Synthesis, biological activity and mechanism of action of novel allosecurinine derivatives as potential antitumor agents
Copyright © 2023 Elsevier Ltd. All rights reserved..
Cancer with low survival rates is the second main cause of death among all diseases in the world and consequently, effective antineoplastic agents are urgently needed. Allosecurinine is a plant-derived indolicidine securinega alkaloid shown bioactivity. The object of this study is to investigate synthetic allosecurinine derivatives with considerable anticancer capacity against nine human cancer cell lines as well as mechanism of action. We synthesized twenty-three novel allosecurinine derivatives and evaluated their antitumor activity against nine cancer cell lines for 72 h by MTT and CCK8 assays. FCM was applied to analyze the apoptosis, mitochondrial membrane potential, DNA content, ROS production, CD11b expression. Western blot was selected to analyze the protein expression. Structure-activity relationships were established and potential anticancer lead BA-3 which induced differentiation of leukemia cells towards granulocytosis at low concentration and apoptosis at high concentration was identified. Mechanism studies showed that mitochondrial pathway mediated apoptosis within cancer cells with cell cycle blocking was induced by BA-3. In addition, western blot assays revealed that BA-3 induced expression of the proapoptotic factor Bax, p21 and reduced the levels of antiapoptotic protein such as Bcl-2, XIAP, YAP1, PARP, STAT3, p-STAT3, and c-Myc. Collectively, BA-3 was a lead compound for oncotherapy at least in part, through the STAT3 pathway. These results were an important step in further studies on allosecurinine-based antitumor agent development.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:82 |
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| Enthalten in: |
Bioorganic & medicinal chemistry - 82(2023) vom: 15. März, Seite 117234 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xu, Xin-Liang [VerfasserIn] |
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| Links: |
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| Themen: |
Alkaloids |
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| Anmerkungen: |
Date Completed 21.03.2023 Date Revised 22.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmc.2023.117234 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM354125796 |
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| 520 | |a Cancer with low survival rates is the second main cause of death among all diseases in the world and consequently, effective antineoplastic agents are urgently needed. Allosecurinine is a plant-derived indolicidine securinega alkaloid shown bioactivity. The object of this study is to investigate synthetic allosecurinine derivatives with considerable anticancer capacity against nine human cancer cell lines as well as mechanism of action. We synthesized twenty-three novel allosecurinine derivatives and evaluated their antitumor activity against nine cancer cell lines for 72 h by MTT and CCK8 assays. FCM was applied to analyze the apoptosis, mitochondrial membrane potential, DNA content, ROS production, CD11b expression. Western blot was selected to analyze the protein expression. Structure-activity relationships were established and potential anticancer lead BA-3 which induced differentiation of leukemia cells towards granulocytosis at low concentration and apoptosis at high concentration was identified. Mechanism studies showed that mitochondrial pathway mediated apoptosis within cancer cells with cell cycle blocking was induced by BA-3. In addition, western blot assays revealed that BA-3 induced expression of the proapoptotic factor Bax, p21 and reduced the levels of antiapoptotic protein such as Bcl-2, XIAP, YAP1, PARP, STAT3, p-STAT3, and c-Myc. Collectively, BA-3 was a lead compound for oncotherapy at least in part, through the STAT3 pathway. These results were an important step in further studies on allosecurinine-based antitumor agent development | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Allosecurinine | |
| 650 | 4 | |a Antitumor | |
| 650 | 4 | |a Derivatives | |
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| 650 | 7 | |a Heterocyclic Compounds, Bridged-Ring |2 NLM | |
| 650 | 7 | |a Lactones |2 NLM | |
| 650 | 7 | |a Alkaloids |2 NLM | |
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| 700 | 1 | |a Huang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Dai, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Xiao-Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Sheng-Lan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Wei-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Le-Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiao-Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Jun-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Xian-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Guan-Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Wen |e verfasserin |4 aut | |
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