Membrane Localized Iridium(III) Complex Induces Endoplasmic Reticulum Stress and Mitochondria-Mediated Apoptosis in Human Cancer Cells

Abstract

The cellular behavior and toxicity effect of organometallic complexes depend largely on their peripheral ligands. In this study, we have synthesized a series of novel luminescent cationic iridium(III) complexes by tuning the ancillary N(∧)N ligand based on a structure [Ir(ppy)2(N(∧)N)](+) (ppy = 1-phenyl-pyridine; N(∧)N = 2,2'-bipyridine (bpy, 1) or phenanthroline (phen, 2) or 4,7-diphenyl-1,10- phenanthroline (DIP, 3)). As the size of coordinated N(∧)N ligand increases, absorbance/emission efficiency, quantum yields, lipophilicity, and cell uptake rates of the complexes also increase, in a general order: 3 > 2 > 1. All three complexes display anticancer activity, with 3 exhibiting the highest cellular uptake efficiency and the greatest cytotoxic activities in several cancer cell lines with IC50s lower than that of cisplatin. Because of its strong hydrophobic nature, the death inducer 3 was found to accumulate favorably to endoplasmic reticulum (ER) and to cause ER stress in cells. The fast cytosolic release of calcium from stressed ER disturbed the morphology and function of mitochondria, initiating an intrinsic apoptotic pathway. Understanding of the cell death mechanism would help further structure-activity optimization on these novel Ir(III) complexes as emerging cancer therapeutics.

Cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms

“…Interestingly, the hydrophilic complex 1 was found accumulated in the cell nucleus after 24-h incubation. In contrast, the more hydrophobic Fe(II) complexes (2e5) tended to localize and accumulate in the cytoplasm, which was similar to the phenomenon observed in Rh(III) complexes [38]. However, due to the slight different of logP, complex 1 and 2 cellular distributions were completely different.…”

Enhanced Photodynamic Cancer Treatment by Mitochondria‐Targeting and Brominated Near‐Infrared Fluorophores

“…Briefly, chloro‐subsitituted cyanine dyes containing symmetric sulfonate, carboxylic acid, and quaternary ammonium cations substituents were prepared through salt concentration using Vilsmeier–Haack reagent. In order to conjugate TPP with meso‐chlorine atoms in the cyanine dye, the triphenylphosphonium moiety, substituted with an amine group, was then conjugated using the S RN 1 displacement pathway 19. Synthesis of MitDt compounds was confirmed using 1 H NMR and high‐resolution mass spectrometry (HR‐MS) methods.…”

Tuning the Cellular Uptake Properties of Luminescent Heterobimetallic Iridium(III)–Ruthenium(II) DNA Imaging Probes

“…[58] Similar effects are seen in other studies, including those on prototypical Ru II (dppz) DNA-binding systems [59,60] and cyclometallated Ir III complexes. [61] Both 3 and 4 possess far superior cellular uptake properties than their dinuclear Ru II -Ru II analogue, the effectively isostructural ruthenium analogue 1, [37] indicating that the lower charge of the heterometallic species has facilitated increased cellular uptake rates. Compounds 3 and 4 also achieve uptake at much lower concentrations than the successfully employed imaging agent 2.…”