Xie, Fu-Li, Huang, Zhi-Tong, Bai, Lan +6 more · 2021 · Journal of Inorganic Biochemistry
Xie, Fu-Li, Huang, Zhi-Tong, Bai, Lan, Zhu, Jian-Wei, Xu, Hui-Hua, Long, Qing-Qin, Guo, Qi-Feng, Wu, Yong, Liu, Si-Hong Show less
Two iridium (III) polypyridine complexes [Ir(ppy)2(BIP)]PF6 (ppy = 2-phenylpyridine, BIP = 2-biphenyl-1H-imidazo[4,5-f][1,10]phenanthroline, Ir1), [Ir(piq)2(BIP)]PFShow more
Two iridium (III) polypyridine complexes [Ir(ppy)2(BIP)]PF6 (ppy = 2-phenylpyridine, BIP = 2-biphenyl-1H-imidazo[4,5-f][1,10]phenanthroline, Ir1), [Ir(piq)2(BIP)]PF6 (piq = 1-phenylisoquinoline, Ir2) and their liposomes Ir1lipo and Ir2lipo were synthesized and characterized. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cytotoxic activity against several cancer cells (A549, HepG2, SGC-7901, Bel-7402, HeLa) and non-cancer cell (mouse embryonic fibroblast, NIH3T3). The results showed that Ir1lipo displays the high cytotoxicity toward SGC-7901 with IC50 value of 5.8 ± 0.2 μM, while the complexes have no cytotoxicity toward A549, HepG2, Bel-7402 and HeLa cells. The cell colony demonstrated that the iridium (III) complexes-loaded liposomes can inhibit cell proliferation, induce cell cycle arrest at G0/G1 phase. Moreover, they also cause autophagy, induce a decrease of mitochondrial membrane potential and increase intracellular reactive oxygen species (ROS) content. These results suggest that the complexes encapsulated liposomes Ir1lipo and Ir2lipo inhibit the growth of SGC-7901 cells through a ROS-mediated mitochondrial dysfunction and activating the PI3K (phosphoinositide-3 kinase)/ AKT (protein kinase B) signaling pathways. Show less
Hao, Hailong, Liu, Xicheng, Ge, Xingxing +6 more · 2019 · Journal of Inorganic Biochemistry
Hao, Hailong, Liu, Xicheng, Ge, Xingxing, Zhao, Yao, Tian, Xue, Ren, Ting, Wang, Yan, Zhao, Chengfeng, Liu, Zhe Show less
Eight half-sandwich iridiumIII (IrIII) complexes of the general formula [(η5-Cpxbiph)Ir(O^N)Cl] (Cpxbiph is tetramethyl(biphenyl)cyclopentadienyl Show more
Eight half-sandwich iridiumIII (IrIII) complexes of the general formula [(η5-Cpxbiph)Ir(O^N)Cl] (Cpxbiph is tetramethyl(biphenyl)cyclopentadienyl, and the O^N is α-picolinic acid chelating ligand and its derivatives) were synthesized and characterized. Compared with cis-platin widely used in clinic, target IrIII complexes showed at most five times more potent antitumor activity against A549 cells by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. IrIII complexes could be transported by serum albumin, bind with DNA, catalyze the oxidation of nicotinamide-adenine dinucleotid (NADH) and induce the production of reactive oxygen species, which confirmed the antitumor mechanism of oxidation. IrIII complexes could enter A549 cells followed by an energy-dependent cellular uptake mechanism, meanwhile, target the mitochondria and lysosomes with the Pearson's colocalization coefficient of 0.33 and 0.74, respectively, lead to the lysosomal destruction and the change of mitochondrial membrane potential (ΔΨm), and eventually induce apoptosis. Show less
Liu, Zhe, Li, JuanJuan, Ge, XingXing +3 more · 2019 · Journal of Inorganic Biochemistry
Liu, Zhe, Li, JuanJuan, Ge, XingXing, Zhang, Shumiao, Xu, Zhishan, Gao, Wenyuan Show less
A range of phosphorescent Ir(III) complexes containing four diverse P^P-chelating ligands of the type [Ir(ppy)2(L)][PF6], (ppy = 2‑phenylpyridine) where L is 1,2‑bis(diphenylphos Show more
