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.

5-Aminomethyl-8-hydroquinoline and its copper(ii) complex look very promising in inhibiting cell growth and proteasome activity.

8-Hydroxyquinoline derivatives are metal-binding compounds that have recently attracted interest as therapeutic agents for cancer therapy. In this scenario, we designed and synthesized three new glucoconjugates, 5,7-dichloro-8-quinolinyl-β-D-glucopyranoside, 5-chloro-8-quinolinyl-β-D-glucopyranoside and 2-methyl-8-quinolinyl-β-D-glucopyranoside and investigated their biological properties in comparison to the parent 8-hydroxyquinoline derivatives in the presence of Cu²⁺. In vitro data show that 2 out of 3 glycosylated compounds possess a pharmacologically-relevant antiproliferative activity against tumor cells, similar to that of their parent compounds; this activity is associated with a relevant triggering of apoptosis. The pharmacological profile of the glucoconjugates depends on the cellular enzymatic β-glucosidase activity, as demonstrated by the inhibition of antiproliferative activity in the presence of the 2,5-dideoxy-2,5-imino-D-mannitol.

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.