title: Mobilization of iron from cells by hydroxyquinoline-based chelators.
abstract: With the aim of identifying an iron (Fe) chelator which is effective at mobilizing intracellular Fe, two novel ligands were synthesized and tested. Hydroxyquinoline is known to possess a high affinity for Fe and was thus chosen as the Fe binding motif for the hexadentate chelators, C1 (2,2'-[ethane-1,2-diylbis(iminomethylene)]diquinolin-8-ol) and C2 (2,2'-[cyclohexane-1,2-diylbis(iminomethylene)]diquinolin-8-ol). Both chelators are lipophilic, with Fe3+ complexes slightly more hydrophilic than the free ligands. C1 and C2 were equally toxic to K562 cells, and partial protection was afforded by supplementing the culture medium with human holotransferrin, suggesting that some of the toxicity of the ligands is due to cellular Fe depletion. Micromolar concentrations of both ligands effectively mobilized 59Fe from reticulocytes and K562 cells. In reticulocytes, 50 microM C1 caused the release of 60% of the cells' initial 59Fe uptake after a 4h incubation. Under the same conditions, C2 revealed a release of 50% of the 59Fe. Overall, both ligands merit in vivo study for oral activity. Their effectiveness at low concentrations makes them candidates for therapeutic use.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, 3755 Chemin de la Cote-Ste-Catherine, Montreal, Quebec, Canada H3T 1E2.
authors.forename: C
authors.initials: C
authors.lastname: Mouralian
authors.forename: J L
authors.initials: JL
authors.lastname: Buss
authors.forename: B
authors.initials: B
authors.lastname: Stranix
authors.forename: J
authors.initials: J
authors.lastname: Chin
authors.forename: P
authors.initials: P
authors.lastname: Ponka
mesh_terms: D002614:Chelating Agents / Q000494:pharmacology* / Q000633:toxicity; D003514:Cyclohexylamines / Q000494:pharmacology* / Q000633:toxicity; D005029:Ethylenediamines / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology* / Q000633:toxicity; D007501:Iron / Q000378:metabolism*; D020014:K562 Cells; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D013053:Spectrophotometry / Q000379:methods
chemical_list: D002614:Chelating Agents; D003514:Cyclohexylamines; D005029:Ethylenediamines; D006912:Hydroxyquinolines; C507519:bis(8-hydroxyquinoline-2-carbaldehyde)-N,N'-cyclohexane-1,2-diamine; C507518:bis(8-hydroxyquinoline-2-carbaldehyde)-N,N'-ethylenediamine; D007501:Iron