A range of phosphorescent Ir(III) complexes containing four diverse P^P-chelating ligands of the type [Ir(ppy)2(L)][PF6], (ppy = 2‑phenylpyridine) where L is 1,2‑bis(diphenylphosphino)benzene (L1), 1,2‑bis(diphenylphosphino)ethane (L2), 1,2‑bis(diphenylphosphino)propane(L3) and 1,8‑bis(diphenylphosphino)naphthalene (L4) were synthesized respectively. The iridium complexes possessed excellent antiproliferative properties, which was a substantial improvement over cisplatin, especially complex Ir1. Generally, the order of in vitro antiproliferative activity of the complexes is Ir1 > Ir2 = Ir3 > Ir4 > CDDP (Cisplatin). Two X-ray crystal structures were determined. The best complex, Ir1, was chosen to further study the mechanism of action. The self-luminescence of complex Ir1 was also successfully used to elucidate the subcellular localization. Complex Ir1 was specifically targeted to lysosomes in A549 cancer cells. This targeting caused lysosomal damage and the induction of ROS (reactive oxygen species) production in cancer cells. Flow cytometry studies confirmed that this complex induced apoptosis, especially late apoptosis. Our results suggested that changes in the mitochondrial membrane potential were responsible for apoptosis. The chemistry and biological studies showed that this class of metal complexes is worthy of further exploration to design novel anticancer drugs. Show less
Liu, Xicheng, Hao, Hailong, Ge, Xingxing +8 more · 2019 · Journal of Inorganic Biochemistry
Liu, Xicheng, Hao, Hailong, Ge, Xingxing, He, Xiangdong, Liu, Yifei, Wang, Yan, Wang, Haojie, Shao, Mingxiao, Jing, Zhihong, Tian, Laijin, Liu, Zhe Show less
Four triphenylamine (TPA)-appended cyclometallated iridium(III) complexes were designed and synthesized. Photophysical properties of these complexes were studied, and density functional theory (DFT) w Show more
Four triphenylamine (TPA)-appended cyclometallated iridium(III) complexes were designed and synthesized. Photophysical properties of these complexes were studied, and density functional theory (DFT) was utilized to analyze the influence of the ancillary ligands (TPA-modified bipyridine) to these complexes. The introduction of TPA units could effectively adjust the lipid solubility of complexes (logP), and endowed complexes with potential bioactivity (anticancer, antibacterial and bactericidal activity), especially in the field of anticancer (the best value of IC50 is 4.34±0.01μM). Interestingly, complexe 4 show some selectivity for cancer cells versus normal cells. Meanwhile, complexes could effectively prevent the metastasis of cancer cells. Complexes can be transported by serum albumin and followed by the static quenching mechanism (Kq: 1013M-1s-1), disturb cell cycle at G0/G1 phase, and induce apoptosis. The favorable fluorescence property confirmed these complexes followed by an energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (PCC: >0.95) and induced lysosomal damage, and eventually leaded to cell death. Our study demonstrates that these complexes are potential anticancer agents with dual functions, including metastasis inhibition and lysosomal damage. Show less
Zhang, Yuanyuan, Fei, Weidong, Zhang, Huiwen +6 more · 2021 · Journal of Inorganic Biochemistry
Zhang, Yuanyuan, Fei, Weidong, Zhang, Huiwen, Zhou, Yi, Tian, Li, Hao, Jing, Yuan, Yuhan, Li, Wenlong, Liu, Yunjun Show less
The studies of iridium (III) complexes as potent anticancer reagents have attracted great attention. Here, a new iridium (III) complex [Ir(bzq)2(PYIP)](PF6) (Ir1, bzq = benzo[h]q Show more
The studies of iridium (III) complexes as potent anticancer reagents have attracted great attention. Here, a new iridium (III) complex [Ir(bzq)2(PYIP)](PF6) (Ir1, bzq = benzo[h]quinoline, PYIP = 2-(pyren-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) was synthesized and its liposomes (Ir1Lipo) was prepared. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the cytotoxic activity of Ir1 and Ir1Lipo on HepG2, SGC-7901, BEL-7402, HeLa, B16, A549 and normal NIH3T3 cells. The complex Ir1 displays no obvious inhibitory effect on the growth of BEL-7402 cells, while the Ir1Lipo shows significant cytotoxic activity on BEL-7402 cells (IC50 = 2.6 ± 0.03 μM). In further studies, Ir1Lipo induced apoptosis by the mitochondrial pathways, such as increasing intracellular reactive oxygen species (ROS) content and intracellular Ca2+ level, decreasing the mitochondrial membrane potential (MMP). In addition, after incubation with Ir1Lipo, the colony formation of BEL-7402 cells was significantly inhibited. Moreover, flow cytometry was used to detect the impact of Ir1Lipo on cell cycle distribution, and western blot was used to detect the expression of caspases and Bcl-2 (B-cell lymphoma-2) family proteins. Furthermore, Ir1Lipo exhibited significant antitumor activity in vivo with an inhibitory rate of 65.8%. These results indicated that Ir1Lipo induces apoptosis in BEL-7402 cells through intrinsic mitochondrial pathway. Show less
