Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone
<i>α</i>-Mangostin, a natural xanthone, was found to have anticancer effects, but these effects are not sufficient to be effective. To increase anticancer potential and selectivity, a triphenylphosphonium cation moiety (TPP) was introduced to <i>α</i>-mangostin to specificall...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/3/1016 |
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| author | Sibei Wang Qi Zhang Maoqin Peng Jing Xu Yuanqiang Guo |
| author_facet | Sibei Wang Qi Zhang Maoqin Peng Jing Xu Yuanqiang Guo |
| author_sort | Sibei Wang |
| collection | DOAJ |
| description | <i>α</i>-Mangostin, a natural xanthone, was found to have anticancer effects, but these effects are not sufficient to be effective. To increase anticancer potential and selectivity, a triphenylphosphonium cation moiety (TPP) was introduced to <i>α</i>-mangostin to specifically target cancer cell mitochondria. Compared to the parent compound, the cytotoxicity of the synthesized compound <b>1b</b> increased by one order of magnitude. Mechanistic analysis revealed that the anti-tumor effects were involved in the mitochondrial apoptotic pathway by prompting apoptosis and arresting the cell cycle at the G0/G1 phase, increasing the production of reactive oxygen species (ROS), and reducing mitochondrial membrane potential (Δψ<sub>m</sub>). More notably, the antitumor activity of compound <b>1b</b> was further confirmed by zebrafish models, which remarkably inhibited cancer cell proliferation and migration, as well as zebrafish angiogenesis. Taken together, our results for the first time indicated that TPP-linked <b>1b</b> could lead to the development of new mitochondrion-targeting antitumor agents. |
| first_indexed | 2024-03-11T09:33:29Z |
| format | Article |
| id | doaj.art-86546be18515413f9151f4ed6ee1ea70 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T09:33:29Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-86546be18515413f9151f4ed6ee1ea702023-11-16T17:26:28ZengMDPI AGMolecules1420-30492023-01-01283101610.3390/molecules28031016Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted XanthoneSibei Wang0Qi Zhang1Maoqin Peng2Jing Xu3Yuanqiang Guo4State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China<i>α</i>-Mangostin, a natural xanthone, was found to have anticancer effects, but these effects are not sufficient to be effective. To increase anticancer potential and selectivity, a triphenylphosphonium cation moiety (TPP) was introduced to <i>α</i>-mangostin to specifically target cancer cell mitochondria. Compared to the parent compound, the cytotoxicity of the synthesized compound <b>1b</b> increased by one order of magnitude. Mechanistic analysis revealed that the anti-tumor effects were involved in the mitochondrial apoptotic pathway by prompting apoptosis and arresting the cell cycle at the G0/G1 phase, increasing the production of reactive oxygen species (ROS), and reducing mitochondrial membrane potential (Δψ<sub>m</sub>). More notably, the antitumor activity of compound <b>1b</b> was further confirmed by zebrafish models, which remarkably inhibited cancer cell proliferation and migration, as well as zebrafish angiogenesis. Taken together, our results for the first time indicated that TPP-linked <b>1b</b> could lead to the development of new mitochondrion-targeting antitumor agents.https://www.mdpi.com/1420-3049/28/3/1016<i>α</i>-mangostintriphenylphosphoniummitochondrial targetingantitumor activityapoptosiszebrafish |
| spellingShingle | Sibei Wang Qi Zhang Maoqin Peng Jing Xu Yuanqiang Guo Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone Molecules <i>α</i>-mangostin triphenylphosphonium mitochondrial targeting antitumor activity apoptosis zebrafish |
| title | Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone |
| title_full | Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone |
| title_fullStr | Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone |
| title_full_unstemmed | Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone |
| title_short | Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone |
| title_sort | design synthesis biological evaluation and preliminary mechanistic study of a novel mitochondrial targeted xanthone |
| topic | <i>α</i>-mangostin triphenylphosphonium mitochondrial targeting antitumor activity apoptosis zebrafish |
| url | https://www.mdpi.com/1420-3049/28/3/1016 |
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