title: Conjugates of desferrioxamine B (DFOB) with derivatives of adamantane or with orally available chelators as potential agents for treating iron overload.
abstract: Desferrioxamine B (DFOB) conjugates with adamantane-1-carboxylic acid, 3-hydroxyadamantane-1-carboxylic acid, 3,5-dimethyladamantane-1-carboxylic acid, adamantane-1-acetic acid, 4-methylphenoxyacetic acid, 3-hydroxy-2-methyl-4-oxo-1-pyridineacetic acid (N-acetic acid derivative of deferiprone), or 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox) were prepared and the integrity of Fe(III) binding of the compounds was established from electrospray ionization mass spectrometry and RP-HPLC measurements. The extent of intracellular (59)Fe mobilized by the DFOB-3,5-dimethyladamantane-1-carboxylic acid adduct was 3-fold greater than DFOB alone, and the IC(50) value of this adduct was 6- or 15-fold greater than DFOB in two different cell types. The relationship between logP and (59)Fe mobilization for the DFOB conjugates showed that maximal mobilization of intracellular (59)Fe occurred at a logP value approximately 2.3. This parameter, rather than the affinity for Fe(III), appears to influence the extent of intracellular (59)Fe mobilization. The low toxicity-high Fe mobilization efficacy of selected adamantane-based DFOB conjugates underscores the potential of these compounds to treat iron overload disease in patients with transfusional-dependent disorders such as beta-thalassemia.
authors.affiliation: School of Medical Sciences (Pharmacology) and Bosch Institute, University of Sydney, New South Wales 2006, Australia.
authors.forename: Joe
authors.initials: J
authors.lastname: Liu
authors.forename: Daniel
authors.initials: D
authors.lastname: Obando
authors.forename: Liam G
authors.initials: LG
authors.lastname: Schipanski
authors.forename: Ludwig K
authors.initials: LK
authors.lastname: Groebler
authors.forename: Paul K
authors.initials: PK
authors.lastname: Witting
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.forename: Rachel
authors.initials: R
authors.lastname: Codd
mesh_terms: D000218:Adamantane / Q000737:chemistry* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D003676:Deferoxamine / Q000737:chemistry* / Q000378:metabolism; D004285:Dogs; D005290:Ferric Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019190:Iron Overload / Q000188:drug therapy*; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000188:drug therapy; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014168:Transferrin / Q000378:metabolism
chemical_list: D002264:Carboxylic Acids; D002614:Chelating Agents; D005290:Ferric Compounds; D007502:Iron Chelating Agents; D014168:Transferrin; D007501:Iron; D003676:Deferoxamine; D000218:Adamantane