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A new ligand DFIP (2-(dibenzo[b,d]furan-3-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its two complexes iridium(III) [Ir(ppy)2(DFIP)](PF6) (ppy = 2-phenylpyridine, Ir1) and ruthenium(II) [Ru(bpy)2(DFIP)](PF6)2 (bpy = 2,2′-bipyridine, Ru1) were synthesized and characterized. The anticancer effects of the two complexes on A549, BEL-7402, HepG2, SGC-7901, HCT116 and normal LO2 cells were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complex Ir1 shows high cytotoxic activity on A549, BEL-7402, SGC-7901 and HepG2, Ru1 exhibits moderate anticancer activity toward A549, BEL-7402 and SGC-7901 cells. The IC50 values of Ir1 and Ru1 toward A549 are 7.2 ± 0.1 and 22.6 ± 1.4 μM, respectively. The localization of complexes Ir1 and Ru1 in the mitochondrial, intracellular accumulation of reactive oxygen species (ROS) levels, and the changes of mitochondrial membrane potential (MMP) and cytochrome c (cyto-c) were investigated. Apoptosis and cell cycle were detected by flow cytometry. Immunogenic cell death (ICD) was used to detect the effects of Ir1 and Ru1 on the A549 using a confocal laser scanning microscope. The expression of apoptosis-related proteins was detected by western blotting. Ir1 and Ru1 can increase the intracellular ROS levels and release cyto-c, reduce the MMP, leading to the apoptosis of A549 cells and blocking the A549 cells at the G0/G1 phase. Additionally, the complexes caused a decrease of the expression of polyADP-ribose polymerase (PARP), caspase 3, Bcl-2 (B-cell lymphoma-2), PI3K (phosphoinositide-3 kinase) and upregulated the expression of Bax. All these findings indicated that the complexes exert anticancer efficacy to induce cell death through immunogenic cell death, apoptosis, and autophagy. [ABSTRACT FROM AUTHOR]

In this article, ligand IPP (IPP = 4-(1 H -imidazo[4,5-f][1,10]phenanthrolin-2-yl)- N , N -diphenylaniline) and its three Ru(II) complexes: [Ru(bpy) 2 (IPP)](ClO 4) 2 (1) (bpy = 2,2′-bipyridine), [Ru(dmbpy) 2 (IPP)](ClO 4) 2 (2) (dmbpy = 4,4′-dimethyl-2,2′-bipyridine), and [Ru(phen) 2 (IPP)](ClO 4) 2 (3) (phen = 1,10-phenanthroline) were synthesized and characterized. The anticancer activity in vitro of the complexes was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The scratching and colony-forming experiments confirmed the complexes 1 , 2 , 3 interfered with the proliferation and migration ability of cells. The accumulation of the complexes in cells was researched and we found that these complexes directly accumulated in mitochondria, then the complexes cause a decline of the mitochondrial membrane potential and induce an increase of intracellular reactive oxygen species (ROS) levels. The growth of B16 cells were inhibited by 1 , 2 and 3 at G0/G1 phase. Apoptosis was induced through mitochondrial pathway and the expression of apoptosis-related factors was regulated. In addition, the complexes promoted the transition of poly(ADP-ribose)polymerase (PARP) into the cleaved form (Cleaved PARP), downregulated the anti-apoptotic proteins, and upregulated the pro-apoptotic proteins. Consequently, complexes 1 , 2 and 3 exerted their anticancer activity by regulating B-cell lymphoma-2 (Bcl-2) family proteins. Complex 2 showed excellent antitumor effects with a high inhibitory rate of 65.95% in vivo. Taken together, the complexes cause apoptosis in B16 cells through a ROS-mediated mitochondrial dysfunction pathway. Three new Ru(II) complexes [Ru(N-N) 2 (IPP)](ClO 4) 2 (N-N: bpy = 2,2'-bipyridine 1 , dmbpy = 4,4'-dimethyl-2,2'-bipyridine 2 , phen = 1,10-phenanthroline 3 , IPP = 4-(1 H -imidazo[4,5-f][1,10]phenanthrolin-2-yl)-N,N-diphenylaniline) were synthesized and characterized. The antitumor in vivo shows that the complex 2 can effectively inhibit the tumor growth with an inhibitory rate of 65.95%. [Display omitted] • Three new Ru(II) complexes were synthesized and characterized. • The cytotoxicity in vitro and in vivo of the complexes was investigated. • Apoptosis, reactive oxygen species, autophagy and cell cycle arrest were performed. • The location and mitochondrial membrane potential were assayed. • The expression of B-cell lymphoma-2 family proteins was explored. [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]

