Highly Regioselective Preparation and Characterization of New 6-O-Substituted Dieckol Derivatives

Abstract Dieckol is a brown algae-derived polyphenol that has broad bioactivity and low toxicity. Therefore, it is a promising lead compound for the development of therapeutic agents to treat various pathological conditions, including viral infections, allergies, diabetes, skin ageing, cancers, and neurodegenerative conditions. To exploit the pharmacological potential of dieckol, its stability, solubility, pharmacokinetics, and drug delivery must be improved. This can be achieved by the controlled modification of the hydroxyl groups, but the presence of eleven nearly equivalent hydroxyl groups makes the task highly challenging. In this study, the regioselectivities in five substitution reactions of the hydroxyl groups of dieckol under various SN2 reaction conditions were investigated. After reaction optimization, five substituents (methyl, benzyl, methoxymethyl, 3-hydroxypropyl, and 3-(ethoxycarbonyl)propyl) could be introduced at the 6-Oposition of dieckol with surprisingly high regioselectivity, as confirmed by 2D-NMR spectroscopic analyses. The prepared dieckol derivatives showed antioxidant and anticancer activities analogous to those of unmodified dieckol, indicating that the mono-O-substitutions did not affect the biochemical and biological characteristics of dieckol. Therefore, the proposed methodology for the mono-O-substitution of a specific oxygen of dieckol is a powerful tool to add various pharmaceutical attributes to dieckol, thus contributing to the development of various dieckol-based drug candidates.