Synthesis, biological evaluation of novel iridium(III) complexes targeting mitochondria toward melanoma B16 cells.

A new ligand 2-(1 E ,3 E ,5 E ,7 E)-2,6-dimethyl-8-(2,6,6-trimethylcyclohex-1-yl)octa-1,2,5,7-tetraen-1-yl)-1 H -imidazo[4,5-f][1,10]phenanthroline (DTOIP) was synthesized and combined with [Ir(ppy) 2 Cl] 2 ·2H 2 O (ppy = deprotonated Hppy: 2-phenylpyridine), [Ir(piq) 2 Cl] 2 ·2H 2 O (piq = deprotonated Hpiq: 1-phenylisoquinoline) and [Ir(bzq) 2 Cl] 2 ·2H 2 O (bzq = deprotonated Hbzq: benzo[h]quinolone) to form [Ir(ppy) 2 (DTOIP)](PF 6) (Ir1), [Ir(piq) 2 (DTOIP)](PF 6) (Ir2), and [Ir(bzq) 2 (DTOIP)](PF 6) (Ir3), respectively. The complexes were characterized by elemental analysis, high-resolution mass spectrometry (HRMS), 1H NMR and 13C NMR. The antiproliferative activity of the complexes toward B16, BEL-7402, Eca-109 and normal LO2 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complexes Ir1 , Ir2 and Ir3 showed high antiproliferative activity against B16 cells with a low IC 50 values of 0.4 ± 0.1, 2.0 ± 0.1 and 1.4 ± 0.09 μM, respectively. Three-dimensional (3D) in vitro cell models also demonstrated that the iridium(III) complexes have a remarkable cytotoxicity to B16 cells. The experiments of cellular uptake, mitochondrial localization, and intracellular distribution of the drugs proved that the three iridium(III) complexes can enter the mitochondria, leading to the loss of mitochondrial membrane potential (MMP), decreased glutathione (GSH) levels, causing an increase of intracellular ROS content, and DNA damage, finally inducing apoptosis. RNA-sequence and bioinformatics analyses were used to analyze the differentially expressed genes and enriched biology processes. Antitumor in vivo demonstrated that complex Ir1 (5 mg/kg) exhibits a high efficacy to inhibit the tumor growth with an inhibitory rate of 71.67%. These results show that the complexes may be potent anticancer candidate drugs. Three new iridium(III) complexes [Ir(ppy) 2 (DTOIP)](PF 6) (Ir1) (DTOIP = 2-(1 E ,3 E ,5 E ,7 E)-2,6-dimethyl-8-(2,6,6-trimethylcyclohex-1-yl)octa-1,2,5,7-tetraen-1-yl)-1 H -imidazo[4,5-f][1,10]phenanthroline, ppy = deprotonated 2-phenylpyridine), [Ir(piq) 2 (DTOIP)](PF 6) (Ir2) (piq = deprotonated 1-phenylisoquinoline) and [Ir(bzq) 2 (DTOIP)](PF 6) (Ir3) (bzq = deprotonated benzo[h]quinolone) were synthesized. The cytotoxicity of the complexes against B16, BEL-7402, A549, Eca-109 cancer cells and normal LO2 was evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. The inhibitory rate in vivo reaches 71.67% for Ir1. [Display omitted] • Three new iridium(III) complexes were synthesized and characterized. • The cytotoxicity in vitro and in vivo of the complexes was investigated. • Apoptosis, reactive oxygen species and cell cycle arrest were carried out. • The distribution of the complexes in the cytoplasm, mitochondria and nuclei were explored. • The antitumor efficacy in vivo was investigated. [ABSTRACT FROM AUTHOR]