Prenylation preserves antioxidant properties and effect on cell viability of the natural dietary phenol curcumin

•Prenylated curcumin, like curcumin, protected cholesterol/LDL/liposomes from oxidation.•Prenylated curcumin did not exert toxic effect on intestinal epithelial cells up to 100 μM.•C-prenylation reduced permeation through intestinal Caco-2 cells.•Our data qualify PRCM as probe to explore the pharmacophore of curcuminoids.

Curcumin (CRM) is a naturally occurring phenolic compound with a variety of biological and pharmacological activities. We have investigated the effect of aromatic C-prenylation on the antioxidant activity of this natural compound. The protective effect of CRM and its diprenyl derivative (PCRM) was investigated against neat cholesterol degradation (at 140 °C) and Cu2 +-induced oxidation (at 37 °C) of liposomes and human low density lipoproteins. The activity of two simplified vanilloid analogs (vanillin and vanillyl alcohol) was also compared in the same systems. Cytotoxicity and cell permeation of both curcuminoids were also assessed using differentiated Caco-2 cell monolayers. PCRM, like CRM, significantly inhibited the oxidative degradation of polyunsaturated fatty acids and cholesterol, and the formation of their oxidation products in the oxidative stress systems, acting as scavenger of peroxyl radicals, without toxic effect (in the range 10-100 μM) on differentiated Caco-2 cell viability. Nevertheless, the structural modification of the lead compound severely affected membrane permeation through the Caco-2 monolayers, with apparent permeability coefficient (Papp) values in the apical-to-basolateral direction (2-h incubation) of 2.93 ± 0.94 × 10− 6 cm/s and < 10− 7 cm/s for CRM and PCRM, respectively. Taken together, our observations reveal a surprising bioactivity of PCRM, and qualify this compound as an interesting probe to explore the antioxidant pharmacophore of curcuminoids.