Zhang, Yuanyuan, Zhou, Yi, Zhang, Huiwen +5 more · 2021 · Journal of Inorganic Biochemistry
Zhang, Yuanyuan, Zhou, Yi, Zhang, Huiwen, Tian, Li, Hao, Jing, Yuan, Yuhan, Li, Wenlong, Liu, Yunjun Show less
In this report, we synthesized three new iridium(III) complexes: [Ir(piq)2(apip)]PF6 (Ir1, piq = 1-phenylisoquinoline, apip = 2-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) Show more
In this report, we synthesized three new iridium(III) complexes: [Ir(piq)2(apip)]PF6 (Ir1, piq = 1-phenylisoquinoline, apip = 2-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(piq)2(maip)]PF6 (Ir2, maip = 3-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(piq)2(paip)]PF6 (Ir3, paip = 4-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline). The DNA binding was investigated. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the cytotoxic activity of Ir1, Ir2 and Ir3, the complexes show highly active against B16 cells with IC50 values of 0.3 ± 0.2 μM, 3.7 ± 0.2 μM and 4.6 ± 1.1 μM, respectively. Subsequently, cellular uptake suggested that the cytotoxicity of the complexes is attributed to their differences in cellular uptake levels. In addition, complexes Ir1, Ir2 and Ir3 induce cell cycle arrest at the G0/G1 phase and regulate the cell cycle mediators such as cyclin D1, CDK6 (cyclin-dependent kinase 6), CDK4 and p21, leading to the inhibition of B16 cells proliferation. The autophagy was investigated by monodansylcadaverine (MDC) staining. The complexes can promote the change from LC3-I to LC3-II, up-regulate levels of Beclin-1 and down-regulate expression of p62. The complexes induced apoptosis by regulating the expression levels of related indicators such as PARP (poly ADP-ribose polymerase), PI3K (phosphoinositide-3 kinase), AKT (protein kinase B), Caspase, Bcl-2 (B-cell lymphoma-2), Bad (Bcl2 associated death promoter), Bax (Bcl2-associated X) and Cyto C (cytochrome C). Additionally, Ir1 exerted significant antitumor activity in the suppression of malignant melanoma proliferation in vivo. As indicated in the above results, these complexes were highly effective for malignant melanoma treatment through the intrinsic pathway and provided much insight into anticancer drugs for tumor therapy. Show less
Zhou, Yi, Bai, Lan, Tian, Li +6 more · 2021 · Journal of Inorganic Biochemistry
Zhou, Yi, Bai, Lan, Tian, Li, Yang, Linlin, Zhang, Huiwen, Zhang, Yuanyuan, Hao, Jing, Gu, Yiying, Liu, Yunjun Show less
The new ligand BBIP (BBIP = 2-(7-bromo-2H-benzo[d]imidazole-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) with its iridium(III) complexes: [Ir(ppy)2(BBIP)](PF6) (ppy = 2-phenylpyr Show more
The new ligand BBIP (BBIP = 2-(7-bromo-2H-benzo[d]imidazole-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) with its iridium(III) complexes: [Ir(ppy)2(BBIP)](PF6) (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)2(BBIP)](PF6) (bzq = benzo[h]quinolone, Ir2) and [Ir(piq)2(BBIP)](PF6) (piq = 1-phenylisoquinoline, Ir3) were synthesized and characterized by elemental analysis, High Resolution Mass Spectrometer (HRMS), 1H NMR and 13C{1H} NMR. The cytotoxicity of the complexes against A549, HepG2, SGC-7901, BEL-7402, HeLa and normal LO2 was evaluated through 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. The results show that Ir1 exhibits high cytotoxic activity against A549 cells with a low IC50 value of 4.9 ± 0.5 μM. A series of biological activities such as cell cycle arrest, endoplasmic reticulum localization assay, apoptosis, western blotting, cellular uptake