This paper unveils a novel perspective on synthesis and characterization of the ligand 5-bromo-2-amino-2'-(phenyl-1H-imidazo[4,5-f][1,10]phenanthroline) (BAPIP), and its iridium(III) complexes [Ir(PPY−) 2 (BAPIP)](PF 6) (1a, with PPY− as deprotonated 2-phenylpyridine), [Ir(PIQ−) 2 (BAPIP)](PF 6) (1b, piq− denoting deprotonated 1-phenylisoquinoline), and [Ir(BZQ−) 2 (BAPIP)](PF 6) (1c, bzq− signifying deprotonated benzo[h]quinoline). Systematic evaluation of the cytotoxicity of 1a, 1b, and 1c across diverse cell lines encompassing B16, HCT116, HepG2, A549, HeLa, and LO2 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Unexpectedly, compounds 1b and 1c demonstrated no cytotoxicity against the above cell lines. Motivated by the pursuit of heightened anti-proliferative potential, a strategic encapsulation approach yielded liposomes 1alip, 1blip, and 1clip. As expectation, 1alip, 1blip, and 1clip displayed remarkable anti-proliferative efficacy, particularly noteworthy in A549 cells, exhibiting IC 50 values of 4.9 ± 1.0, 5.9 ± 0.1, and 7.6 ± 0.2 μM, respectively. Moreover, our investigation illuminated the mitochondrial accumulation of these liposomal entities, 1alip, 1blip, and 1clip, evoking apoptosis through the mitochondrial dysfunction mediated by reactive oxygen species (ROS). The ferroptosis was confirmed by decrease in glutathione (GSH) concentrations, the downregulation of glutathione peroxidase 4 (GPX4), increase of high mobility group protein 1 (HMGB1), and lipid peroxidation. Simultaneously, pyroptosis as another mode of cell death was undertaken. RNA-sequencing was employed to investigate intricate signalling pathways. In vivo examination provided tangible evidence of 1alip in effectively curbing tumor growth. Collectively, this study provides a multifaceted mode of cellular demise orchestrated by 1a, 1alip, 1blip, and 1clip, involving pathways encompassing apoptosis, ferroptosis, and pyroptosis. Three new iridium(III) complexes were synthesized and characterized. The anticancer activity of the complexes toward A549 cells were explored, the liposomes entrapped complexes exhibit high antitumor efficacy in vivo. [Display omitted] • Three new iridium(III) complexes and their liposomes were synthesized and characterized. • The cytotoxicity in vitro and in vivo of the complexes and their liposomes was investigated. • Apoptosis, reactive oxygen species and cell cycle arrest were examined. • The RNA-sequence were carried out. • The antitumor efficacy in vivo was studied. [ABSTRACT FROM AUTHOR]

In this study, ligands 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (PIP), 2-(2-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (NPIP), 2-(2-nitronaphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (NNIP) and their iridium(III) metal compounds [Ir(ppy) 2 (PIP)](PF 6) (ppy = 2-phenylpyridine, 1a), [Ir(ppy) 2 (NPIP)](PF 6) (1b), [Ir(ppy) 2 (NNIP)](PF 6) (1c) were designed and synthesized. The anti-cancer activities of 1a, 1b and 1c on BEL-7402, HepG2, SK-Hep1 and non-cancer LO2 were detected using MTT method. 1a shows moderate, 1b and 1c display low or no anti-cancer activities. To elevate the anti-cancer effectiveness, encapsulating the compounds 1a, 1b and 1c into the ordinary or targeted liposomes to produce 1alip, 1blip, 1clip, or targeted 1aTlip, 1bTlip and 1cTlip. The IC 50 values of 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip against HepG2 cells are 7.9 ± 0.1, 8.6 ± 0.2, 16.9 ± 0.5, 5.9 ± 0.2, 7.3 ± 0.1 and 9.7 ± 0.7 μM, respectively. Specifically, the anti-tumor activity assays in vivo found that the inhibitory rates are 23.24 % for 1a, 61.27 % for 1alip, 76.06 % for 1aTlip. It is obvious that the targeted liposomes entrapped iridium(III) compound greatly enhance anti-cancer efficacy. Additionally, 1alip, 1blip and 1clip or targeted 1aTlip, 1bTlip and 1cTlip can effectively restrain the cell colony and proliferation in the G0/G1 period. 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip can increase reactive oxygen species (ROS) concentration, arouse a decline in the mitochondrial membrane potential and promote Ca2+ release. RNA-sequence was applied to examine the signaling pathways. Taken together, the liposomes or targeted liposomes encapsulated compounds trigger cell death by way of apoptosis, autophagy, ferroptosis, disruption of mitochondrial function and PI3K/AKT/mTOR signaling pathways. Three iridium(III) polypyridyl compounds 1a, 1b, 1c and compound-loaded ordinary 1alip, 1blip, 1clip and targeted liposomes 1aTlip, 1bTlip and 1cTlip were synthesized and characterized. The antiproliferative ability of 1a, 1b, 1c, 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip against BEL-7402, HepG2, SK-Hep1 and non-cancer LO2 cells was investigated. The inhibitory rate in vivo of 1a, 1alip and 1aTlip inhibiting HepG2 tumor growth attains 23.24, 61.27 and 76.06 %. [Display omitted] • Three new iridium(III) complexes, ordinary and targeted liposomes were synthesized and characterization. • The cytotoxicity in vitro and in vivo of the complexes and their liposomes was investigated. • Cell cycle arrest, apoptosis, ferroptosis, reactive oxygen species were examined. • The RNA-sequence was explored. • The antitumor efficacy in vivo was evaluated. [ABSTRACT FROM AUTHOR]

