Synthesis of water-soluble ester-linked ursolic acid–gallic acid hybrids with various hydrolytic stabilities

Abstract

To obtain derivatives of ursolic acid with improved water solubility and antioxidant activity, new ester-linked hybrids of ursolic acid and gallic acid were synthesized. In the reaction of methyl gallate with ursoloyl chloride acetate, both mono- and diacylation products were obtained. To prepare mono-alkylated and mono-acylated derivatives of gallic acid, 4,5-O-methoxymethylene-protected methyl gallate was used. It was found that ursolic-gallic acid hybrids containing phenolic ester linkage readily underwent hydrolysis at C-28 of triterpenoid. The dioxolane protection allowed selective hydrolysis of the methyl ester at the aromatic moiety of the hybrid compound leaving intact the labile C-28 ester at the triterpenoid moiety. The hybrids possessing an ester–ether linker (terpenoid-COO–CH₂CH₂–O-aryl) are stable to the hydrolysis. The majority of the obtained ursolic–gallic acid hybrids containing free phenolic hydroxyl groups possess excellent antioxidant activity. Notable water solubilities (∼0.5 mg/mL) of novel hybrids containing both carboxyl group and hydroxyls at aromatic moiety were found.

Graphical abstract

Keywords:

• Ursolic acid
• gallic acid
• ester-type hybrids
• antioxidant
• water solubility

Acknowledgments

This work was performed within the framework of the international project ERA.Net RUS Plus project # RUS_ST2017-139 “AnticancerBet”. According to the rules of this international project, funding was provided by RFBR national fund (Foundation of Basic Research Grant 18-53-76001). In accordance with the rules of the international project, it is necessary to indicate the number of ERA.Net RUS Plus project # RUS_ST2017-139 “AnticancerBet” and the number of the grant for which the funding is being carried out. Additionally two state Russian Federal programs should be mentioned.

Additional information

Funding

This research was financially supported by the ERA.Net RUS Plus project # RUS_ST2017-139 “AnticancerBet” (Foundation of Basic Research Grant 18-53-76001) and by Federal programs AAAA-A21-121011490016-8 and AAAA-A21-121011490015-1.