Synthesis of novel hydroxytyrosol analogues as potential anti-amyloidogenic agents

The antiamyloidogenic properties of the natural derived antioxidant oleuropein (OE) for Alzheimer's disease have been already cited. Our group has previously reported the noncovalent complex between amyloid beta peptide (Aβ) or its oxidized form and oleuropein (OE) by electrospray ionization mass spectrometry (ESI MS) and nuclear magnetic resonance (NMR) spectroscopy. Additionally, hydroxytyrosol, the main phenolic compound of olive oil and one of the major metabolites of OE has been reported as neuroprotective agent against Aβ-induced toxicity. Prompted by these observations we decided to synthesize simple hydroxytyrosol esters, by substitution of the OE aglycon moiety with simple lipophilic groups, in order to further investigate the effect on Aβ complexation and identify new lead compound(s) with improved properties, which will be the scaffold for further optimization and development of novel anti-amyloidogenic agents. We synthesized a series of novel compounds bearing various aliphatic substitutes in the ester moiety (i.e. methyl, heptyl, cyclohexyl, etc). Additionally, we synthesized some aromatic esters of hydroxytyrosol in order to study the impact of the aromatic group on the Aβ complexation. The interaction of the new compounds with the amyloid peptide Aβ was evaluated in vitro with electrospray ionization mass spectrometry (ESI MS) and circular dichroism (CD). The preliminary result suggests that their activity is lower than Oleuropeins. Furthermore, from a direct comparison of the activity with hydroxytyrosol, it is evident that the interaction of the new derivatives with the amyloid peptide Aβ via non covalent complex, is higher. In general, it seems that the compounds bearing the aromatic ester group posses the best activity among the new derivatives, a finding that would require further studies in the future.