Synthesis and antioxidant evaluation of desmethylxanthohumol analogs and their dimers

Four ring-closed analogs of natural prenylated chalcone desmethylxanthohumol (1) and their dimers were synthesized from the commercially available 1-(2,4,6-trihydroxyphenyl)ethan-1-one in five and six linear steps, respectively. The structures of the eight new derivatives were confirmed using¹H NMR, ¹³C NMR and HRMS. The antioxidant activity of the new chalcone derivatives were evaluated in a PC12 cell model of H₂O₂-induced oxidative damage. The SAR studies suggested that the catechol motif was essential for the antioxidant activity. Moreover, the dimers showed better antioxidant activity than their corresponding monomers did. Among them, compound 14d was the most potent and increased PC12 cell viability from 25% to 85%. Flow cytometric analysis showed that compound 14d, the most potent compound, decreased the apoptotic PC12 cell percentage and significantly reduced the LDH release and 8-OHdG generation but increased the GSH levels in H₂O₂-treated PC12 cells. Furthermore, compound 14d had a higher FRAP value than that of gallic acid. It also reduced the stable ABTS⁺ free radical with a lower EC₅₀ than that of gallic acid.