Bahadır BÜLBÜL, Kaan BİRGÜL, Miray İLHAN, Didem ORAL, Göknil Pelin COŞKUN, Duygu POLAT, Dudu ALTINTAŞ GÜNDÜZ, Demet ERDÖNMEZ
Journal of Research in Pharmacy - 2026;30(3):795-811
The "French Paradox" describes an epidemiological association between resveratrol (RSV) consumption and reduced incidence of certain chronic diseases. However, consuming large amounts of wine for one epidemiological reason, would be inappropriate due to the alcohol toxicity. Since RSV has poor pharmacokinetics, this study aimed to synthesize novel RSV ester derivatives, elucidate their structures, and evaluate their in vitro toxicity and transmembrane prodrug potential. For that purpose, considering the carbonate anion which is not a foreigner to the body, RSV carbonate esters were designed and synthesized. Then, the toxicity, IC50 values, and phase-I metabolic stability of the synthesized compounds were tested. Finally, the transmembrane properties of RSV carbonate esters were tested through a Franz Cell study. The results demonstrated that esterification of RSV hydroxyl groups markedly reduced intrinsic biological activity, consistent with the expected behavior of prodrug forms. Among the synthesized derivatives, compound 2 exhibited favorable release properties; however, its excessive metabolic stability limited efficient conversion to RSV, reducing its suitability for further development, whereas the other derivative was identified as a promising candidate for subsequent studies.
