Efficient Enzymatic Synthesis of Lipophilic Phenolic Glycoside Azelaic Acid Esters and Their Depigmenting Activity

In this paper, an enzymatic route for synthesizing phenolic glycoside azelaic acid esters was successfully set up via lipase-catalyzed esterification and transesterification. Among the lipases tested, Candida antarctica lipase B (Novozyme 435) showed the highest activity in catalyzing esterification and Thermomyces lanuginosus (Lipozyme TLIM) gave the highest substrate conversion in catalyzing transesterification for the synthesis of ester. The addition of 4A molecular sieves into the reaction system is found to be an effective method for in situ absorption of the byproduct water and methanol, with which the substrate conversions of the enzymatic esterification and transesterification were 98.7 and 95.1%, respectively. Also, the main product ratios in transesterification were above 99.0% with lipozyme TLIM as a catalyst because the hydrolysis reaction was hindered. The results of the physical and biological properties indicate that all esters had higher Clog p values than their parent compounds. Also, the esters showed higher intracellular tyrosinase inhibitory and depigmentating activities than phenolic glycosides, azelaic acid (AA), and their physical mixtures due to their higher membrane penetration and tyrosinase inhibitory effects. In particular, piceid 6-O-azelaic acid ester (PIA) showed the strongest inhibitory effect against melanin production. Its inhibitory rate was 77.4% at a concentration of 0.25 mM, about 4.2 times higher than that of arbutin (18.5%).

Automated summary

In this study, an enzymatic route for synthesizing phenolic glycoside azelaic acid esters was successfully established through lipase-catalyzed esterification and transesterification. Candida antarctica lipase B (Novozyme 435) and Thermomyces lanuginosus (Lipozyme TLIM) were found to be efficient catalysts, with the addition of 4A molecular sieves improving substrate conversions. The synthesized esters showed higher bioactivities and inhibitory effects on melanin production compared to phenolic glycosides, azelaic acid, and their physical mixtures, with piceid 6-O-azelaic acid ester (PIA) exhibiting the strongest inhibitory effect against melanin production.