Anticancer activity, DNA binding and cell mechanistic studies of estrogen-functionalised Cu(II) complexes

Abstract

Four estrogen-functionalised copper complexes were synthesised and investigated as electrochemical active DNA binding and cleavage agents. These complexes strategically contain a biocompatible metal centre [Cu(II)], a planar aromatic ligand as DNA intercalative agent and an estradiol-derivative moiety which acts as delivery vector to target estrogen-receptor-positive (ER+) cancer cells. Cytotoxic activity was studied over a panel of estrogen-receptor-positive (ER+) and negative (ER−) human cancer cell lines by means of both 2D and 3D cell viability studies. The complexes showed high in vitro intercalative interaction with nuclear DNA and demonstrated to be strong DNA cleaving agents. This series of Cu compounds are potent anticancer agents with low and sub-micromolar IC 50 values and the cellular uptake follows the lipophilicity order meaning that the internalisation mainly happened via passive diffusion. Finally, the estrogen-complexes are involved in the cellular redox stress by stimulating the production of ROS (reactive oxygen species).

Synthesis, structural studies, interaction with DNA/HSA and antitumor evaluation of new Cu(ii) complexes containing 2-(1H-imidazol-2-yl)pyridine and amino acids

“…According to the above experimental results, it could be inferred that CuI1 , CuI2 and CuI3 interacted with CT-DNA via an insertion mode, which mainly included hydrophobic interaction induced by the IPY ligand and hydrogen-bonding interactions induced by l -Phe/ l -Val. 23 CuI1 had a stronger interaction with CT-DNA due to its good planarity, which was consistent with the above-mentioned results.…”

Role of Copper on Mitochondrial Function and Metabolism

“…Estrogen-functionalized Cu(II) complexes are potent anticancer agents with low IC50 values. Their cellular uptake occurred via passive diffusion, and their mechanisms involved high DNA intercalation, intense DNA cleaving activity, and stimulation ROS production ( Barrett et al, 2020 ). [Cu( l -proline methyl ester DTC)2] copper compounds into micelles with a cancer-targeting biomolecule are presented as a proper “Trojan Horse” strategy for the delivery of Cu-DTC chemotherapeutics ( Brustolin et al, 2020 ).…”

Copper(II) Complexes with Mixed Heterocycle Ligands as Promising Antibacterial and Antitumor Species

“…Several such complexes that exhibit potential antitumor and/or DNA cleavage abilities have been reported. For example, complexes with ancillary ligands (an N-N-chelating heterocycle and a bioactive scaffold containing species [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]), antibiotics [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ], or anti-inflammatory drugs [ 15 , 16 , 17 , 18 ] have been shown to have potent anticancer effect, in some cases even better than the anti-tumor activity of cisplatin [ 2 , 3 , 4 ].…”