determination and in vivo antitumor activity were investigated. The assays implied that the complexes inhibit cancer cell migration through blocking mitotic progress. Cell cycle distribution stated that the complexes depress cell growth at G0/G1 phase. Additionally, the complexes acted on the endoplasmic reticulum and induce apoptosis through endoplasmic reticulum stress pathway. Especially, the western blotting showed that the complexes activated Bcl-2 (B-cell lymphoma-2) family and decreased PI3K (phosphoinositide-3 kinase) and AKT (protein kinase B), up-regulated the expression of mTOR (mammalian target of rapamycin) and p-mTOR (phosphorylated mammalian target of rapamycin). Therefore, the complexes induce apoptosis through activating PI3K-AKT-mTOR pathway. Antitumor in vivo demonstrated that Ir1 can effectively prevent the tumor growth with an inhibitory rate of 48.89%. Show less
Du, Fan, Bai, Lan, He, Miao +4 more · 2019 · Journal of Inorganic Biochemistry
Du, Fan, Bai, Lan, He, Miao, Zhang, Wen-Yao, Gu, Yi-Ying, Yin, Hui, Liu, Yun-Jun Show less
Cisplatin and its analogs have been used for the treatment of various cancers, but their serious side effect has limited clinical application. Presently, scientists are developing other metal drugs as Show more
Cisplatin and its analogs have been used for the treatment of various cancers, but their serious side effect has limited clinical application. Presently, scientists are developing other metal drugs as an alternative of cisplatin. In this paper, three new iridium(III) complexes [Ir(ppy)2(adppz)](PF6) (adppz = 7-aminodipyrido[3,2-a:2',3'-c]phenazine; ppy = 2-phenylpyridine 1), [Ir(bzq)2(adppz)](PF6) (bzq = benzo[h]quinolone 2) and [Ir(piq)2(adppz)](PF6) (piq = 1-phenylisoquinoline 3) were synthesized and characterized. The complexes can effectively inhibit the cell colonies. The cytotoxicity in vitro of the complexes against A549, HepG2, SGC-7901, BEL-7402 and normal NIH3T3 cells was evaluated by 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) methods. The intracellular reactive oxygen species (ROS) levels and Ca2+ concentrations were assayed. The mitochondrial membrane potential, a release of cytochrome c and the expression of B-cell lymphoma/leukemia-2 (Bcl-2) family protein have been investigated. The data reveal that the complexes 1-3 can effectively inhibit the cell proliferation in A549 cells with low IC50 value of 3.2 ± 0.4 μM, 4.8 ± 0.5 μM and 1.2 ± 0.2 μM, respectively. The antitumor in vivo shows that complex 3 can inhibit tumor growth with an inhibitory rate of 76.34%. The studies on the mechanism indicate that these complexes cause apoptosis in A549 cell via a ROS-mediated lysosomal-mitochondrial dysfunction pathway. In addition, the interaction of the complexes with BSA was explored. Show less
Peng, Wan, Hegazy, Ahmed M., Jiang, Ning +6 more · 2020 · Journal of Inorganic Biochemistry
Peng, Wan, Hegazy, Ahmed M., Jiang, Ning, Chen, Xi, Qi, Hua-Xin, Zhao, Xu-Dong, Pu, Jun, Ye, Rui-Rong, Li, Rong-Tao Show less
Glioma stem cells (GSCs) are thought to be responsible for the recurrence and invasion of glioblastoma multiform (GBM), which have been evaluated and exploited as the therapeutic target for GBM. Cyclo Show more
Glioma stem cells (GSCs) are thought to be responsible for the recurrence and invasion of glioblastoma multiform (GBM), which have been evaluated and exploited as the therapeutic target for GBM. Cyclometalated iridium(III) complexes have been demonstrated as the potential anticancer agents, however, their antitumor efficacies against GSCs are still unknown. Herein, we investigated the antitumor activity of two cyclometalated iridium(III) complexes [Ir(ppy)2L](PF6) (Ir1) and [Ir(thpy)2L](PF6) (Ir2) (ppy = 2-phenylpyridine, thpy = 2-(2-thienyl)pyridine and L = 4,4'-Bis(hydroxymethyl)-2,2'-bipyridine) against GSCs. The results clearly indicate that Ir1 and Ir2 kill GSCs selectively with IC50 values ranging from 5.26-9.05 μM. Further mechanism research display that Ir1 and Ir2 can suppress the proliferation of GSCs, penetrate into GSCs efficiently, localize to mitochondria, and induce mitochondria-mediated apoptosis, including the loss of mitochondrial membrane (MMP), elevation of intracellular reactive oxygen species (ROS) and caspases activation. Moreover, Ir1 and Ir2 can destroy the GSCs self-renewal and unlimited proliferation capacity by affecting the GSCs colony formation. According our knowledge, this is the first study to investigate the anti-GSCs properties of cyclometalated iridium(III) complexes. Show less
