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In this article, four new Ru(II) complexes [Ru(dmbpy) 2 (TFBIP)](PF 6) 2 (dmbpy = 4,4′-dimethyl-2,2′-bipyridine, TFPIP = 2-(4′-trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1 H -imidazo[4,5-f][1,10]phenanthroline) (Ru1), [Ru(bpy) 2 (TFBIP)](PF 6) 2 (bpy = 2,2′-bipyridine) (Ru2), [Ru(phen) 2 (TFBIP)](PF 6) 2 (phen = 1,10-phenanthroline) (Ru3) and [Ru(dmp) 2 (TFBIP)](PF 6) 2 (dmp = 2,9-dimethyl-1,10-phenanthroline) (Ru4) were synthesized and characterized by elemental analysis, HRMS, IR, 1H NMR, 13C NMR and 19F NMR. The in vitro anticancer effect of the complexes on HepG2, A549, B16, HeLa, BEL-7402 and non-cancer LO2 cells was screened using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results illustrate that the complexes display moderate anticancer activity. Apoptotic assay with Annexin V/PI double staining method indicated that complexes induce apoptosis in HepG2 cells. Also, the complexes interfere with the mitochondrial functions, accompanied by the production of intracellular ROS as well as a reduction of mitochondrial membrane potential. The results obtained from the western blot demonstrated that the complexes upregulate pro-apoptotic Bax and downregulate anti-apoptotic Bcl-2, which further activates caspase 3 and promotes the cleavage of PARP. RNA-sequence showed that the complexes upregulate the expression of 40 genes and downregulate 66 genes. Antitumour in vivo demonstrated that Ru1 inhibits the tumor growth with a high inhibitory rate of 51.19%. Taken together, these results revealed that complexes Ru1 , Ru2 , Ru3 and Ru4 induce cell death in HepG2 cells via autophagy and a ROS-mediated mitochondrial apoptotic pathway. Four new Ru(II) complexes were synthesized and characterized. The anticancer activity of the complexes against HepG2 cells were investigated, the complexes display high antitumour efficacy in vivo. [Display omitted] • Four new Ru(II) complex 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 detected. • The RNA-sequence was determined. • The expression of B-cell lymphoma-2 family proteins was examined. [ABSTRACT FROM AUTHOR]

In this study, two new iridium(III) polypyridyl complexes [Ir(bzq) 2 (DIPH)](PF 6) (bzq = deprotonated benzo[ h ]quinoline, DIPH = 4-(2,5-dibromo-4-(1 H -imidazo[4,5-f][1,10]phenanthrolim-2-yl)-4-hydroxybutan-2-one) (Ir1) and [Ir(piq) 2 (DIPH)](PF 6) (piq = deprotonated 1-phenylisoquinoline) (Ir2) were synthesized and characterized by elemental analysis, HRMS, 1H and 13C NMR. The cytotoxic activity of Ir1 , Ir2 , Ir1lipo and Ir2lipo against cancer cells SGC-7901, HepG2, A549, HeLa, B16 and normal NIH3T3 cells in vitro was evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. Ir1 and Ir2 showed no cytotoxic activity, but their liposome-entrapped Ir1 (Ir1lipo) and Ir2 (Ir2lipo) showed significant cellular activity, especially sensitive to SGC-7901 with IC 50 values of 4.7 ± 0.2 and 12.4 ± 0.5 μM, respectively. The cellular uptake, endoplasmic reticulum (ER) localization, autophagy, tubulin polymerization, glutathione (GSH), malondialdehyde (MDA) and release of cytochrome c were investigated to explore the mechanisms of apoptosis. The calreticulin (CRT), heat shock protein 70 (HSP70), high mobility group box 1 (HMGB1) were also explored. Western blotting showed that Ir1lipo and Ir2lipo inhibited PI3K (phosphoinositide-3 kinase), AKT (protein kinase B), p-AKT and activated Bcl-2 (B-cell lymphoma-2) protein and apoptosis-regulated factor caspase 3 (cysteinyl aspartate specific proteinase-3) and cleaving PARP (poly ADP-ribose polymerase). The results demonstrated that Ir1lipo and Ir2lipo induce cell apoptosis through targeting the endoplasmic reticulum (ER), cause oxidative stress damage, inhibiting PI3K/AKT signaling pathway, immunogenic cell death (ICD) and inhibit the cell growth at G2/M phase. Two new iridium(III) complexes were synthesized and