Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20<i>S</i>)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives
A novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effect...
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| Format: | Article |
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MDPI AG
2020-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/22/8495 |
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| author | Xiufen Dai Guanzhao Wu Yixuan Zhang Xiaomin Zhang Ruijuan Yin Xin Qi Jing Li Tao Jiang |
| author_facet | Xiufen Dai Guanzhao Wu Yixuan Zhang Xiaomin Zhang Ruijuan Yin Xin Qi Jing Li Tao Jiang |
| author_sort | Xiufen Dai |
| collection | DOAJ |
| description | A novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effects. Here, two series of novel 20-substituted (20S)-10,11-methylenedioxy-camptothecin coupled with 5-substituted uracils and other heterocyclic rings through glycine were synthesized. All the derivatives showed superior cytotoxic activities in vitro with IC<sub>50</sub> values in the nanomolar range. Among them, 12e displayed higher cytotoxic activities in several cancer cell lines with better water solubility than FL118. Our results further showed that, like FL118, 12e inhibited cell proliferation resulting from cell cycle arrest and apoptosis by blocking the anti-apoptotic gene transcription of survivin, Mcl-1, Bcl-2, and XIAP in both A549 cells and NCI-H446 cells. Furthermore, 12e did not show any inhibitory activity on Topo I, which is involved in hematopoietic toxicity. In vivo, 12e showed similar antitumor efficacy to FL118 but lower toxicity. Our findings indicate that 12e is a promising therapeutic agent for cancer treatment, and the core structure of FL118 represents a promising platform to generate novel FL118-based antitumor drugs. |
| first_indexed | 2024-03-10T14:56:04Z |
| format | Article |
| id | doaj.art-a4245f00e2c343b88e0e220875425e45 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:56:04Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a4245f00e2c343b88e0e220875425e452023-11-20T20:37:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-012122849510.3390/ijms21228495Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20<i>S</i>)-10,11-Methylenedioxy-Camptothecin Heterocyclic DerivativesXiufen Dai0Guanzhao Wu1Yixuan Zhang2Xiaomin Zhang3Ruijuan Yin4Xin Qi5Jing Li6Tao Jiang7Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaA novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effects. Here, two series of novel 20-substituted (20S)-10,11-methylenedioxy-camptothecin coupled with 5-substituted uracils and other heterocyclic rings through glycine were synthesized. All the derivatives showed superior cytotoxic activities in vitro with IC<sub>50</sub> values in the nanomolar range. Among them, 12e displayed higher cytotoxic activities in several cancer cell lines with better water solubility than FL118. Our results further showed that, like FL118, 12e inhibited cell proliferation resulting from cell cycle arrest and apoptosis by blocking the anti-apoptotic gene transcription of survivin, Mcl-1, Bcl-2, and XIAP in both A549 cells and NCI-H446 cells. Furthermore, 12e did not show any inhibitory activity on Topo I, which is involved in hematopoietic toxicity. In vivo, 12e showed similar antitumor efficacy to FL118 but lower toxicity. Our findings indicate that 12e is a promising therapeutic agent for cancer treatment, and the core structure of FL118 represents a promising platform to generate novel FL118-based antitumor drugs.https://www.mdpi.com/1422-0067/21/22/8495Camptothecin derivativesFL11812eanticancer agentmolecular design |
| spellingShingle | Xiufen Dai Guanzhao Wu Yixuan Zhang Xiaomin Zhang Ruijuan Yin Xin Qi Jing Li Tao Jiang Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20<i>S</i>)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives International Journal of Molecular Sciences Camptothecin derivatives FL118 12e anticancer agent molecular design |
| title | Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20<i>S</i>)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives |
| title_full | Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20<i>S</i>)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives |
| title_fullStr | Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20<i>S</i>)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives |
| title_full_unstemmed | Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20<i>S</i>)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives |
| title_short | Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20<i>S</i>)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives |
| title_sort | design synthesis and in vitro in vivo anti cancer activities of novel 20 i s i 10 11 methylenedioxy camptothecin heterocyclic derivatives |
| topic | Camptothecin derivatives FL118 12e anticancer agent molecular design |
| url | https://www.mdpi.com/1422-0067/21/22/8495 |
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