A Cancer Stem Cell Potent Copper(II) Complex with a S, N, S‐Schiff base Ligand and Bathophenanthroline

Abstract

We investigate the anti‐cancer stem cell (CSC) properties of two copper(II) complexes containing 4,7‐diphenyl‐1,10‐phenanthroline and a S, N, X‐Schiff base ligand, where X=O (1) or S (2). Complex 1 was previously reported by us, and is the first metal complex to induce cytotoxic and immunogenic cell death of breast CSCs. Complex 2 is a structural analogue of 1, where the phenolate moiety (within the Schiff base ligand) is replaced by a thiophenolate group. Complex 2 kills bulk breast cancer cells and breast CSCs in the sub‐micromolar range, with reduced toxicity towards non‐cancerous epithelial breast cells. Remarkably, 2 is over 10‐fold more potent towards breast CSC spheroids than salinomycin (an established anti‐breast CSC agent) and cisplatin (a clinically approved anticancer drug). Complex 2 readily enters breast CSCs, accumulates in the cytosol, and increases intracellular reactive oxygen species (ROS) levels upon short exposure (1 h). The latter is likely to be the mechanism by which 2 induces breast CSC death.

A bioinspired redox-modulating copper(ii)–macrocyclic complex bearing non-steroidal anti-inflammatory drugs with anti-cancer stem cell activity

“…The ROS generation profile of 1 is atypical, as most CSC-potent copper( ii ) complexes reported thus far induce a short ROS burst within the first few hours of exposure. 25,52 The difference in the ROS generation profiles could be related to the varying stability thresholds of the copper( ii ) complexes in solution. The copper( ii ) complex 1 is able to access copper( i / ii ) oxidation states without leaching copper, and thus can potentially generate ROS over relatively long periods of time.…”

“…The ROS generation profile of 1 is atypical, as most CSC-potent copper (II) complexes reported thus far induce a short ROS burst within the first few hours of exposure. 25,52 The difference in the ROS generation profiles could be related to the varying stability thresholds of the copper(II) complexes in solution.…”

“…The copper(II) complex 1 is able to access copper(I/II) oxidation states without leaching copper, and thus can potentially generate ROS over relatively long periods of time. Previously reported CSC-potent copper(II) complexes on the other hand, tend to disassemble upon reduction leading to copper release or structural changes, 29,52 which can evoke uncontrolled redox perturbations over short periods of time. HMLER-shEcad cells treated with 3 (IC 50 value × 2) displayed a statistically significant increase in ROS levels after 6 h exposure (80% increase, p < 0.05) (Fig.…”

Copper(II) Phenanthroline-Based Complexes as Potential AntiCancer Drugs: A Walkthrough on the Mechanisms of Action

“…Both complexes show higher anticancer potencies compared to approved drugs cisplatin and salinomycin. Moreover, they can reduce the number and dimensions of 3D HMLER-shEcad mammospheres [ 61 ].…”

Water-soluble copper pyrithione complexes with cytotoxic and antibacterial activity

“…1C and D). 14,15 Pyrithione (PyS) is another well-known bidentate chelator, widely used as an active ingredient in personal care products such as shampoo and also as an antifouling agent upon formation of square planar complexes with zinc(II) or copper(II) ions (Fig. 1B).…”