The death of dopaminergic neurons is a major pathological hallmark of Parkinson's disease (PD). Elevated iron within the substantia nigra of the PD brain is thought to catalyze this neuronal death through hydroxyl radical-derived oxidative damage. Removing this excess iron presents a potential therapeutic strategy for PD. Seventeen derivatives of the non-toxic iron chelator desferrioxamine B (DFOB) were prepared by the conjugation of adamantyl- (1-4,8-12), deconstructed adamantyl units (5-7), norborna(e)ne- (13-16) or bicyclo[2.2.2]octane-based (17) ancillary fragments to the terminal amine group. The range of experimental logP values of 1-17 (logP = 0.15-2.82) was greater than water soluble DFOB (logP -2.29), with the increased hydrophobicity designed to improve cell membrane carriage to facilitate intracellular iron sequestration. The first activity screen showed compounds with methyl-substituted adamantyl (1-3), noradamantyl (5), or 1-pentylbicyclo[2.2.21octane (17) ancillary groups significantly rescued iron-mediated oxidative stress in confluent PD-relevant SK-N-BE2-M17 neuroblastoma cells (M17 cells) exposed to 1,1'-dimethy1-4,4'-bipyridinium (paraquat, PQ) or H2O2. The second dose-dependence screen ranked 1-3 and 17 as the top candidates (EC50 similar to 10 mu M) in the rescue of PQ-treated M17 cells. The ancillary fragments of 1-3 and 17 clustered in a region defined by a close-to-zero dipole moment, logP values of 2-2.8 and a surface area:volume ratio of 0.60-0.61. Results of iron leaching studies indicate that the compounds may be operating via mechanisms beyond solely removing intracellular iron. The DFOB conjugates with methyl-substituted adamantyl ancillary groups (1-3) were the top and most consistent performers in this class of compound designed for PD. (C) 2017 Elsevier Ltd. All rights reserved.
|Authors||Telfer, Thomas J.; Liddell, Jeffrey R.; Duncan, Clare; White, Anthony R.; Codd, Rachel|
|Journal||BIOORGANIC & MEDICINAL CHEMISTRY LETTERS|