Synthesis Of Resveratrol And Curcumin Metabolites And Their Antiproliferative Activity Against Cancer Cells

Resveratrol and curcumin, which are both polyphenols, have attracted much attention as excellent agents for cancer prevention over the past two decades. After intake of resveratrol, it is rapidly metabolized, mainly into hydroresveratrol, resveratrol glucuronide and resveratrol sulphate which are eliminated in urine. Concerning curcumin, its main metabolites are hydrocurcumin, curcumin glucuronide and curcumin sulphate. Rapid metabolism of resveratrol and curcumin severely curtails their bioavailability. However, it is still unclear whether the parent molecules (resveratrol and curcumin) exert their biological effects directly or through their metabolites. Therefore, we synthesized main metabolites of resveratrol and curcumin, and evaluated their antiproliferative activity against cancer cells.In charpter 2, (E)-resveratrol-3-O-β-D-glucuronide and (E)-resveratrol-4’-O-β-D-glucuronide were prepared by direct coupling of resveratrol whose two phenolic hydroxyl groups were protected by silyl with trichloroacetimidate donor. Condensation of vanillin glucuronide and vanillin with acetylacetone-B2O3 complex gave curcumin-mono-O-β-D-glucuronide. To the best of our knowledge, it was first synthesized through this method. Dihydroresveratrol was prepared by hydrogenation over 10% Pd/C. It is difficult to reduce selectively one double bond of curcumin because of its symmetrical structure, we first synthesized dihydrocurcumin with non-reduce method. Tetrahydrocurcumin and hexahydrocurcumin were prepared by hydrogenation over 10% Pd/C. Octahydrocurcumin was prepared by reducing carbonyl group with NaBH4. Moreover, metabolites of resveratrol (dihydroresveratrol, (E)-resveratrol-3-O-β-D-glucuronide and (E)-resveratrol-4’-O-β-D-glucuronide) exerted a lower growth inhibition in HepG2, A549, MCF-7 and HeLa cell lines than resveratrol itself.In charpter 3, we synthesized a series of methoxy- and hydroxy-diphenylethane by hydrogenation of the corresponding stilbene and characterized the compounds concering their antiproliferative effect on human hepatoma HepG2 cells.3,4,5,4’-Tetramethoxydiphenylethane displayed the highest activity among the compounds tested with IC50 value of 1.79μmol/L. This activity was mediated by inducing an accumulation of cells predominantly in G2/M phase in a dose and time depended manner.