12 to 0.21 μM. Tubulin polymerisation experiments indicated that 10t potently inhibited tubulin polymerisation at concentrations of 3 μM and 5 μM, and immunostaining assays revealed that 10t remarkably disrupted tubulin microtubule dynamics at a concentration of 0.12 μM. Furthermore, cell cycle studies and cell apoptosis analyses demonstrated that 10t at concentrations of 0.12 μM, 0.24 μM, and 0.36 μM significantly caused G2/M phase cell cycle arrest and apoptosis. The results of molecular modelling studies suggested that 10t interacts with tubulin by forming hydrogen bonds with colchicine sites Thrα179 and Asnβ349. In addition, the prediction of physicochemical properties disclosed that 10t conformed well to the Lipinski’s rule of five.https://www.tandfonline.com/doi/10.1080/14756366.2024.2302320Tubulin combreastatin A-4 restriction configuration 1H-pyrrolo[32-c]pyridine molecular docking |
| spellingShingle | Chao Wang Yujing Zhang Shanbo Yang Lingyu Shi Rong Rong Tingting Zhang Yudong Wu Dongming Xing Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities Journal of Enzyme Inhibition and Medicinal Chemistry Tubulin combreastatin A-4 restriction configuration 1H-pyrrolo[32-c]pyridine molecular docking |
| title | Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities |
| title_full | Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities |
| title_fullStr | Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities |
| title_full_unstemmed | Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities |
| title_short | Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities |
| title_sort | design synthesis and bioevaluation of 1h pyrrolo 3 2 c pyridine derivatives as colchicine binding site inhibitors with potent anticancer activities |
| topic | Tubulin combreastatin A-4 restriction configuration 1H-pyrrolo[32-c]pyridine molecular docking |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2302320 |
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