Synthesis and Evaluation of Astaxanthin Derivatives for Improved Water Solubility and Stability

ABSTRACT

Astaxanthin (ASTX) is a lipophilic carotenoid with potent antioxidant activity; however, its extremely low aqueous solubility limits pharmaceutical applications, particularly in injectable formulations. In this study, dicarboxylic acid‐ and diamino acid‐type ASTX ester derivatives were designed and synthesized to improve water solubility while retaining antioxidant activity. All synthesized derivatives exhibited markedly enhanced aqueous solubility compared with native ASTX. N‐terminal methyl substitution further increased solubility, whereas the introduction of cyclic moieties reduced solubility. In contrast, radical scavenging activity measured by the DPPH assay showed an opposite structural trend: cyclic substituents enhanced antioxidant activity, while N‐methyl substitution decreased it. These findings indicate that the structure of the introduced functional groups critically influences both solubility and antioxidant performance. Metabolic activation studies using human liver and intestinal microsomes revealed minimal enzymatic hydrolysis of selected derivatives, suggesting limited prodrug potential under the tested conditions. Stability studies demonstrated partial conversion to ASTX in aqueous media, indicating possible regeneration of the active parent compound. Collectively, these results provide a rational design strategy for modulating physicochemical and biological properties of ASTX through structural modification and highlight a promising molecular approach for the development of aqueous ASTX formulations.