characterized. The anticancer activity of the liposome-entrapped complexes against SGC-7901 cells were investigated, the liposome-entrapped complexes exhibit high anticancer activity toward SGC-7901 cells. [Display omitted] • Two iridium(III) complexes and liposomes was synthesized and characterized. • The cytotoxicity of the complexes and their liposomes was investigated. • Apoptosis, reactive oxygen species and cell cycle arrest were carried out. • The immunogenic cell death and molecular docking were performed. • The expression of B-cell lymphoma-2 family proteins was examined. [ABSTRACT FROM AUTHOR]

Herein, we synthesized and characterized two novel iridium (III) complexes: [Ir(bzq) 2 (PPD)](PF 6) (4a, with bzq = deprotonated benzo[ h ]quinoline and PPD = pteridino[6,7-f][1,10]phenanthroline-11,13-diamine) and [Ir(piq) 2 (PPD)](PF 6) (4b, with piq = deprotonated 1-phenylisoquinoline). The anticancer efficacy of these complexes, 4a and 4b, was investigated using 3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide (MTT). Complex 4a exhibited no cytotoxic activity, while 4b demonstrated moderate efficacy against SGC-7901, A549, and HepG2 cancer cells. To enhance their anticancer potential, we explored two strategies: (I) light irradiation and (II) encapsulation of the complexes in liposomes, resulting in the formation of 4alip and 4blip. Both strategies significantly increased the ability of 4a, 4b to kill cancer cells. The cellular studies indicated that both the free complexes 4a, 4b and their liposomal forms 4alip and 4blip effectively inhibited cell proliferation. The cell cycle arrest analysis uncovered 4alip and 4blip arresting cell growth in the S period. Additionally, we investigated apoptosis and ferroptosis pathways, observing an increase in malondialdehyde (MDA) levels, a reduction of glutathione (GSH), a down-regulation of GPX4 (glutathione peroxidase) expression, and lipid peroxidation. The effects on mitochondrial membrane potential and intracellular Ca2+ concentrations were also examined, revealing that both light-activated and liposomal forms of 4alip and 4blip caused a decline in mitochondrial membrane potential and an enhancement in intracellular Ca2+ levels. In conclusion, these complexes and them encapsulated liposomes induce cell death through apoptosis and ferroptosis. Two iridium(III) complexes were synthesized and characterized. The anticancer activity of the complexes and them encapsulated liposomes toward SGC-7901 cells were studied upon irradiation. [Display omitted] • Two new iridium(III) complexes were synthesized and characterized. • The cytotoxicity in vitro of the complexes and them encapsulated liposomes was studied. • Apoptosis and cell cycle arrest were detected. • The ferroptosis was investigated. • The expression of B-cell lymphoma-2 family proteins was explored. [ABSTRACT FROM AUTHOR]

In recent years, the studies of the ruthenium(II) complexes on anticancer activity have been paid great attention, many Ru(II) complexes possess high anticancer efficiency. In this paper, three ligands CPIP (2-(4-chlorophenyl)-1 H -imidazo[4,5-f][1,10]phenanthroline), DCPIP (2-(3,4-dichlorophenyl)-1 H -imidazo[4,5-f][1,10]phenanthroline), TCPIP (2-(2,3,5-trichlorophenyl)-1 H -imidazo[4,5-f][1,10]phenanthroline) and their three ruthenium (II) complexes [Ru(dip) 2 (CPIP)](PF 6) 2 (1 , dip = 4,7-diphenyl-1,10-phenanthroline), [Ru(dip) 2 (DCPIP)](PF 6) 2 (2) and [Ru(dip) 2 (TCPIP)](PF 6) 2 (3) were synthesized and characterized. 