Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers
A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound <b>(<i>R</i>, <i>S</i>)-12a</b> strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC<sub...
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| Natura: | Articolo |
| Lingua: | English |
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MDPI AG
2022-08-01
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| Serie: | Molecules |
| Soggetti: | |
| Accesso online: | https://www.mdpi.com/1420-3049/27/17/5359 |
| _version_ | 1827665694558257152 |
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| author | Han Yao Yuanyuan Ren Jun Yan Jiadai Liu Jinhui Hu Ming Yan Xingshu Li |
| author_facet | Han Yao Yuanyuan Ren Jun Yan Jiadai Liu Jinhui Hu Ming Yan Xingshu Li |
| author_sort | Han Yao |
| collection | DOAJ |
| description | A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound <b>(<i>R</i>, <i>S</i>)-12a</b> strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC<sub>50</sub> value of 0.002 μM, compared to tepotinib (IC<sub>50</sub> = 0.013 μM). Mechanistic studies revealed that compound <b>(<i>R, S</i>)-12a</b> significantly inhibited c-Met activation, as well as the downstream AKT signaling pathway, and suppressed wound closure. Moreover, compound <b>(<i>R, S</i>)-12a</b> induced cellular apoptosis and cell cycle arrest at the G<sub>1</sub> phase in a dose-dependent fashion. |
| first_indexed | 2024-03-10T01:31:42Z |
| format | Article |
| id | doaj.art-7d5dbdb3ec2d4d9a9d7633d4b8d4b00e |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T01:31:42Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-7d5dbdb3ec2d4d9a9d7633d4b8d4b00e2023-11-23T13:40:38ZengMDPI AGMolecules1420-30492022-08-012717535910.3390/molecules27175359Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral CentersHan Yao0Yuanyuan Ren1Jun Yan2Jiadai Liu3Jinhui Hu4Ming Yan5Xingshu Li6School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaA series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound <b>(<i>R</i>, <i>S</i>)-12a</b> strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC<sub>50</sub> value of 0.002 μM, compared to tepotinib (IC<sub>50</sub> = 0.013 μM). Mechanistic studies revealed that compound <b>(<i>R, S</i>)-12a</b> significantly inhibited c-Met activation, as well as the downstream AKT signaling pathway, and suppressed wound closure. Moreover, compound <b>(<i>R, S</i>)-12a</b> induced cellular apoptosis and cell cycle arrest at the G<sub>1</sub> phase in a dose-dependent fashion.https://www.mdpi.com/1420-3049/27/17/5359c-Met inhibitorstepotinibchiral compoundskinasecancer |
| spellingShingle | Han Yao Yuanyuan Ren Jun Yan Jiadai Liu Jinhui Hu Ming Yan Xingshu Li Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers Molecules c-Met inhibitors tepotinib chiral compounds kinase cancer |
| title | Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers |
| title_full | Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers |
| title_fullStr | Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers |
| title_full_unstemmed | Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers |
| title_short | Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers |
| title_sort | design synthesis and evaluation of new mesenchymal epithelial transition factor c met kinase inhibitors with dual chiral centers |
| topic | c-Met inhibitors tepotinib chiral compounds kinase cancer |
| url | https://www.mdpi.com/1420-3049/27/17/5359 |
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