Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor Agents
Podophyllotoxin has long been used as an active substance for cytotoxic activity. Fourteen novel biotinylated podophyllotoxin derivatives were designed, synthesized, and evaluated for cytotoxic activity for this study. The synthesized compounds were evaluated for cytotoxic activity in the following...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-06-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2019.00434/full |
| _version_ | 1818997769745989632 |
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| author | Cheng-Ting Zi Cheng-Ting Zi Cheng-Ting Zi Ying-Sheng Gao Liu Yang Shu-Yun Feng Yue Huang Li Sun Yi Jin Feng-Qing Xu Fa-Wu Dong Yan Li Zhong-Tao Ding Jun Zhou Zi-Hua Jiang Sheng-Tao Yuan Jiang-Miao Hu |
| author_facet | Cheng-Ting Zi Cheng-Ting Zi Cheng-Ting Zi Ying-Sheng Gao Liu Yang Shu-Yun Feng Yue Huang Li Sun Yi Jin Feng-Qing Xu Fa-Wu Dong Yan Li Zhong-Tao Ding Jun Zhou Zi-Hua Jiang Sheng-Tao Yuan Jiang-Miao Hu |
| author_sort | Cheng-Ting Zi |
| collection | DOAJ |
| description | Podophyllotoxin has long been used as an active substance for cytotoxic activity. Fourteen novel biotinylated podophyllotoxin derivatives were designed, synthesized, and evaluated for cytotoxic activity for this study. The synthesized compounds were evaluated for cytotoxic activity in the following human cancer cell lines, SW480, MCF-7, A-549, SMMC-7721, and HL-60 by MTT assay. Most of them exhibited potent cytotoxic effects and compound 15 showed the highest cytotoxic activity among the five cancer cell lines tested, having its IC50 values in the range of 0.13 to 0.84 μM. Apoptosis analysis revealed that compound 15 caused obvious induction of cell apoptosis. Compound 15 significantly down-regulated the expression level of the marker proteins (caspase-3 and PARP) in H1299 and H1975 cells, activated the transcription of IRE1α, increased the expression of GRP78 and XBP-1s, and finally induced apoptosis of H1299 cells. In vivo studies showed that 15 at a dose of 20 mg/kg suppressed tumor growth of S180 cell xenografts in icr mice significantly. Further molecular docking studies suggested that compound 15 could bind well with the ATPase domain of Topoisomerase-II. These data suggest that compound 15 is a promising agent for cancer therapy deserving further research. |
| first_indexed | 2024-12-20T21:50:54Z |
| format | Article |
| id | doaj.art-42c648a234c34b5481d840b4ad5af963 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-20T21:50:54Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-42c648a234c34b5481d840b4ad5af9632022-12-21T19:25:33ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462019-06-01710.3389/fchem.2019.00434459778Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor AgentsCheng-Ting Zi0Cheng-Ting Zi1Cheng-Ting Zi2Ying-Sheng Gao3Liu Yang4Shu-Yun Feng5Yue Huang6Li Sun7Yi Jin8Feng-Qing Xu9Fa-Wu Dong10Yan Li11Zhong-Tao Ding12Jun Zhou13Zi-Hua Jiang14Sheng-Tao Yuan15Jiang-Miao Hu16State Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaKey Laboratory of Pu-er Tea Science, College of Science, Ministry of Education, Yunnan Agricultural University, Kunming, ChinaKey Laboratory of Medicinal Chemistry for Nature Resource, School of Chemical Science and Technology, Ministry of Education, Yunnan University, Kunming, ChinaJiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaJiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, ChinaJiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, ChinaJiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, ChinaKey Laboratory of Medicinal Chemistry for Nature Resource, School of Chemical Science and Technology, Ministry of Education, Yunnan University, Kunming, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaKey Laboratory of Medicinal Chemistry for Nature Resource, School of Chemical Science and Technology, Ministry of Education, Yunnan University, Kunming, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaDepartment of Chemistry, Lakehead University, Thunder Bay, ON, CanadaJiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaPodophyllotoxin has long been used as an active substance for cytotoxic activity. Fourteen novel biotinylated podophyllotoxin derivatives were designed, synthesized, and evaluated for cytotoxic activity for this study. The synthesized compounds were evaluated for cytotoxic activity in the following human cancer cell lines, SW480, MCF-7, A-549, SMMC-7721, and HL-60 by MTT assay. Most of them exhibited potent cytotoxic effects and compound 15 showed the highest cytotoxic activity among the five cancer cell lines tested, having its IC50 values in the range of 0.13 to 0.84 μM. Apoptosis analysis revealed that compound 15 caused obvious induction of cell apoptosis. Compound 15 significantly down-regulated the expression level of the marker proteins (caspase-3 and PARP) in H1299 and H1975 cells, activated the transcription of IRE1α, increased the expression of GRP78 and XBP-1s, and finally induced apoptosis of H1299 cells. In vivo studies showed that 15 at a dose of 20 mg/kg suppressed tumor growth of S180 cell xenografts in icr mice significantly. Further molecular docking studies suggested that compound 15 could bind well with the ATPase domain of Topoisomerase-II. These data suggest that compound 15 is a promising agent for cancer therapy deserving further research.https://www.frontiersin.org/article/10.3389/fchem.2019.00434/fullpodophyllotoxin derivativesbiotinanticancer activitysynthesisapoptosis |
| spellingShingle | Cheng-Ting Zi Cheng-Ting Zi Cheng-Ting Zi Ying-Sheng Gao Liu Yang Shu-Yun Feng Yue Huang Li Sun Yi Jin Feng-Qing Xu Fa-Wu Dong Yan Li Zhong-Tao Ding Jun Zhou Zi-Hua Jiang Sheng-Tao Yuan Jiang-Miao Hu Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor Agents Frontiers in Chemistry podophyllotoxin derivatives biotin anticancer activity synthesis apoptosis |
| title | Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor Agents |
| title_full | Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor Agents |
| title_fullStr | Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor Agents |
| title_full_unstemmed | Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor Agents |
| title_short | Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor Agents |
| title_sort | design synthesis and biological evaluation of novel biotinylated podophyllotoxin derivatives as potential antitumor agents |
| topic | podophyllotoxin derivatives biotin anticancer activity synthesis apoptosis |
| url | https://www.frontiersin.org/article/10.3389/fchem.2019.00434/full |
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