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assay was used to investigate in vitro cytotoxicity of complexes against various cancer cells. The results showed that complexes 1 – 3 exhibited pronounced cytotoxic effect on B16 cells with low IC 50 values of 7.2 ± 0.1, 11.7 ± 0.6 and 1.2 ± 0.2 μM, respectively. The 3D model demonstrated that the complexes can validly prevent the cell proliferation. Apoptosis determined using Annexin V-FITC/PI double staining revealed that complexes 1 – 3 can effectively induce apoptosis in B16 cells. The intracellular localization of 1 – 3 in the mitochondria, the levels of intracellular reactive oxygen species (ROS), the opening of mitochondrial permeability transition pore as well as the decline of mitochondrial membrane potential were investigated, which demonstrated that the complexes 1 – 3 led to apoptosis via a ROS-mediated mitochondrial dysfunction pathway. The RNA-sequence indicated that the complexes upregulate the expression of 74 genes and downregulate the expression of 81 genes. The molecular docking showed that the complexes interact with the proteins through hydrogen bond, π-cation and π-π interaction. The results show that ruthenium(II) complexes 1 , 2 and 3 can block tumor cell growth and induce cell death through autophagy and ROS-mediated mitochondrial dysfunction pathways. Three new Ru(II) complexes were synthesized and characterized. The anticancer activity in vitro of the complexes against B16 cells were investigated. [Display omitted] • Three new iridium(III) complexes were synthesized and characterized. • The complexes can induce apoptosis and inhibit the cell proliferation at the S phase. • RNA-sequence demonstrate that complexes induce cell death via autophagy. • Molecular docking shows that complexes interact on protein by hydrogen bond, π-cation. • The complexes can regulate the expression of B-cell lymphoma-2 proteins. [ABSTRACT FROM AUTHOR]

Iridium(III) complexes are largely studied as anti-cancer complexes due to their excellent anti-cancer activity. In this article, two new iridium(III) complexes [Ir(piq) 2 (THPIP)]PF 6 (THPIP = 2,4-di-tert-butyl-6-(1 H -imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol, piq = deprotonated 1-phenylisoquinoline) (Ir1) and [Ir(bzq) 2 (THPIP)]PF 6 (bzq = deprotonated benzo[ h ]quinolone) (Ir2) were synthesized. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that complex Ir1 exhibits moderate activity (IC 50 = 29.9 ± 4.6 μM) and Ir2 shows high cytotoxicity (IC 50 = 9.8 ± 1.8 μM) against BEL-7402 cells. Further studies on the mechanism showed that Ir1 and Ir2 induced apoptosis by changing the mitochondrial membrane potential, Ca2+ release, ROS accumulation, and cell cycle arrest at the S phase. The complexes can effectively inhibit cell colony formation and migration. The expression of B-cell lymphoma-2 (Bcl-2) family proteins, PI3K (phosphatidylinositol 3-kinase), AKT (protein kinase B), mTOR (mammalian target of rapamycin), and p-mTOR was studied by immunoblotting. Complexes Ir1 and Ir2 downregulated the expression of anti-apoptotic protein Bcl-2 and increased the expression of autophagy-related proteins of Beclin-1 and LC3-II. Further experiments showed that the complexes inhibited the production of glutathione (GSH) and increased the amounts of malondialdehyde (MDA). Fluorescence of HMGB1 was significantly increased. We also investigated the effect of the complexes on the expression of genes using RNA-sequence analysis, we further calculated the lowest binding energies between the complexes and proteins using molecular docking. Taken together, the above results indicated that complexes Ir1 and Ir2 induce apoptosis in BEL-7402 cells through a ROS-mediated mitochondrial dysfunction and inhibition of the PI3K/AKT/mTOR signaling pathway. Two new iridium(III) complexes were synthesized and characterized. The anticancer activity of the complexes against BEL-7402 cells were studied, the complexes display high anticancer activity toward BEL-7402 cells. [Display omitted] • Two new iridium(III) complex was synthesized and characterized. • The cytotoxicity in vitro of the complexes was studied. • Apoptosis, reactive oxygen species and cell cycle arrest were carried out. • The RNA-sequence was assayed. • The expression of B-cell lymphoma-2 family proteins was examined. [ABSTRACT FROM AUTHOR]