Adamantyl- and other polycyclic cage-based conjugates of desferrioxamine B (DFOB) for treating iron-mediated toxicity in cell models of Parkinson’s disease

Abstract 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 log  P values of 1 – 17 (log  P  = 0.15–2.82) was greater than water soluble DFOB (log  P −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[2.2.2]octane ( 17 ) ancillary groups significantly rescued iron-mediated oxidative stress in confluent PD-relevant SK- N -BE2-M17 neuroblastoma cells (M17 cells) exposed to 1,1ʹ-dimethyl-4,4ʹ-bipyridinium (paraquat, PQ) or H 2 O 2 . The second dose-dependence screen ranked 1 – 3 and 17 as the top candidates (EC 50 ∼10 µM) 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, log  P 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.