Abstract
New dihydroxytyrosyl esters 2a, 2c–2j of dicarboxylic acids were synthesized from methyl orthoformate protected hydroxytyrosol 3 and diacyl chlorides. New compounds were characterized (HRMS, FT-IR, 1H- and 13C-NMR), and tested for antioxidant activity both in vitro (ABTS) and on L6 myoblasts and THP1 leukemic monocytes cell culture by DCF assay. According to the ABTS assay, compounds 2a, 2c–2j showed a TEAC value of antioxidant capacity up to twice that of Trolox. Very high or complete ROS protections were obtained in the cell environment where lipophilicity and rigidity of dicarboxylic structure seem to facilitate the antioxidant effect. MTT assay and proliferation test were used for assessment of cell viability. These compounds can be envisaged as a new class of preservatives for food or cosmetic products.
Highlights
Hydroxytyrosol 1 (HTyr), a natural polyphenolic antioxidant, was recently recommended by EFSA as a food supplement in a balanced diet for its important health benefits [1], and is the ideal candidate to answer to the compelling demands for new nutraceuticals and safe natural preservatives [2]
The synthesis of hydroxytyrosyl esters generally suffers a few drawbacks: (i) the presence of alkylic and phenolic alcohols can compete to the esterification reaction with acyl chlorides; and (ii) the catecholic group oxidation during the work-up and purification can decrease the yields
HTyr nicotinate and HTyr lipoate were synthetized by chemical procedures including the protection and the deprotection of the catecholic moiety of HTyr [21,22], while lipophilic HTyr esters were generally prepared enzymatically using Candida antarctica lipase B [23,24]
Summary
Hydroxytyrosol 1 (HTyr), a natural polyphenolic antioxidant, was recently recommended by EFSA as a food supplement in a balanced diet for its important health benefits [1], and is the ideal candidate to answer to the compelling demands for new nutraceuticals and safe natural preservatives [2]. Its human health benefits collide with its high reactivity and low solubility in a lipophilic environment To overcome these drawbacks, lipophilic HTyr derivatives were synthesized and extensively studied in recent years [13,14]. Lipophilic HTyr derivatives were synthesized and extensively studied in recent years [13,14] These compounds demonstrated an in vitro antioxidant activity comparable to the natural precursor, with higher fat solubility that could enhance their bioavailability and pharmacodynamic profile. The dicarboxylic acid structure could modulate the lipophilicity of the final compound, and the distance between the hydroxytyrosyl moiety and the rigidity of the structure These last features might be helpful to understand if a correlation between the acidic structure and antioxidant activity could be drawn. The synthesis of new dihydroxytyrosyl dicarboxylic acid esters and the determination of their antioxidant activity both in vitro and in cell cultures are reported, the cell viability is analyzed and the structural variability of the acidic moiety is utilized to rationalize some structure–activity correlations
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