Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity
Simultaneous inhibition of more than one target is considered to be a novel strategy in cancer therapy. Owing to the importance of histone deacetylases (HDACs) and p53-murine double minute 2 (MDM2) interaction in tumor development and their synergistic effects, a series of MDM2/HDAC bifunctional sma...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.972372/full |
| _version_ | 1797737018468335616 |
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| author | Qian Zhao Shan-Shan Xiong Can Chen Can Chen Hong-Ping Zhu Hong-Ping Zhu Xin Xie Cheng Peng Gu He Bo Han |
| author_facet | Qian Zhao Shan-Shan Xiong Can Chen Can Chen Hong-Ping Zhu Hong-Ping Zhu Xin Xie Cheng Peng Gu He Bo Han |
| author_sort | Qian Zhao |
| collection | DOAJ |
| description | Simultaneous inhibition of more than one target is considered to be a novel strategy in cancer therapy. Owing to the importance of histone deacetylases (HDACs) and p53-murine double minute 2 (MDM2) interaction in tumor development and their synergistic effects, a series of MDM2/HDAC bifunctional small-molecule inhibitors were rationally designed and synthesized by incorporating an HDAC pharmacophore into spirooxindole skeletons. These compounds exhibited good inhibitory activities against both targets. In particular, compound 11b was demonstrated to be most potent for MDM2 and HDAC, reaching the enzyme inhibition of 68% and 79%, respectively. Compound 11b also showed efficient antiproliferative activity towards MCF-7 cells with better potency than the reference drug SAHA and Nutlin-3. Furthermore, western blot analysis revealed that compound 11b increased the expression of p53 and Ac-H4 in MCF-7 cells in a dose-dependent manner. Our results indicate that dual inhibition of HDAC and MDM2 may provide a novel and efficient strategy for the discovery of antitumor drug in the future. |
| first_indexed | 2024-03-12T13:21:23Z |
| format | Article |
| id | doaj.art-65bc2372d20549dda93cc9377cd563b8 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-12T13:21:23Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-65bc2372d20549dda93cc9377cd563b82023-08-25T18:30:10ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-08-011210.3389/fonc.2022.972372972372Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activityQian Zhao0Shan-Shan Xiong1Can Chen2Can Chen3Hong-Ping Zhu4Hong-Ping Zhu5Xin Xie6Cheng Peng7Gu He8Bo Han9State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaDepartment of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaSchool of Pharmacy, Chengdu Medical College, Chengdu, ChinaThe First Affiliated Hospital, Chengdu Medical College, Chengdu, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaAntibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaDepartment of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaSimultaneous inhibition of more than one target is considered to be a novel strategy in cancer therapy. Owing to the importance of histone deacetylases (HDACs) and p53-murine double minute 2 (MDM2) interaction in tumor development and their synergistic effects, a series of MDM2/HDAC bifunctional small-molecule inhibitors were rationally designed and synthesized by incorporating an HDAC pharmacophore into spirooxindole skeletons. These compounds exhibited good inhibitory activities against both targets. In particular, compound 11b was demonstrated to be most potent for MDM2 and HDAC, reaching the enzyme inhibition of 68% and 79%, respectively. Compound 11b also showed efficient antiproliferative activity towards MCF-7 cells with better potency than the reference drug SAHA and Nutlin-3. Furthermore, western blot analysis revealed that compound 11b increased the expression of p53 and Ac-H4 in MCF-7 cells in a dose-dependent manner. Our results indicate that dual inhibition of HDAC and MDM2 may provide a novel and efficient strategy for the discovery of antitumor drug in the future.https://www.frontiersin.org/articles/10.3389/fonc.2022.972372/fullmultitarget drugshistone deacetylase inhibitorsMDM2 inhibitorsspirooxindoledual inhibitorsanticancer |
| spellingShingle | Qian Zhao Shan-Shan Xiong Can Chen Can Chen Hong-Ping Zhu Hong-Ping Zhu Xin Xie Cheng Peng Gu He Bo Han Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity Frontiers in Oncology multitarget drugs histone deacetylase inhibitors MDM2 inhibitors spirooxindole dual inhibitors anticancer |
| title | Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity |
| title_full | Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity |
| title_fullStr | Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity |
| title_full_unstemmed | Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity |
| title_short | Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity |
| title_sort | discovery of spirooxindole derived small molecule compounds as novel hdac mdm2 dual inhibitors and investigation of their anticancer activity |
| topic | multitarget drugs histone deacetylase inhibitors MDM2 inhibitors spirooxindole dual inhibitors anticancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.972372/full |
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