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)

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.

Fleck, H. R.,Ward, A. M.

, p. 388 - 395 (1933)

Immobilization of Cu-chelate onto SBA-15 for partial oxidation of benzyl alcohol using water as the solvent

Hu, Jing,Zou, Yongcun,Liu, Jing,Sun, Jian,Yang, Xiaoyuan,Kan, Qiubin,Guan, Jingqi

, p. 5703 - 5712 (2015)

Bis(8-quinolinolato)copper(II) complex immobilized onto SBA-15 catalyst has been synthesized through a stepwise procedure. The characterization results indicated that the BET surface area, total pore volume, and average pore width decrease after stepwise modification of SBA-15, while the structure stays intact. Catalytic tests showed that CuQ2-SBA-15 catalyzes the oxidation reaction well with 32.5 % conversion of benzyl alcohol and 81.8 % selectivity to benzaldehyde when water is used as the solvent. In addition, homogeneous catalyst bis(8-quinolinolato)copper(II) exhibits very bad catalytic behavior using water as the solvent.

Xin, Xin-Quan,Zheng, Li-Min

, p. 451 - 460 (1993)

Skraup, H.

, (1882)

Abou Sekkina, Morsi M.,El-Helbaway, S. M.

, p. 223 - 230 (1984)

Moeller, T.

, p. 346 - 349 (1943)

Copper (II) complexes of bidentate ligands exhibit potent anti-cancer activity regardless of platinum sensitivity status

Wehbe, Mohamed,Lo, Cody,Leung, Ada W. Y.,Dragowska, Wieslawa H.,Ryan, Gemma M.,Bally, Marcel B.

, p. 682 - 690 (2017/10/06)

Insensitivity to platinum, either through inherent or acquired resistance, is a major clinical problem in the treatment of many solid tumors. Here, we explored the therapeutic potential of diethyldithiocarbamate (DDC), pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ), clioquinol (CQ) copper complexes in a panel of cancer cell lines that differ in their sensitivity to platins (cisplatin/carboplatin) using a high-content imaging system. Our data suggest that the copper complexes were effective against both platinum sensitive (IC50?~?1?μM platinum) and insensitive (IC50?>?5?μM platinum) cell lines. Furthermore, copper complexes of DDC, Pyr and 8-HQ had greater therapeutic activity compared to the copper-free ligands in all cell lines; whereas the copper-dependent activities of Plum and CQ were cell-line specific. Four of the copper complexes (Cu(DDC)2, Cu(Pyr)2, Cu(Plum)2 and Cu(8-HQ)2) showed IC50 values less than that of cisplatin in all tested cell lines. The complex copper DDC (Cu(DDC)2) was selected for in vivo evaluation due to its low nano-molar range activity in vitro and the availability of an injectable liposomal formulation. Liposomal (Cu(DDC)2) was tested in a fast-growing platinum-resistant A2780-CP ovarian xenograft model and was found to achieve a statistically significant reduction (50%; p??0.05) in tumour size. This work supports the potential use of copper-based therapeutics to treat cancers that are insensitive to platinum drugs.