15731-41-6Relevant articles and documents
Clioquinol, a drug for Alzheimer's disease specifically interfering with brain metal metabolism: Structural characterization of its zinc(II) and copper(II) complexes
Di Vaira, Massimo,Bazzicalupi, Carla,Orioli, Pierluigi,Messori, Luigi,Bruni, Bruno,Zatta, Paolo
, p. 3795 - 3797 (2004)
Clioquinol, a 8-hydroxyquinoline derivative, is producing very encouraging results in the treatment of Alzheimer's disease (AD). Its biological effects are most likely ascribed to complexation of specific metal ions, such as copper(II) and zinc(II), critically associated with protein aggregation and degeneration processes in the brain. We report here, for the first time, a structural characterization of the zinc(II) and copper(II) complexes of clioquinol. A ligand to metal stoichiometry of 2:1 is found in both cases, though in the presence of quite different coordination polyhedra. The present findings are discussed in the frame of modern approaches to AD treatment.
Solution Chemistry of Copper(II) Binding to Substituted 8-Hydroxyquinolines
Dolgova, Natalia V.,George, Graham N.,Harris, Hugh H.,James, Ashley K.,Kroll, Thomas,Pickering, Ingrid J.,Pushie, M. Jake,Sokaras, Dimosthenis,Sopasis, George J.,Summers, Kelly L.
, p. 13858 - 13874 (2020/10/09)
8-Hydroxyquinolines (8HQs) are a family of lipophilic metal ion chelators that have been used in a range of analytical and pharmaceutical applications over the last 100 years. More recently, CQ (clioquinol; 5-chloro-7-iodo-8-hydroxyquinoline) and PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) have undergone clinical trials for the treatment of Alzheimer's disease and Huntington's disease. Because CQ and PBT2 appear to redistribute metals into cells, these compounds have been redefined as copper and zinc ionophores. Despite the attention surrounding the clinical trials and the clear link between 8HQs and metals, the fundamental solution chemistry of how these compounds bind divalent metals such as copper and zinc, as well as their mechanism(s) of action in mammalian systems, remains poorly understood. In this study, we used a combination of X-ray absorption spectroscopy (XAS), high-energy resolution fluorescence detected (HERFD) XAS, electron paramagnetic resonance (EPR), and UV-visible absorption spectroscopies to investigate the aqueous solution chemistry of a range of 8HQ derivatives. To circumvent the known solubility issues with 8HQ compounds and their complexes with Cu(II), and to avoid the use of abiological organic solvents, we have devised a surfactant buffer system to investigate these Cu(II) complexes in aqueous solution. Our study comprises the first comprehensive investigation of the Cu(II) complexes formed with many 8HQs of interest in aqueous solution, and it provides the first structural information on some of these complexes. We find that halogen substitutions in 8HQ derivatives appear to have little effect on the Cu(II) coordination environment; 5,7-dihalogenated 8HQ conformers all have a pseudo square planar Cu(II) bound by two quinolin-8-olate anions, in agreement with previous studies. Conversely, substituents in the 2-position of the 8HQ moiety appear to cause significant distortions from the typical square-planar-like coordination of most Cu(II)-bis-8HQ complexes, such that the 8HQ moieties in the Cu(II)-bis-8HQ complex are rotated approximately 30-40° apart in a propeller-like arrangement.
Copper-dependent cytotoxicity of 8-hydroxyquinoline derivatives correlates with their hydrophobicity and does not require caspase activation
Tardito, Saverio,Barilli, Amelia,Bassanetti, Irene,Tegoni, Matteo,Bussolati, Ovidio,Franchi-Gazzola, Renata,Mucchino, Claudio,Marchiò, Luciano
, p. 10448 - 10459 (2013/02/23)
This study reports the structure-activity relationship of a series of 8-hydroxoquinoline derivatives (8-HQs) and focuses on the cytotoxic activity of 5-Cl-7-I-8-HQ (clioquinol, CQ) copper complex (Cu(CQ)). 8-HQs alone cause a dose-dependent loss of viability of the human tumor HeLa and PC3 cells, but the coadministration of copper increases the ligands effects, with extensive cell death occurring in both cell lines. Cytotoxic doses of Cu(CQ) promote intracellular copper accumulation and massive endoplasmic reticulum vacuolization that precede a nonapoptotic (paraptotic) cell death. The cytotoxic effect of Cu(CQ) is reproduced in normal human endothelial cells (HUVEC) at concentrations double those effective in tumor cells, pointing to a potential therapeutic window for Cu(CQ). Finally, the results show that the paraptotic cell death induced by Cu(CQ) does not require nor involve caspases, giving an indication for the current clinical assessment of clioquinol as an antineoplastic agent.
