Solution Chemistry of Copper(II) Binding to Substituted 8-Hydroxyquinolines

Kelly L Summers; M Jake Pushie; George J Sopasis; Ashley K James; Natalia V Dolgova; Dimosthenis Sokaras; Thomas Kroll; Hugh H Harris; Ingrid J Pickering; Graham N George

doi:10.1021/acs.inorgchem.0c01356

Solution Chemistry of Copper(II) Binding to Substituted 8-Hydroxyquinolines

Inorg Chem. 2020 Oct 5;59(19):13858-13874. doi: 10.1021/acs.inorgchem.0c01356. Epub 2020 Sep 16.

Authors

Kelly L Summers^{1

2}, M Jake Pushie¹, George J Sopasis³, Ashley K James^{1

4

5}, Natalia V Dolgova¹, Dimosthenis Sokaras⁶, Thomas Kroll⁶, Hugh H Harris³, Ingrid J Pickering^{1

2

5}, Graham N George^{1

2

4}

Affiliations

¹ Molecular and Environmental Sciences Group, Department of Geological Sciences, University of Saskatchewan, 114 Science Place, Saskatoon, Saskatchewan S7N 5E2, Canada.
² Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.
³ Department of Chemistry, University of Adelaide, South Australia 5005, Australia.
⁴ Department of Anatomy and Cell Biology, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada.
⁵ Toxicology Centre, University of Saskatchewan, 44 Campus Dr, Saskatoon, Saskatchewan S7N 5B3, Canada.
⁶ Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, California 94025, United States.

PMID: 32936627
DOI: 10.1021/acs.inorgchem.0c01356

Abstract

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.