Conventional cancer therapies suffer from severe off-target effects because most of them target critical facets of cells that are generally shared by all rapidly proliferating cells. The development of new therapeutic agents should aim to increase selectivity and therefore reduce side effects. In addition, these agents should overcome cancer cell resistance and target cancer stem cells. Some copper ionophores have shown promise in this direction thanks to an intrinsic selectivity in preferentially inducing cuproptosis of cancer cells compared to normal cells. Here, Cu ionophores are discussed with a focus on selectivity towards cancer cells and on the mechanisms responsible for this selectivity. The proposed strategies, to further improve the targeting of cancer cells by copper ionophores, are also reported.
Mounting evidence suggests an important role of cyclodextrins in providing protection in neurodegenerative disorders. Metal dyshomeostasis is reported to be a pathogenic factor in neurodegeneration because it could be responsible for damage involving oxidative stress and protein aggregation. As such, metal ions represent an effective target. To improve the metal-binding ability of cyclodextrin, we synthesized three new 8-hydroxyquinoline-cyclodextrin conjugates with difunctionalized cyclodextrins. In particular, the 3-difunctionalized regioisomer represents the first example of cyclodextrin with two pendants at the secondary rim, resulting in a promising compound. The derivatives have significant antioxidant capacity and the powerful activity in inhibiting self-induced amyloid-β aggregation seems to be led by synergistic effects of both cyclodextrin and hydroxyquinoline. Moreover, the derivatives are also able to complex metal ions and to inhibit metal-induced protein aggregation. Therefore, these compounds could have potential as therapeutic agents in diseases related to protein aggregation and metal dyshomeostasis.
Recent investigations have rekindled interest in 8-hydroxyquinolines as therapeutic agents for cancer, Alzheimer's disease, and other neurodegenerative disorders. Three new β-cyclodextrin conjugates of 8-hydroxyquinolines and their copper(II) and zinc(II) complexes have been synthesized and characterized spectroscopically. In addition to improving aqueous solubility, due to the presence of the cyclodextrin moiety, the hybrid systems have interesting characteristics including antioxidant activity, and their copper(II) complexes are efficient superoxide dismutase (SOD) mimics. The ligands and their copper(II) complexes show low cytotoxicity, attributed to the presence of the cyclodextrin moiety. These compounds have potential as therapeutic agents in diseases related both to metal dyshomeostasis and oxidative stress.
Oxidative stress and protein aggregation have been demonstrated to be the major factors involved in neurodegenerative diseases. Metal ions play a pivotal role, acting as mediators of neurotoxicity either by favoring or redox cycling. Thus, they represent a promising and suitable therapeutic target for the treatment of neurodegenerative disorders. In particular, the development of bifunctional or multifunctional molecules, which have antiaggregant and metal-chelating/antioxidant properties, may be considered as a valuable strategy for the treatment of neurodegeneration considering its multifactorial nature. Herein, we report the design and the characterization of four new multifunctional sugar-appended 8-hydroxyquinolines focusing on the effects of the conjugation with trehalose, a nonreducing disaccharide involved in the protection of proteins and cells against environmental stresses. These glycoconjugates do not exhibit any antiproliferative activity against three human cell lines of different histological origin, unlike 8-hydroxyquinolines. The multiple properties of the new derivatives are highlighted, reporting their Cu(2+) and Zn(2+) binding ability, and antioxidant and antiaggregant capacities. In particular, these latter were determined by different assays, including the evaluation of their ability to modulate or even suppress the aggregation of Aβ1-40 and Aβ1-42 peptides induced by copper or zinc ions.
8-Hydroxyquinolines are systems of great interest in the field of inorganic and bioinorganic chemistry. They are metal-binding compounds and are known to exhibit a variety of biological activities, such as antibacterial and anticancer activities. Among these systems, clioquinol has been the focus of a renewed interest in recent years. In this scenario, we synthesized and characterized the new clioquinol glucoconjugate, 5-chloro-7-iodo-8-quinolinyl-β-D-glucopyranoside in order to compare this system to that of clioquinol. We also synthesized, 8-quinolinyl-β-D-glucopyranoside, an 8-hydroxyquinoline glucoconjugate. The reason for the development of glucoconjugates is the glucose avidity, and the over-expression of glucose transporters in cancer cells. Here we demonstrate that glycoconjugates are cleaved in vitro by β-glucosidase and these systems exhibit antiproliferative activity against different tumor cell lines in the presence of copper(II) ions.
Magnetic Fe 3 O 4 nanoparticles (MNPs) have been covalently modified with β-cyclodextrin (β-CD) cavities by adopting a two-step anchoring route based on particle prefunctionalization with a phosphonic monolayer, which acts as a covalent linker between the MNPs and β-CD. Particular attention has been devoted to the study of the functionalization process by adopting bifunctional phosphonic linkers to investigate the efficiency of the anchoring group (phosphonic acid or ester)[a]
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