Hao, Jing, Zhang, Huiwen, Tian, Li +5 more · 2021 · Journal of Inorganic Biochemistry
Hao, Jing, Zhang, Huiwen, Tian, Li, Yang, Linlin, Zhou, Yi, Zhang, Yuanyuan, Liu, Yunjun, Xing, Degang Show less
Iridium(III) complexes have the potential to serve as novel therapeutic drugs for treating tumor. In this work, three new complexes [Ir(ppy)2(cdppz)](PF6) (1) (ppy = 2-phenylpyri Show more
Iridium(III) complexes have the potential to serve as novel therapeutic drugs for treating tumor. In this work, three new complexes [Ir(ppy)2(cdppz)](PF6) (1) (ppy = 2-phenylpyridine, cdppz = 11-chlorodipyrido[3,2-a,2',3'-c]phenazine), [Ir(bzq)2(cdppz)](PF6) (2) (bzq = benzo[h]quinolone) and [Ir(piq)2(cdppz)](PF6) (3) (piq = 1-phenylisoquinoline) were prepared as well as characterized. MTT (3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide) assay revealed that the complex 2 exerted potent cytotoxicity against to various cancer cells lines and particularly for SGC-7901 cells. Meanwhile, the complexes could suppress cell colonies formation and migration ability. Apoptosis assays of AO/EB staining as well as flow cytometry revealed that the synthesized complexes may cause apoptosis of SGC-7901 cells. Moreover, the decline of mitochondrial membrane potential (MMP), elevation of intracellular reactive oxygen species (ROS) levels and release of cytochrome c demonstrated the complexes could cause apoptosis mainly through the mitochondrial death pathway and arrest cell at G0/G1 phase. Additionally, the complexes have significant influence on the expression of proteins which is interrelated to cell apoptosis. In summary, our studies provided fundamental information regarding the further study of the possible anticancer mechanisms of iridium (III) complexes. Show less
Chen, Bing-Bing, Pan, Nan-Lian, Liao, Jia-Xin +7 more · 2021 · Journal of Inorganic Biochemistry
Chen, Bing-Bing, Pan, Nan-Lian, Liao, Jia-Xin, Huang, Min-Ying, Jiang, Dong-Chun, Wang, Jun-Jie, Qiu, Hai-Jun, Chen, Jia-Xi, Li, Lin, Sun, Jing Show less
Mitochondrial damage will hinder the energy production of cells and produce excessive ROS (reactive oxygen species), resulting in cell death through autophagy or apoptosis. In this paper, four cyclome Show more
Mitochondrial damage will hinder the energy production of cells and produce excessive ROS (reactive oxygen species), resulting in cell death through autophagy or apoptosis. In this paper, four cyclometalated iridium(III) complexes (Ir1: [Ir(piq)2L]PF6; Ir2: [Ir(bzq)2L]PF6; Ir3: [Ir(dfppy)2L]PF6; Ir4: [Ir(thpy)2L]PF6; piq = 1-phenylisoquinoline; bzq = benzo[h]quinoline; dfppy = 2-(2,4-difluorophenyl)pyridine;thpy = 2-(2-thienyl)pyridine; L = 1,10-phenanthroline-5-amine) were synthesized and characterized. Cytotoxicity tests show that these complexes have excellent cytotoxicity to cancer cells, and mechanism studies indicatethat these complexes can specifically target mitochondria. Complexes Ir1 and Ir2 can damage the function of mitochondria, subsequently increasing intracellular levels of ROS, decreasing MMP (mitochondrial membrane potential), and interfering with ATP energy production, which leads to autophagy and apoptosis. Furthermore, autophagy induced by Ir1 and Ir2 can promote cell death in coordination with apoptosis. Surprisingly, these four complexes also showed moderate antibacterial activity to S. aureusand P. aeruginosa. Show less
