Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors
The molecular chaperone HSP90 plays an essential role in cancer occurrence and development. Therefore, it is an important target for the development of anticancer drugs. 1,3-Dibenzyl-2-aryl imidazolidine (8) is a previously reported inhibitor of HSP90; however, its anticancer activity is poor. In th...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2124407 |
| _version_ | 1798035524610424832 |
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| author | Man Yang Chenyao Li Yajing Li Chen Cheng Meiyun Shi Lei Yin Hongyu Xue Yajun Liu |
| author_facet | Man Yang Chenyao Li Yajing Li Chen Cheng Meiyun Shi Lei Yin Hongyu Xue Yajun Liu |
| author_sort | Man Yang |
| collection | DOAJ |
| description | The molecular chaperone HSP90 plays an essential role in cancer occurrence and development. Therefore, it is an important target for the development of anticancer drugs. 1,3-Dibenzyl-2-aryl imidazolidine (8) is a previously reported inhibitor of HSP90; however, its anticancer activity is poor. In this work, chemical modification of 8 led to the discovery of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as two types of novel HSP90 N-terminal inhibitors. 16l and 22k exhibited antiproliferative activity against multiple breast cancer cell lines with IC50 values at the low micromolar level. 16l and 22k induced significant degradation of the client proteins AKT and ERK and a lower level of the heat shock response in comparison with tanespimycin (17-AAG). 22k exhibited a strong affinity for the HSP90α N-terminus with an IC50 value of 0.21 μM. A molecular docking study revealed that 16l and 22k successfully bind to the geldanamycin binding site at the N-terminus of HSP90α. |
| first_indexed | 2024-04-11T20:59:23Z |
| format | Article |
| id | doaj.art-a685b0d58420405f8bf6e4d228f833f1 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-11T20:59:23Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-a685b0d58420405f8bf6e4d228f833f12022-12-22T04:03:33ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013712551256510.1080/14756366.2022.2124407Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitorsMan Yang0Chenyao Li1Yajing Li2Chen Cheng3Meiyun Shi4Lei Yin5Hongyu Xue6Yajun Liu7School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaSchool of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, ChinaThe molecular chaperone HSP90 plays an essential role in cancer occurrence and development. Therefore, it is an important target for the development of anticancer drugs. 1,3-Dibenzyl-2-aryl imidazolidine (8) is a previously reported inhibitor of HSP90; however, its anticancer activity is poor. In this work, chemical modification of 8 led to the discovery of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as two types of novel HSP90 N-terminal inhibitors. 16l and 22k exhibited antiproliferative activity against multiple breast cancer cell lines with IC50 values at the low micromolar level. 16l and 22k induced significant degradation of the client proteins AKT and ERK and a lower level of the heat shock response in comparison with tanespimycin (17-AAG). 22k exhibited a strong affinity for the HSP90α N-terminus with an IC50 value of 0.21 μM. A molecular docking study revealed that 16l and 22k successfully bind to the geldanamycin binding site at the N-terminus of HSP90α.https://www.tandfonline.com/doi/10.1080/14756366.2022.2124407HSP902 4-diarylimidazoles2 4-bis(benzyloxy)-5-arylpyrimidinesmolecular dockinganticancer |
| spellingShingle | Man Yang Chenyao Li Yajing Li Chen Cheng Meiyun Shi Lei Yin Hongyu Xue Yajun Liu Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry HSP90 2 4-diarylimidazoles 2 4-bis(benzyloxy)-5-arylpyrimidines molecular docking anticancer |
| title | Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors |
| title_full | Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors |
| title_fullStr | Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors |
| title_full_unstemmed | Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors |
| title_short | Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors |
| title_sort | design synthesis biological evaluation and molecular docking study of 2 4 diarylimidazoles and 2 4 bis benzyloxy 5 arylpyrimidines as novel hsp90 n terminal inhibitors |
| topic | HSP90 2 4-diarylimidazoles 2 4-bis(benzyloxy)-5-arylpyrimidines molecular docking anticancer |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2124407 |
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