Thesis (M.Sc.)--Chulalongkorn University, 2006

This research was aimed to study the effects of structural modification of glabridin, a pyranoisoflavan isolated from licorice extract, on tyrosinase inhibitory and free radical scavenging activities. Five diacyl esters and seven dibenzoyl esters were successfully prepared on the phenolic hydroxyls at C-2' and C-4' of glabridin with the corresponding acid anhydrides and acid chlorides. The 3",4"-dihydroglabridin was also synthesized. All of the synthesized compounds were evaluated for tyrosinase inhibitory and free radical scavenging activities. Among the tested compounds, only the 3",4"-dihydroglabridin exhibited higher activity than the parent compound. The 3",4"-dihydroglabridin showed potent tyrosinase inhibitory activity with the IC₅₀ value of 11.40 µM, but it was a weak free radical scavenger. The study of structure-activity relationships of these synthesized derivatives indicate that the 4-substitued resorcinol skeleton is essential for tyrosinase inhibitory activity and the lacking of double bond between carbon atom 3" and 4" on the structure of the 3".4"-dihydroglabridin, give more conformational flexibily to interact with the enzyme more effectively. While the phenolic hydroxyl moiety plays a critical role in free radical scavenging activity. The lipophilicity of the diacyl esters were obtained as n-octanol/phosphate buffer pH 5.5 partition coefficient (log P). The esters 18-20 showed increased log P as comparison with the parent compound. In addition, the chemical and enzymatic hydrolysis of the glabridin diacetate ester has been investigated. The results indicated that the diacetate ester was rapidly hydrolyzed by porcine liver esterase with the half-life of 2.34 min, while it was sufficiently stable in phosphate buffer, both pH 5.5 and 7.4, at 37 ℃ with more than 15 days half-life.