Two polypyridyl ruthenium(II) complexes [Ru(DIP) 2 (BIP)](PF 6) 2 (DIP = 4,7-diphenyl-1,10-phenanthrolie, BIP = 2-(1,1′-biphenyl-4-yl)-1 H -imidazo[4,5-f][1,10]phenanthroline, Ru1) and [Ru(DIP) 2 (CBIP)](PF 6) 2 (CBIP = 2-(4′-chloro-1,1′-biphenyl-4-yl)-1 H -imidazo[4,5-f][1,10]phenanthroline, Ru2) were synthesized. The cytotoxic activities in vitro of Ru1, Ru2 toward B16, A549, HepG2, SGC-7901, HeLa, BEL-7402, non-cancer LO2 were investigated using MTT method (3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide). Unexpectedly, Ru1, Ru2 can't prevent these cancer cells proliferation. To improve the anti-cancer effect, we used liposomes to entrap the complexes Ru1, Ru2 to form Ru1lipo, Ru2lipo. As expectation, Ru1lipo and Ru2lipo exhibit high anti-cancer efficacy, especially, Ru1lipo (IC 50 3.4 ± 0.1 μM), Ru2lipo (IC 50 3.5 ± 0.1 μM) display strong ability to block the cell proliferation in SGC-7901. The cell colony, wound healing, and cell cycle distribution show that the complexes can validly inhibit the cell growth at G2/M phase. Apoptotic studied with Annex V/PI doubling method showed that Ru1lipo and Ru2lipo can effectively induce apoptosis. Reactive oxygen species (ROS), malondialdehyde, glutathione and GPX4 demonstrate that Ru1lipo and Ru2lipo improve ROS and malondialdehyde levels, inhibit generation of glutathione, and finally result in a ferroptosis. Ru1lipo and Ru2lipo interact on the lysosomes and mitochondria and damage mitochondrial dysfunction. Additionally, Ru1lipo and Ru2lipo increase intracellular Ca2+ concentration and induce autophagy. The RNA-sequence and molecular docking were performed, the expression of Bcl-2 family was investigated by Western blot analysis. Antitumor in vivo experiments confirm that 1.23 mg/kg, 2.46 mg/kg of Ru1lipo possesses a high inhibitory rate of 53.53% and 72.90% to prevent tumor growth, hematoxylin-eosin (H&E) results show that Ru1lipo doesn't cause chronic organ damage and strongly promotes the necrosis of solid tumor. Taken together, we conclude that Ru1lipo and Ru2lipo cause cell death through the following pathways: autophagy, ferroptosis, ROS-regulated mitochondrial dysfunction, and blocking the PI3K/AKT/mTOR. Two new Ru(II) polypyridyl complexes [Ru(dip) 2 (BIP)](PF 6) 2 (dip = 4,7-diphenyl-1,10-phenanthrolie, BIP = 2-(1,1′-biphenyl-4-yl)-1 H -imidazo[4,5-f] [1,10]phenanthroline, Ru1) and [Ru(dip) 2 (CBIP)](PF 6) 2 (CBIP = 2-(4′-chloro-1,1′-biphenyl-4-yl)-1 H -imidazo[4,5-f] [1,10]phenanthroline, Ru2) and complexes-loaded liposomes Ru1lipo and Ru2lipo were synthesized and characterized. The cytotoxicity of the complexes Ru1, Ru2, Ru1lipo and Ru2lipo against B16, BEL-7402, A549, HepG2, SGC-7901 cancer cells and non-cancer cell LO2 was evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. The high inhibitory rate in vivo of Ru1lipo inhibiting SGC-7901 tumor growth reaches 72.90%. [Display omitted] • Two new Ru(II) polypyridyl complexes were synthesized and characterized. • The cytotoxicity in vitro and in vivo of the complexes and liposomes was investigated. • Apoptosis, reactive oxygen species and cell cycle arrest were performed. • RNA-sequence assay was investigated. • The antitumor activity in vivo was investigated. [ABSTRACT FROM AUTHOR]

