In recent years the higher lipophilicity thus better

In recent years, the ‘higher lipophilicity’-thus-‘better performance’ tenet, derived from the polar paradox theory applied to micro-structured media, was challenged by novel and unexpected experimental results. In particular, the synthesis of many complete series of fatty orexin receptor esters of natural antioxidants, and the experiments performed on them either in model systems, mainly oil-in-water emulsion [7], [8], [9], but also liposomes [10], and in cells in culture [11], [12] have revealed an unexpected influence of alkyl chain length on antioxidant efficiency [13], [14]. As a matter of fact, the radical scavenging properties of these antioxidant series have a parabolic behaviour characterized by an initial enhancement of antioxidant efficiency with alkyl chain length until a critical chain length is reached. Antioxidants with hydrophobic chains longer than the critical length show a drop of their activity completely in contrast with paradox effect. This yet unexplained pattern has been called the ‘cut-off’ effect and it is common to many long-chain surface-active substances and to polyphenolic antioxidants as well [14], [15]. In phenolipids, depending on the antioxidant moiety, the optimal chain lengths for their lipophilic derivatives varies of a certain degree, for instance from C12 in the case of chlorogenate fatty acid esters [7] to C8 in the case of rosmarinate lipophilic derivatives [10] or hydroxytyrosyl esters [8], [12]. Various alleged mechanisms of action have been hypothesized to explain the cut-off phenomenon such as a micellar self-aggregation that subtract more lipophilic antioxidant from the interface where protection is more needed, or the tendency of long chain phenolipids to internalise inside the oil-water interface or the bilayer of cell membrane. However, the overall picture remains uncertain. Actually, the problem is to find the physico-chemical reasons to this phenomenon. The amphiphilic nature of lipophilic antioxidant derivatives strongly affects their physical behaviour in solution and in micro-structured media. Partition equilibria among polar and non-polar phases, adsorption/desorption rates, self-association in colloidal particles, molecular mobility, depth of penetration in biological membranes, and so on, are all properties ultimately controlled by the balance between the interactions driven by the hydrophilic head (and its chemical nature) and by the hydrophobic tail. In other words, the drop of antioxidant activity measured for long chain derivatives likely results from an alteration of the physical behaviour of the molecule in the system to which it is added, rather than from a reduction of the intrinsic antioxidant power of the functional moiety [15]. The lipophilic tail, therefore, contributes indirectly, yet in significant manner, to determine the antioxidant efficiency when the antioxidants are employed in living systems. Recently we have investigated the antioxidant properties of hydroxytyrosol (HT, Fig. 1) and of its lipophilic derivatives. HT is a natural catecholic antioxidant present in olive oil [16]. It has antimicrobial activity [17] and is active in the prevention of cardiovascular [18], neurological [19] and cancer diseases [20]. Hydroxytyrosyl esters [12] or ethers [21], and their homologous derivatives [11] have been extensively studied as a valid alternative to HT itself. They have high antioxidant activity in bulk (ABTS assay in ethanol), comparable with HT [12] but at the same time higher lipophilicity, so that they are promising antioxidants for practical applications where systems with high interfacial surface are concerned, e.g., food, pharmaceutical, and cosmetic antioxidants. Attempts to correlate the increase of antioxidant capacity in bulk until a value (C8) and its afterwards rapid drop failed: a possible explanation being the conformational freedom of the ester chain that could result in folded structures with partially shielded catechol hydroxyls [12]. On the other hand, their bioavailability result enhanced when compared with HT. When HT esters have been tested in cultured L6 rat skeletal muscle cells (DCF assay) their antioxidant activity depends non-linearly from the ester chain length, following a distinctive parabolic curve due to phenolipids cut-off effect, irrespective to both the alcohol side chain length and/or the phenol hydroxyls position [11], [12].