Prenylation preserves antioxidant properties and effect on cell viability of the natural dietary phenol curcumin Antonella Rosa a, ⁎, Angela Atzeri a , Monica Deiana a , M. Paola Melis a , Alessandra Incani a , Alberto Minassi b , Barbara Cabboi a , Giovanni Appendino b a Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, SS 554, Km 4.5, 09042 Monserrato, Cagliari, Italy b Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy abstract article info Article history: Received 15 November 2013 Accepted 19 January 2014 Keywords: Diprenylcurcumin Cholesterol LDL Liposomes Caco-2 monolayers Curcumin (CRM) is a naturally occurring phenolic compound with a variety of biological and pharmacological ac- tivities. We have investigated the effect of aromatic C-prenylation on the antioxidant activity of this natural com- pound. The protective effect of CRM and its diprenyl derivative (PCRM) was investigated against neat cholesterol degradation (at 140 °C) and Cu 2+ -induced oxidation (at 37 °C) of liposomes and human low density lipopro- teins. 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 via- bility. Nevertheless, the structural modification of the lead compound severely affected membrane permeation through the Caco-2 monolayers, with apparent permeability coefficient (P app ) values in the apical-to- basolateral direction (2-h incubation) of 2.93 ± 0.94 × 10 -6 cm/s and b 10 -7 cm/s for CRM and PCRM, respec- tively. 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. © 2014 Elsevier Ltd. All rights reserved. 1. Introduction Oxidative stress and resulting lipid peroxidation are involved in various and numerous pathological conditions (Guéraud et al., 2010). It is well known the role of food antioxidants in preventing oxidative dam- age induced by free radicals and reactive oxygen species generated in vivo as byproducts of metabolism or inflammatory processes. Moreover, food antioxidants provided a network protective system eliminating from the gastrointestinal tract injurious free radicals and other potential initiators (Gorelik, Ligumsky, Kohen, & Kanner, 2008; Kanner, Gorelik, Roman, & Kohen, 2012). Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3,5-dione (diferuloyl methane)] (CRM) (Fig. 1) is a naturally occurring phenolic compound isolated as an orange pigment from tur- meric (dry rhizomes of the perennial herb Curcuma longa) which is com- monly used as a spice and food colorant and used for centuries in a variety of pharmaceutical applications (Goel, Kunnumakkara, & Aggarwal, 2008). The dietary phenol CRM has been reported to possess a variety of biological and pharmacological activities, including anti- inflammatory, antimicrobial, anticarcinogenic, antiangiogenic, and anti- oxidant properties (Anand, Kunnumakkara, Newman, & Aggarwal, 2007; Goel et al., 2008; Maheshwari, Singh, Gaddipati, & Srimal, 2006). Much effort has been devoted to investigating the radical-scavenging mechanisms of CRM (Ak & Gülçin, 2008; Barik et al., 2007; Chen, Deng, Zou, Yang, & Liu, 2006; Dairam, Fogel, Daya, & Limson, 2008; Maheshwari et al., 2006). This nutraceutical compound is a potent anti- oxidant inhibiting lipid peroxidation in different in vitro and animal models and a potent scavenger of a variety of reactive oxygen species (Barik et al., 2007; Maheshwari et al., 2006); in addition, CRM has an ef- fective DPPH and ABTS radical scavenging, hydrogen peroxide scaveng- ing, ferric ion reducing power, and ferrous ion chelating activity (Ak & Gülçin, 2008; Chen et al., 2006; Dairam et al., 2008; Wei, Chen, Zhou, Yang, & Liu, 2006). The putative therapeutic properties of CRM have also been associated with its antioxidant properties, therefore this phe- nol has been used as a lead compound to design more potent antioxidant agents (Anand et al., 2008; Chen et al., 2006; Wei et al., 2006). Several CRM derivatives, compounds that retain the basic structural features of CRM (two o-methoxy phenolic OH groups attached to the α,β-unsatu- rated β-diketone moiety), have been synthesized in order to find more active antioxidants (Anand et al., 2008). CRM is a hydrophobic molecule, practically insoluble in aqueous solutions and ether but soluble in methanol, ethanol, dimethylsulfoxide, and acetone (Goel et al., 2008). Studies to date in humans and various animal models have suggested Food Research International 57 (2014) 225–233 ⁎ Corresponding author at: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Km 4.5 SS554, 09042 Monserrato (CA), Italy. Tel.: +39 070 6754124; fax: +39 070 6754032. E-mail address: anrosa@unica.it (A. Rosa). 0963-9969/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.foodres.2014.01.045 Contents lists available at ScienceDirect Food Research International journal homepage: www.elsevier.com/locate/foodres