Novel 4-/5-bromo-8-hydroxyquinoline cyclometalated iridium(III) complexes as highly potent anticancer and bioimaging agents

Abstract

In this study, two new cyclometalated iridium(III) complexes, [IrIII(phq)2(4Br)]⋅CH3OH (4BrIr) and [IrIII(phq)2(5Br)] (5BrIr), carrying [Ir(phq)2Cl]2 precursors (phq = 2-phenylisoquinoline, 4-bromo-8-hydroxyquinoline [4Br], or 5-bromo-8-hydroxyquinoline [5Br]) were synthesized and characterized using X-ray crystallography, 1H NMR spectroscopy, elemental analysis, and mass spectrometry. Both 4BrIr and 5BrIr were found to be more effective than cisplatin in inhibiting tumor cell growth in cisplatin resistant lung cancer A549 cells (A549/DDP, IC50 = 0.53 ± 0.11 and 0.09 ± 0.03 μM, respectively), with 4BrIr being 473.9 times more effective than cisplatin (66.34 ± 1.21 μM) against A549/DDP cells. Confocal microscopy using the red luminescence of 4BrIr and 5BrIr revealed the accumulation of these complexes primarily in the mitochondria, increase in the levels of reactive oxygen species (ROS) and Ca2+, decrease in mitochondrial membrane potential, and ultimately, cell death via mitochondrial dysfunction. In vivo studies revealed that 5BrIr can significantly inhibit A549/DDP-tumor growth (ca. 45.3%) in a mouse model. The variable 4- and 5-bromo-substituted groups in 4Br and 5Br ligands are associated with the diverse biological activities of 4BrIr and 5BrIr. Overall, we demonstrated that the novel 4-/5-bromo-8-hydroxyquinoline cyclometalated Ir(III) complexes 4BrIr and 5BrIr can overcome the resistance to cisplatin and be developed/used as iridium-based bioimaging and anticancer drugs.