Research paper ‘In vitro’ antioxidant and photoprotective properties and interaction with model membranes of three new quercetin esters Antonella Saija a, * , Antonio Tomaino a , Domenico Trombetta a , Maria Luisa Pellegrino a , Beatrice Tita b , Chiara Messina c , Francesco P. Bonina d , Concetta Rocco e , Giovanni Nicolosi e , Francesco Castelli c a Department Farmaco-Biologico, University of Messina, Messina, Italy b Department of Pharmacology of Natural Substances and General Physiology, University of Rome ‘La Sapienza’, Rome, Italy c Department of Chemical Sciences, University of Catania, Catania, Italy d Department of Pharmaceutical Sciences, University of Catania, Catania, Italy e Institute CNR for the Study of Natural Substances, Valverde, Italy Received 12 June 2002; accepted in revised form 20 May 2003 Abstract Quercetin is well known to possess the strongest protective effect against UV light-induced lipoperoxidation. However, the absolute water insolubility of quercetin is a key step that may limit its bioavailability and, thus, its ‘in vivo’ employment as a photoprotective agent. The aim of the present paper was to evaluate ‘in vitro’ the antioxidant and photoprotective properties and the interaction with model membranes of three new semisynthetic quercetin derivatives, quercetin-3-O-acetate (Q-ac), quercetin-3-O-propionate (Q-pr) and quercetin-3-O-palmitate (Q-pal), obtained by esterification of the C-3 OH function with an aliphatic side-chain of different length. The antioxidant activity of quercetin and of its three esters was assessed in two ‘in vitro’ experimental models: (a) the bleaching of the stable 1,1-diphenyl-2- picrylhydrazyl radical; (b) UV radiation-induced peroxidation in multilamellar vesicles (MLVs). Differential scanning calorimetry on dimyristoylphosphatidylcholine MLVs and unilamellar vesicles was employed to investigate the interaction of the drugs tested with model membranes. Finally, the stability following UV light exposure and the lipophilicity and water solubility of quercetin and its three esters were examined. The findings obtained demonstrated that the esterification with an opportune aliphatic side chain of the OH function located at the C-3 position allows the production of new quercetin derivatives, which may be good candidates as photoprotective agents. In particular, one could speculate that the esterification with a short side-chain (such as in Q-ac and Q-prop) provides the suitable chemico – physical features not only to maintain the antioxidant and photoprotective effectiveness of the parent drug, but also to be able to migrate through the aqueous environment and to interact with and cross phospholipid membranes. q 2003 Elsevier B.V. All rights reserved. Keywords: Quercetin esters; Antioxidant activity; Photoprotection; Liposomes; Differential scanning calorimetry 1. Introduction In the last few decades the knowledge of the effects of ultraviolet (UV) radiation on human health, especially in some skin pathological conditions, but also in immunosup- pression and eye damage, has grown strongly [1–5]. The range of UV spectrum consists of ultraviolet A (UVA; 320 – 400 nm), ultraviolet B (UVB; 280–320 nm) and ultraviolet C (UVC; 200–280 nm). However, the human population is exposed mainly to the dangerous effects of UVA and UVB radiation, since UVC arrives only partially to the earth and is absorbed by the superficial skin layers. Reactive oxygen species (ROS) such as superoxide anion (O 2 z ), hydroxyl radical (z OH) and hydrogen peroxide (H 2 O 2 ) are responsible, partially at least, for UV-induced deleterious effects. In fact, UVA is absorbed by all cellular constituents and induces mainly oxidative damage indirectly, whereas UVB induces mainly dipyri- midine photoproducts in DNA by a direct photochemical mechanism [1]. 0939-6411/03/$ - see front matter q 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0939-6411(03)00101-2 European Journal of Pharmaceutics and Biopharmaceutics 56 (2003) 167–174 www.elsevier.com/locate/ejpb * Corresponding author. Department Farmaco-Biologico School of Pharmacy, University of Messina Contrada Annunziata, 98168 Messina, Italy. Tel.: þ39-90-6766530; fax: þ39-90-3533142. E-mail address: saija@pharma.unime.it (A. Saija).