Analogues of desferrioxamine B designed to attenuate iron-mediated neurodegeneration: synthesis, characterisation and activity in the MPTP-mouse model of Parkinson's disease

作者：Got**acher Michael P; Telfer Thomas J; Witting Paul K; Double Kay L; Finkelstein David I; Codd Rachel^*

来源：Metallomics, 2017, 9(7): 852-864.

DOI：10.1039/c7mt00039a

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain and formation of alpha-synuclein-containing intracellular inclusions. Excess intraneuronal iron in the SNpc increases reactive oxygen species (ROS), which identifies removing iron as a possible therapeutic strategy. Desferrioxamine B (DFOB, 1) is an iron chelator produced by bacteria. Its high Fe(III) affinity, water solubility and low chronic toxicity is useful in removing iron accumulated in plasma from patients with transfusion-dependent blood disorders. Here, lipophilic analogues of DFOB with increased potential to cross the blood-brain barrier (BBB) have been prepared by conjugating ancillary compounds onto the amine terminus. The ancillary compounds included the antioxidants rac-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (rac-trolox, rac-TLX (a truncated vitamin E variant)), R-TLX, S-TLX, methylated derivatives of 3-(6-hydroxy-2-methylchroman-2-yl) propionic acid (alpha-CEHC, gamma-CEHC, delta-CEHC), or 4-(5-hydroxy-3-methyl-1H-pyrazol-1-yl) benzoic acid (carboxylic acid derivative of edaravone, EDA). Compounds 2-8 could have dual function in attenuating ROS by chelating Fe(III) and via the antioxidant ancillary group. A conjugate between DFOB and an ancillary unit without antioxidant properties (3,5-dimethyladamantane-1-carboxylic acid (AdA(dMe))) was included (9). Compounds 2-9 were more lipophilic (logP -0.05 to 3.39) than DFOB (logP -2.62) and showed an average plasma protein binding 6 times greater than DFOB. The ABTS(center dot broken vertical bar) radical assay indicated 2-8 had antioxidant activity ascribable to the ancillary fragment. Administration of 2 and 9 in the mouse model of PD using the neurotoxin prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which recapitulates elevated iron of human PD, resulted in significant neuronal protection (p < 0.05; up to 89% of that in non-lesioned control animals), demonstrating the neuroprotective potential of these compounds for PD.

• 出版日期2017-7-1