Multifunctional Heterometallic Ir^III−Au^I Probes as Promising Anticancer and Antiangiogenic Agents

Abstract

A new class of emissive cyclometallated IrIII−AuI complexes with a bis(diphenylphosphino) methanide bridging ligand was successfully synthesised from the diphosphino complex [Ir(N^C)2(dppm)]+ (1). The different gold ancillary ligand, a triphenylphosphine (2), a chloride (3) or a thiocytosine (4) did not reveal any significant effect on the photophysical properties, which are mainly due to metal‐to‐ligand charge‐transfer (3MLCT) transitions based on IrIII. However, the AuI fragment, along with the ancillary ligand, seemed crucial for the bioactivity in A549 lung carcinoma cells versus endothelial cells. Both cell types display variable sensitivities to the complexes (IC50=0.6–3.5 μM). The apoptotic pathway is activated in all cases, and paraptotic cell death seems to take place at initial stages in A549 cells. Species 2–4 showed at least dual lysosomal and mitochondrial biodistribution in A549 cells, with an initial lysosomal localisation and a possible trafficking process between both organelles with time. The bimetallic IrIII−AuI complexes disrupted the mitochondrial transmembrane potential in A549 cells and increased reactive oxygen species (ROS) generation and thioredoxin reductase (TrxR) inhibition in comparison with that displayed by the monometallic complex 1. Angiogenic activity assays performed in endothelial cells revealed the promising antimetastatic potential of 1, 2 and 4.

Dual Emissive Ir(III) Complexes for Photodynamic Therapy and Bioimaging

“…Microscopy analysis revealed cytoplasmic vacuolization and typical apoptotic and necrotic features which were confirmed by cytotoxicity assays, suggesting that complex 4 prompts paraptotic and apoptotic cell death. In fact, we have previously described several heterometallic Ir(III)-Au(I) compounds that appear to activate the paraptotic pathway first and the apoptotic pathway ultimately [ 14 ]. Confocal fluorescence microscopy studies propose that complex 3 entirely localized in mitochondria, and compounds 2 and 4 , although also partly localized in these organelles, present other subcellular distribution.…”

“…Alternatively, to this therapy function, Ir(III) complexes have also demonstrated to be suitable luminescent probes to target different organelles within the cells. Thus, many of them have been described to selectively localize preferentially in mitochondria [ 11 ], nuclei [ 12 ] or lysosomes [ 13 ] among other inner compartments, or even pass through one organelle to another [ 14 ] by simple modification of their ligand scaffolds.…”

Synthesis and antiproliferative study of phosphorescent multimetallic Re(I)/Au(I) complexes containing fused imidazo[4,5‐f]‐1,10‐phenanthroline core

“…The disappearance of the imidazolyl proton at 10.06 ppm in 1 H-NMR together with the shift observed for the aromatic protons upon coordination is indicative of the accomplishment of the reaction (see Figure 3). Moreover, 13 C-NMR spectroscopy showed a peak downfield shifted to 188.9 ppm correspondent to the carbenic carbon. As a gold chloride complex, [AuCl (tht)], was used for the formation of 1, there is the possibility that the chloride would remain directly bonded to the gold centre instead of a iodide.…”

“…All the complexes were successfully characterised by 1 H, 13 C{ 1 H} NMR spectroscopy, infrared spectroscopy and mass spectrometry. Characteristic shifts in 1 H, 13 C { 1 H} NMR are observed for all the complexes corroborating the gold coordination to the desired ancillary ligand.…”

“…All the complexes were successfully characterised by 1 H, 13 C{ 1 H} NMR spectroscopy, infrared spectroscopy and mass spectrometry. Characteristic shifts in 1 H, 13 C { 1 H} NMR are observed for all the complexes corroborating the gold coordination to the desired ancillary ligand. Specifically, the alkynyl carbons suffer a shift to low field from 50 to 120 ppm upon coordination to the gold fragment in the case of complex 2.…”