RESUMO
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.
RESUMO
Rosmarinic acid (RA), commonly found in Nepetoidae subfamily of Lamiaceae family, possesses various biological activities. To expand its application, RA was modified by esterification with methyl (me), propyl (pro), and hexyl (hex) alcohols and then tested antibacterial, α-glucosidase inhibitory, and lipid accumulation suppression activities. Consequently, RA derivatives enhanced antibacterial activity, especially the RA-pro and RA-hex, which effectively inhibited the growth of Bacillus cereus rather than tannic acid, a natural antibacterial agent. RA-hex also inhibited α-glucosidase inhibitory activity greater than luteolin. By computational molecular docking, dihydroxyphenyl group and hexyl group were selected as essential groups for interaction with the active site of α-glucosidase through hydrogen bonding and hydrophobic interaction, contributing to the great inhibitory activity. Furthermore, RA-pro and RA-hex effectively suppressed lipid accumulation of 3T3-L1 cells, superior to EGCG, a well-known anti-obesity phytochemical. These biological effects of RA derivatives commonly attributed to hydrophobicity, hydrogen bonding, and steric bulkiness of the side chain. PRACTICAL APPLICATIONS: Rosmarinic acid (RA), a fundamental compound in the family Lamiaceae, is one of powerful naturally occurring antioxidants as well as other biological activities. Furthermore, its abundance in nature was also high in amount in the plant kingdom. So, natural RA can be one of possible natural resources for creating potent natural drugs and biologically useful substances after chemical modification. Studies on various biological activities may intensively expand usage and application of RA. In this study, RA was derivatized to corresponding ester such as methyl, propyl, and hexyl alcohols with higher hydrophobicity, and found great antibacterial, α-glucosidase inhibitory, and lipid accumulation suppression activities. RA-pro and RA-hex significantly suppressed lipid accumulation and cell differentiation. Therefore, RA derivatives with multiple biological activities have the potential to be applied in the food and pharmaceutical industries as food ingredients and supplements.