Lipophilic ester and amide derivatives of rosmarinic acid protect cells against H2O2-induced DNA damage and apoptosis: The potential role of intracellular accumulation and labile iron chelation

• Published in: Redox biology 2018-05, Vol.15 (C), p.548-556
• Main Authors: Gerogianni, Paraskevi S., Chatziathanasiadou, Maria V., Diamantis, Dimitrios A., Tzakos, Andreas G., Galaris, Dimitrios
• Format: Article
• Language: English
• Subjects: Cell apoptosis; Cell uptake; DNA damage; Labile iron; Oxidative stress; Research Paper; Rosmarinic acid derivatives
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2018.01.014

Phenolic acids represent abundant components contained in human diet. However, the negative charge in their carboxylic group limits their capacity to diffuse through biological membranes, thus hindering their access to cell interior. In order to promote the diffusion of rosmarinic acid through biological membranes, we synthesized several lipophilic ester- and amide-derivatives of this compound and evaluated their capacity to prevent H2O2-induced DNA damage and apoptosis in cultured human cells. Esterification of the carboxylic moiety with lipophilic groups strongly enhanced the capacity of rosmarinic acid to protect cells. On the other hand, the amide-derivatives were somewhat less effective but exerted less cytotoxicity at high concentrations. Cell uptake experiments, using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS), illustrated different levels of intracellular accumulation among the ester- and amide-derivatives, with the first being more effectively accumulated, probably due to their extensive hydrolysis inside the cells. In conclusion, these results highlight the hitherto unrecognized fundamental importance of derivatization of diet-derived phenolic acids to unveil their biological potential. [Display omitted] •Esterification of rosmarinic acid enhances strongly its biological activity.•Rosmarinic acid amides exerted lower toxicity than their corresponding esters.•Esters accumulated in the cells more effectively than the corresponding amides.•Differential hydrolysis rates inside the cells can determine their accumulation.