title: 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 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[2.2.2]octane (17) ancillary groups significantly rescued iron-mediated oxidative stress in confluent PD-relevant SK-N-BE2-M17 neuroblastoma cells (M17 cells) exposed to 1,1'-dimethyl-4,4'-bipyridinium (paraquat, PQ) or H2O2. The second dose-dependence screen ranked 1-3 and 17 as the top candidates (EC50∼10µM) 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.
authors.affiliation: School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, New South Wales 2006, Australia.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Telfer
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Liddell
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Duncan
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia; Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.affiliation: School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, New South Wales 2006, Australia. Electronic address: rachel.codd@sydney.edu.au.
authors.forename: Rachel
authors.initials: R
authors.lastname: Codd
mesh_terms: D001253:Astrocytes / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007502:Iron Chelating Agents; D011083:Polycyclic Compounds; D007501:Iron; D003676:Deferoxamine
keywords: Desferrioxamine B; Iron chelators; Parkinson’s disease; Polycyclic cage compounds