Highly Charged, Cytotoxic, Cyclometalated Iridium(III) Complexes as Cancer Stem Cell Mitochondriotropics

Abstract

The cancer stem cell (CSC) toxicity and mechanism of action of a series of iridium(III) complexes bearing polypridyl and charged 1-methyl-2-(2-pyridyl)pyridinium ligands, 1-4 is reported. The most effective complex (containing 1,10-phenanthroline), 3, kills CSCs and bulk cancer cells with equal potency (in the micromolar range), indicating that it could potentially remove heterogenous tumour populations with a single dose. Encouragingly, 3 also inhibits mammopshere formation to a similar extent as salinomycin, a well-established anti-CSC agent. This complex induces CSC apoptosis by mitochondrial membrane depolarization, inhibition of mitochondrial metabolism, and intracellular reactive oxygen species (ROS) generation. To the best of our knowledge, this is the first study to investigate the anti-CSC properties of iridium complexes.

Targeting G‐Rich DNA Structures with Photoreactive Bis‐Cyclometallated Iridium(III) Complexes

“…Complexes based on (2,2'-C^N) ancillary ligands have the advantageofb eing highly soluble in aqueous solvent as ar esult of their positive charges. [24] The photophysical properties of compounds 1-4 were investigated and the resultsi ndicatedm ixed charge-transfer (CT) and ligand-centred (LC) transitions. Interestingly,a se videnced by luminescence spectroscopy,complexes 3 and 4 are highly oxidising under light irradiation.T he affinity and selectivity of complexes 3 and 4 towards G-quadruplex DNA were studied by CD melting( T m ), bio-layer interferometry (BLI) and surfacep lasmon resonance (SPR) analyses.…”

“…The CPIP ligand was chosen because it has been reported as an efficient G‐quadruplex ligand (see above) and CPITAP is based on the CPIP ligand, the phenanthroline moiety being replaced by the more π‐deficient TAP group. Complexes based on (2,2′‐C^N) ancillary ligands have the advantage of being highly soluble in aqueous solvent as a result of their positive charges . The photophysical properties of compounds 1 – 4 were investigated and the results indicated mixed charge‐transfer (CT) and ligand‐centred (LC) transitions.…”

Sulfur‐Coordinated Organoiridium(III) Complexes Exert Breast Anticancer Activity via Inhibition of Wnt/β‐Catenin Signaling

“…[12] In addition, some cyclometalated iridium(III) complexes induce apoptosis in breast CSC-enriched HMLER-shEcad cells through targeting mitochondria. [13] These compounds inhibited mammosphere formation to asimilar extent as salinomycin. Salinomycin, an antibiotic potassium ionophore,h as been reported to act as as elective breast CSC inhibitor.I ti nhibits the Wnt signaling pathway and exerts anticancer activity in vitro and in vivo.…”

Sulfur‐Coordinated Organoiridium(III) Complexes Exert Breast Anticancer Activity via Inhibition of Wnt/β‐Catenin Signaling

“…Several cationic amphiphilic tris‐cyclometalated iridium(III) complexes were studied to interact with Ca 2+ ‐CaM complex and then induce cell death [12] . In addition, some cyclometalated iridium(III) complexes induce apoptosis in breast CSC‐enriched HMLER‐shEcad cells through targeting mitochondria [13] . These compounds inhibited mammosphere formation to a similar extent as salinomycin.…”