HYDROXYQUINOLINE-PEPTIDE DERIVATIVES AS NEW POTENTIAL DRUGS FOR ALZHEIMER'S DISEASE

Very recently, chelating agents have been proposed [1] for the therapy of a vast group of severe pathological processes occurring in the brain, which usually lead to extensive neuronal death and consequent loss of function. Neurological (or neurodegenerative) disorders (or deseases) (NDs) share similar critical metabolic processes, such as protein aggregation and oxidative stress. The most important ND pathology is Alzheimer's disease (AD). Enough experimental evidence has been gathered so far which closely correlates AD with abnormal protein folding (misfolding), driving peptides towards their ß-sheet conformation. The observed protein misfolding is greatly affected by a variety of biophysical and chemical factors including metal ions, among which Fe, Cu, and Zn, seem to be the most relevant ones [1,2]. In turn, the newly formed supramolecolar structures may acquire the ability to bind biometals. Moreover, Fe and Cu can generate, by redox cycling, a local excess of reactive oxygen species (ROS) which favour the two pathological processes of protein aggregation and oxidative damage. Even if the roles played by biometals in AD are not yet completely clear, chelation therapy is considered a very challenging task for future pharmacological treatments [1]. However, differently from the classic chelation therapy, here the massive metal removal from the brain should be avoided to prevent severe toxic side effects. A selective binding of the more labile and toxic metal pool, specifically that associated with the protein misfolding, should be acquired. This approach is therefore better defined as metal targeting therapy rather than metal chelation therapy. Up to now, no metal targeting agent is available for AD and for the other NDs. In the present poster, a hydroxyquinoline-peptide derivative (N-Ac-Glu-[Cys(5-methylen-8-hydroxyquinoline)-Gly-OMe]-OMe) is proposed as potential metal targeting agent for the therapy of AD. The hydroxyquinoline is the metal complexing moiety, and the peptide chain aims for the cellular uptake and for the crossing of the blood-brain barrier. This work includes the synthesis of the molecule, and the thermodynamic complexation studies with Fe(III), Cu(II), Zn(II). The results are compared with those obtained by corresponding metal-hydroxyquinoline solutions, in order to evaluate the effect of the peptide chain in the metal chelation. The calculation of KD (=[M]free*SUM[HxL]/SUM[MwHyLz]) for each metal ion allows to predict the suitability of this compound as a metal targeting agent. References: [1] S. Bolognin et al., Med. Res. Rev. 29, 547-570 (2009) [2] R. Crichton et al., Coord. Chem. Rev. 252, 1189-119 (2008)