Synthesis and biological evaluation of mixed-ligand cyclometalated iridium()-quinoline complexes

With the aim of gaining new insight into the underlying apoptosis mechanisms and in vivo efficacy of cyclometalated Ir( iii ) complexes as metalodrugs, six new cyclometalated Ir( iii )-quinoline complexes, [Ir( 1a )(2pq) 2 ] ( 2a ), [Ir( 1b )(2pq) 2 ] ( 2b ), [Ir( 1c )(2pq) 2 ] ( 2c ), [Ir( 1d )(2pq) 2 ] ( 2d ), [Ir( 1e )(2pq) 2 ] ( 2e ), and [Ir( 1f )(2pq) 2 ] ( 2f ) (2pq = 2-phenylisoquinoline), have been synthesized using 5,7-dihalo-8-hydroxylquinoline ligands ( 1a-1f ) and [Ir(2pq) 2 Cl] 2 precursors and characterized. Complexes 2a-2f have shown potent anticancer activity against cisplatin-resistant SK-OV-3/DDP and A549/DDP cells (IC 50 = 0.11-1.83 μM), following the order 2e > 2f > 2b > 2c > 2d > 2a . Confocal microscopy images suggest that 2e and 2b could act as red-color probes for specific cell imaging and efficiently initiate apoptosis and autophagy in the mitochondria, cell cytosol, and nucleus. Overexpression of beclin1, caspase-9, cytochrome c, LC3II, and apaf-1; inhibition of p62, cyclin D1, cyclin A2, and CDK2; and a substantial rapid accumulation suggest a paraptotic mode of cell death induced by autophagy, DNA damage, and mitochondrial stress. In addition, the inhibitory rate of 2e on A549/DDP tumor growth was 64.1% at a concentration of 10.0 mg kg −1 , which is clearly higher than that of cisplatin. According to the biological assay, the cyclometalated Ir( iii )-quinoline complex 2e exhibited a higher anticancer effect than 2b , which may be associated with the electronic effect of the methyl group of the 1e ligand of 2e playing a key role in the mechanism. Cyclometalated Ir( iii )-quinoline complexes 2a-2f induce A549/DDP cell apoptosis. In addition, 2e showed remarkable tumour growth suppression ( ca. 64.1%).