Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety
Tocopheryl succinate (Tsuc) is a succinic acid ester of the well-known antioxidant α-tocopherol (T). Tsuc exhibits various biological activities, including tumor growth suppression via activation of cell signaling and prevention of lipid accumulation in mouse adipocyte 3T3-L1 cells. The latter findi...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-09-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580822001297 |
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| author | Misaki Yamasaki Yuika Seto Mizune Ozono Michiyasu Nakao Akira Shigenaga Akira Otaka Shigeki Sano Kentaro Kogure |
| author_facet | Misaki Yamasaki Yuika Seto Mizune Ozono Michiyasu Nakao Akira Shigenaga Akira Otaka Shigeki Sano Kentaro Kogure |
| author_sort | Misaki Yamasaki |
| collection | DOAJ |
| description | Tocopheryl succinate (Tsuc) is a succinic acid ester of the well-known antioxidant α-tocopherol (T). Tsuc exhibits various biological activities, including tumor growth suppression via activation of cell signaling and prevention of lipid accumulation in mouse adipocyte 3T3-L1 cells. The latter findings suggest that Tsuc may be a drug candidate for the treatment of obesity. However, Tsuc was found to induce apoptosis of normal cells (in addition to cancer cells), demonstrating the need to reduce the cytotoxicity of Tsuc without losing the suppression effect on lipid accumulation. Based on our previous findings, we focused on the ester structure of Tsuc for controlling cytotoxicity. Herein, we examined the cytotoxicity and lipid accumulation suppression effect of various T ester derivatives. We found that the terminal carboxylic group is necessary for suppression of lipid accumulation. We synthesized tocopheryl glutarate (Tglu) and tocopheryl adipate (Tadi) by elongation of carbon atoms 1 and 2 of the dicarboxylic moiety, respectively. Tglu and Tadi did not show any cytotoxicity, and both esters suppressed lipid accumulation, although their suppression activities were weaker than that of Tsuc. Tadi showed a more potent lipid accumulation inhibitory effect than Tglu. Although Tadi inhibited lipogenesis and promoted lipolysis, lipolysis was induced at lower concentrations than inhibition of lipogenesis, suggesting that Tadi mainly affects lipolysis. Taken together, we succeeded in the reduction of cytotoxicity, without loss of the suppression effect on lipid accumulation, by elongation of the dicarboxylic moiety of Tsuc. Tadi may be a promising candidate as an anti-obesity drug. |
| first_indexed | 2024-12-11T00:41:42Z |
| format | Article |
| id | doaj.art-022f4f93669a43458f13f76f7057687a |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-12-11T00:41:42Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-022f4f93669a43458f13f76f7057687a2022-12-22T01:26:54ZengElsevierBiochemistry and Biophysics Reports2405-58082022-09-0131101329Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moietyMisaki Yamasaki0Yuika Seto1Mizune Ozono2Michiyasu Nakao3Akira Shigenaga4Akira Otaka5Shigeki Sano6Kentaro Kogure7Graduate School of Pharmaceutical Sciences, Tokushima University, 1–78–1 Shomachi, Tokushima, 770-8505, JapanFaculty of Pharmaceutical Sciences, Tokushima University, 1–78–1 Shomachi, Tokushima, 770-8505, JapanGraduate School of Biomedical Sciences, Tokushima University, 1–78–1 Shomachi, Tokushima, 770-8505, JapanGraduate School of Biomedical Sciences, Tokushima University, 1–78–1 Shomachi, Tokushima, 770-8505, JapanFaculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Hiroshima, 729-0292, JapanGraduate School of Biomedical Sciences, Tokushima University, 1–78–1 Shomachi, Tokushima, 770-8505, JapanGraduate School of Biomedical Sciences, Tokushima University, 1–78–1 Shomachi, Tokushima, 770-8505, JapanGraduate School of Biomedical Sciences, Tokushima University, 1–78–1 Shomachi, Tokushima, 770-8505, Japan; Corresponding author.Tocopheryl succinate (Tsuc) is a succinic acid ester of the well-known antioxidant α-tocopherol (T). Tsuc exhibits various biological activities, including tumor growth suppression via activation of cell signaling and prevention of lipid accumulation in mouse adipocyte 3T3-L1 cells. The latter findings suggest that Tsuc may be a drug candidate for the treatment of obesity. However, Tsuc was found to induce apoptosis of normal cells (in addition to cancer cells), demonstrating the need to reduce the cytotoxicity of Tsuc without losing the suppression effect on lipid accumulation. Based on our previous findings, we focused on the ester structure of Tsuc for controlling cytotoxicity. Herein, we examined the cytotoxicity and lipid accumulation suppression effect of various T ester derivatives. We found that the terminal carboxylic group is necessary for suppression of lipid accumulation. We synthesized tocopheryl glutarate (Tglu) and tocopheryl adipate (Tadi) by elongation of carbon atoms 1 and 2 of the dicarboxylic moiety, respectively. Tglu and Tadi did not show any cytotoxicity, and both esters suppressed lipid accumulation, although their suppression activities were weaker than that of Tsuc. Tadi showed a more potent lipid accumulation inhibitory effect than Tglu. Although Tadi inhibited lipogenesis and promoted lipolysis, lipolysis was induced at lower concentrations than inhibition of lipogenesis, suggesting that Tadi mainly affects lipolysis. Taken together, we succeeded in the reduction of cytotoxicity, without loss of the suppression effect on lipid accumulation, by elongation of the dicarboxylic moiety of Tsuc. Tadi may be a promising candidate as an anti-obesity drug.http://www.sciencedirect.com/science/article/pii/S2405580822001297Tocopheryl esterCytotoxicityLipid accumulation suppressionAnti-obesity |
| spellingShingle | Misaki Yamasaki Yuika Seto Mizune Ozono Michiyasu Nakao Akira Shigenaga Akira Otaka Shigeki Sano Kentaro Kogure Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety Biochemistry and Biophysics Reports Tocopheryl ester Cytotoxicity Lipid accumulation suppression Anti-obesity |
| title | Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety |
| title_full | Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety |
| title_fullStr | Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety |
| title_full_unstemmed | Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety |
| title_short | Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety |
| title_sort | development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety |
| topic | Tocopheryl ester Cytotoxicity Lipid accumulation suppression Anti-obesity |
| url | http://www.sciencedirect.com/science/article/pii/S2405580822001297 |
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