Design, synthesis, and anticancer activity of three novel palbociclib derivatives
Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibit...
| Main Authors: | , , , , , , , , , , , |
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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 |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.959322/full |
| _version_ | 1818515254291726336 |
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| author | Tian Li An-Di Zhou Li-Fei Bai Xiao-Yang Zhang Yu-Ting Zhou Hai-Li Yang Le-Tian Xu Xin-Qin Guo Xi-Yu Zhu Dong-Jin Wang Hong-Wei Gu Xiao-Ming Wang |
| author_facet | Tian Li An-Di Zhou Li-Fei Bai Xiao-Yang Zhang Yu-Ting Zhou Hai-Li Yang Le-Tian Xu Xin-Qin Guo Xi-Yu Zhu Dong-Jin Wang Hong-Wei Gu Xiao-Ming Wang |
| author_sort | Tian Li |
| collection | DOAJ |
| description | Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives. |
| first_indexed | 2024-12-11T00:26:38Z |
| format | Article |
| id | doaj.art-f84a13e460654bdda28d27d01158d95b |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-11T00:26:38Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-f84a13e460654bdda28d27d01158d95b2022-12-22T01:27:33ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-08-011210.3389/fonc.2022.959322959322Design, synthesis, and anticancer activity of three novel palbociclib derivativesTian Li0An-Di Zhou1Li-Fei Bai2Xiao-Yang Zhang3Yu-Ting Zhou4Hai-Li Yang5Le-Tian Xu6Xin-Qin Guo7Xi-Yu Zhu8Dong-Jin Wang9Hong-Wei Gu10Xiao-Ming Wang11Department of Cardio-Thoracic Surgery, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing, ChinaDepartment of Cardio-Thoracic Surgery, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing, ChinaJiangsu Key Laboratory of Biofunction Molecule, School of Life Science and Chemical Engineering, Jiangsu Second Normal University, Nanjing, ChinaCentral Laboratory, Nanjing Integrated Traditional Chinese and Western Medicine Hospital Affiliated with Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Cardio-Thoracic Surgery, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing, ChinaDepartment of Cardio-Thoracic Surgery, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing, ChinaDepartment of Cardio-Thoracic Surgery, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing, ChinaDepartment of Cardio-Thoracic Surgery, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing, ChinaDepartment of Cardio-Thoracic Surgery, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing, ChinaDepartment of Cardio-Thoracic Surgery, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing, ChinaCentral Laboratory, Nanjing Integrated Traditional Chinese and Western Medicine Hospital Affiliated with Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Cardio-Thoracic Surgery, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing, ChinaCancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives.https://www.frontiersin.org/articles/10.3389/fonc.2022.959322/fullpalbociclib derivativesanticancer activityCDK4/610-hydroxy camptothecinTopo I |
| spellingShingle | Tian Li An-Di Zhou Li-Fei Bai Xiao-Yang Zhang Yu-Ting Zhou Hai-Li Yang Le-Tian Xu Xin-Qin Guo Xi-Yu Zhu Dong-Jin Wang Hong-Wei Gu Xiao-Ming Wang Design, synthesis, and anticancer activity of three novel palbociclib derivatives Frontiers in Oncology palbociclib derivatives anticancer activity CDK4/6 10-hydroxy camptothecin Topo I |
| title | Design, synthesis, and anticancer activity of three novel palbociclib derivatives |
| title_full | Design, synthesis, and anticancer activity of three novel palbociclib derivatives |
| title_fullStr | Design, synthesis, and anticancer activity of three novel palbociclib derivatives |
| title_full_unstemmed | Design, synthesis, and anticancer activity of three novel palbociclib derivatives |
| title_short | Design, synthesis, and anticancer activity of three novel palbociclib derivatives |
| title_sort | design synthesis and anticancer activity of three novel palbociclib derivatives |
| topic | palbociclib derivatives anticancer activity CDK4/6 10-hydroxy camptothecin Topo I |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.959322/full |
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