title: The solution structure of the copper clioquinol complex.
abstract: Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) recently has shown promising results in the treatment of Alzheimer's disease and in cancer therapy, both of which also are thought to be due to clioquinol's ability as a lipophilic copper chelator. Previously, clioquinol was used as an anti-fungal and anti-protozoal drug that was responsible for an epidemic of subacute myelo-optic neuropathy (SMON) in Japan during the 1960s, probably a myeloneuropathy arising from a clioquinol-induced copper deficiency. Previous X-ray absorption spectroscopy of solutions of copper chelates of clioquinol suggested unusual coordination chemistry. Here we use a combination of electron paramagnetic, UV-visible and X-ray absorption spectroscopies to provide clarification of the chelation chemistry between clioquinol and copper. We find that the solution structures for the copper complexes formed with stoichiometric and excess clioquinol are conventional 8-hydroxyquinolate chelates. Thus, the promise of clioquinol in new treatments for Alzheimer's disease and in cancer therapy is not likely to be due to any novel chelation chemistry, but rather due to other factors including the high lipophilicity of the free ligand and chelate complexes.
authors: Molecular and Environmental Sciences Research Group, Department of Geological Sciences, University of Saskatchewan, SK S7N 5E2, Canada.
authors: M Jake
authors: MJ
authors: Pushie
authors: Molecular and Environmental Sciences Research Group, Department of Geological Sciences, University of Saskatchewan, SK S7N 5E2, Canada.
authors: Kurt H
authors: KH
authors: Nienaber
authors: Molecular and Environmental Sciences Research Group, Department of Geological Sciences, University of Saskatchewan, SK S7N 5E2, Canada; Department of Chemistry, University of Saskatchewan, SK S7N 5C9, Canada.
authors: Kelly L
authors: KL
authors: Summers
authors: Molecular and Environmental Sciences Research Group, Department of Geological Sciences, University of Saskatchewan, SK S7N 5E2, Canada; Canadian Light Source Inc., Saskatoon, SK S7N 2V3, Canada.
authors: Julien J H
authors: JJ
authors: Cotelesage
authors: Molecular and Environmental Sciences Research Group, Department of Geological Sciences, University of Saskatchewan, SK S7N 5E2, Canada.
authors: Olena
authors: O
authors: Ponomarenko
authors: Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Helen K
authors: HK
authors: Nichol
authors: Molecular and Environmental Sciences Research Group, Department of Geological Sciences, University of Saskatchewan, SK S7N 5E2, Canada; Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada.
authors: Ingrid J
authors: IJ
authors: Pickering
authors: Molecular and Environmental Sciences Research Group, Department of Geological Sciences, University of Saskatchewan, SK S7N 5E2, Canada; Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada. Electronic address: g.george@usask.ca.
authors: Graham N
authors: GN
authors: George
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D002614:Chelating Agents / Q000737:chemistry / Q000627:therapeutic use; D007464:Clioquinol / Q000737:chemistry / Q000627:therapeutic use; D003300:Copper / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D012996:Solutions / Q000737:chemistry; D056928:X-Ray Absorption Spectroscopy; D015032:Zinc / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D012996:Solutions; D003300:Copper; D007464:Clioquinol; D015032:Zinc
keywords: Clioquinol; Copper chelation; Density functional theory; X-ray absorption spectroscopy