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]

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]

Ligand HMSPIP (2-(4-(methylsulfonyl)phenyl)-1 H -imidazo[4,5-f][1,10]phenanthroline) and its iridium(III) complexes [Ir(ppy) 2 (HMSPIP)]PF 6 (ppy = 2-phenylpyridine, Ir1) and [Ir(bzq) 2 (HMSPIP)]PF 6 (bzq = benzo[ h ]quinoline, Ir2) were synthesized. The complexes were characterized by 1H NMR, 13C NMR, and UV/Vis spectra. The cytotoxicity of the complexes toward cancer cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, the scratch wound healing and colony-forming were also investigated. MTT assay certificated that the complexes show high toxic effect on the HeLa cells. The cell cycle assay illustrated that the complexes blocked cell growth at G 0 /G 1 phase in HeLa cells. A series of subsequent experiments showed that the complexes first enter the endoplasmic reticulum (ER) and then enter the mitochondria, leading to an increase in intracellular Ca2+ and reactive oxygen species (ROS) content, depolarizing mitochondrial membrane potential (MMP), and ultimately resulting in apoptosis. In addition, the experimental results revealed that the complexes not only increase the level of ROS but also inhibit the production of GSH and eventually produce large amounts of MDA and further leading to cell death. Taken together, we consider that the complexes can be used as potential candidate drugs for HeLa cancer treatment. [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 location and mitochondrial membrane potential were investigated. • The expression of B-cell lymphoma-2 family proteins was examined. [ABSTRACT FROM AUTHOR]

The work aimed to synthesize and characterize two iridium(III) complexes [Ir(ppy) 2 (IPPH)](PF 6) (Ir1 , IPPH = (2 S ,3 R ,5 S ,6 R)-2-(2-(1 H -imidazo[4,5- f ][1,10]phenanthrolin-2-yl)phenoxy)-6-(hydroxymethyl)tetrahydro-2 H -pyran-3,4,5-triol, ppy = 2-phenylpyridine), [Ir(piq) 2 (IPPH)](PF 6) (Ir2 , piq = 1-phenylisoquinoline). The cytotoxicity of the complexes against BEL-7402, A549, HCT-116, B16 cancer cells and normal LO2 was evaluated through 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. The complexes show no cytotoxic activity (IC 50 > 100 μM) against these cancer cells, while their cytotoxicity can significantly be elevated upon illumination. The IC 50 values range from 0.2 ± 0.05 to 35.5 ± 3.5 μM. The cellular uptake, endoplasmic reticulum and mitochondria localization, reactive oxygen species, the change of mitochondrial membrane potential, γ-H2AX levels, cycle arrest, apoptosis and the expression of B-cell lymphoma-2 were investigated. The calreticulin (CRT), heat shock protein 70 (HSP70), high mobility group box 1 (HMGB1) were explored. This study demonstrates that photoactivatable complexes induce cell death in A549 through ROS-mediated endoplasmic reticulum stress-mitochondrial pathway, DNA damage pathways, immunogenic cell death (ICD), activation of PI3K/AKT signaling pathway and inhibit the cell growth at S phase. Two new iridium(III) complexes [Ir(ppy) 2 (IPPH)](PF 6) (IPPH = (2 S ,3 R ,5 S ,6 R)-2-(2-(1 H -imidazo[4,5- f ][1,10]phenanthrolin-2-yl)phenoxy)-6-(hydroxymethyl)tetrahydro-2 H -pyran-3,4,5-triol, ppy = 2-phenylpyridine), [Ir(piq) 2 (IPPH)](PF 6) (piq = 1-phenylisoquinoline) were synthesized. The cytotoxicity of the complexes against BEL-7402, A549, HCT-116, B16 cancer cells and normal LO2 was evaluated through 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method in the absence and presence of white irradiation. [Display omitted] • Two new iridium(III) complexes were synthesized and characterized. • The cytotoxicity in vitro of the complexes toward A549 cells was studied. • The apoptosis and cell cycle arrest were performed. • Location of complexes at the endoplasm reticulum and mitochondria was investigated. • The expression of B-cell lymphoma-2 family proteins was explored. [ABSTRACT FROM AUTHOR]