Gu, Yiying, Wen, Haoyu, Bai, Lan +6 more · 2020 · Journal of Inorganic Biochemistry
Gu, Yiying, Wen, Haoyu, Bai, Lan, Zhou, Yi, Zhang, Huiwen, Tian, Li, Zhang, Yuanyuan, Hao, Jing, Liu, Yunjun Show less
We prepared and characterized new iridium(III) complexes: [Ir(NC)2(MPPIP)](PF6) (N-C = 2-phenylpyridine 1; benzo[h]quinolone 2; 1-phenylisoquinolone, 3, MPPIP = 2-(4-(4'-methylpi Show more
We prepared and characterized new iridium(III) complexes: [Ir(NC)2(MPPIP)](PF6) (N-C = 2-phenylpyridine 1; benzo[h]quinolone 2; 1-phenylisoquinolone, 3, MPPIP = 2-(4-(4'-methylpiperazin-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline). MTT (MTT = 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide) method was used to assay anticancer activities of the complexes 1-3 toward SGC-7901, HeLa, A549, BEL-7402, mouse embryonic fibroblast NIH3T3 cell lines. Complexes 1, 2, 3 are sensitive to A549 cells and display a relatively low IC50 value of 5.4 ± 0.3, 4.2 ± 0.03 and 3.8 ± 0.2 μM, respectively. The apoptotic efficiency was investigated and the number of apoptotic cells induced by 1, 2 and 3 is 9.92%, 11.30% and 16.00%. The complexes are able to increase intracellular ROS content and lessen the mitochondrial membrane potential. Besides, anti-tumor activity in vivo reveals that complex 3 exhibits moderate effect on inhibiting the tumor growth, and complex 3 has no influence on liver, brain, kidney, lung and heart. Show less
Bai, Lan, Fei, Wei-Dong, Gu, Yi-Ying +5 more · 2020 · Journal of Inorganic Biochemistry
Bai, Lan, Fei, Wei-Dong, Gu, Yi-Ying, He, Miao, Du, Fan, Zhang, Wen-Yao, Yang, Lin-Lin, Liu, Yun-Jun Show less
Three iridium(III) complexes [Ir(ppy)2(CPIP)](PF6) (Ir-1, ppy = 2-phenylpyridine, CPIP = 2-(4-chlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(DCPIP)](P Show more
Three iridium(III) complexes [Ir(ppy)2(CPIP)](PF6) (Ir-1, ppy = 2-phenylpyridine, CPIP = 2-(4-chlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(DCPIP)](PF6) (Ir-2, DCPIP = 2-(3,4-dichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)2(TCPIP)](PF6) (Ir-3, TCPIP = 2,3,5-trichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The complexes Ir-1, Ir-2 and Ir-3 were encapsulated in liposomes to form Ir-1-Lipo, Ir-2-Lipo and Ir-3-Lipo. Morphology, size distribution, and zeta potential of liposomes were examined by transmission electron microscopy (TEM) and Zetasizer. The cytotoxic activity in vitro of Ir-1, Ir-2 and Ir-3 against cancer A549, HTC-116, HepG2, BEL-7402, Eca-109, B16, HeLa SGC-7901 and normal NIH3T3 cells was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. Ir-2 and Ir-3 show no cytotoxic activity against the selected cancer cells, and Ir-1 displays moderate cytotoxic effect on the cell growth in A549 cells. However, Ir-1, Ir-2 and Ir-3 were encapsulated in liposomes, the cytotoxic activity was greatly enhanced. In particular, Ir-1-Lipo and Ir-2-Lipo can effectively inhibit the cell growth in A549 cells with a low IC50 value of 3.1 ± 0.3 and 1.2 ± 0.4 μM. The apoptosis was assayed by flow cytometry. Ir-1, Ir-2 and Ir-3 reveal weak apoptotic effect, whereas Ir-1-Lipo, Ir-2-Lipo and Ir-3-Lipo induce an apoptotic percentage of 55.6%, 69.3% and 16.7% in A549 cells, respectively. Specially, in the assay of antitumor activity in vivo, the inhibiting percentage of tumor growth induced by Ir-2 is 27.65%, while inhibiting percentage of tumor growth caused by Ir-2-Lipo is 57.45%. Obviously, the liposomes can enhance anticancer activity in vitro and in vivo compared with the complexes. The results show that the iridium(III) complexes encapsulated liposomes induce apoptosis in A549 cells through ROS-mediated lysosome-mitochondria dysfunction pathway and target the microtubules. Show less
Li, Yi, Wang, Kang-Nan, He, Liang +2 more · 2020 · Journal of Inorganic Biochemistry
Li, Yi, Wang, Kang-Nan, He, Liang, Ji, Liang-Nian, Mao, Zong-Wan Show less
Metal N-Heterocyclic carbene (NHC) complexes are expected to be new opportunities for the development of anticancer metallodrugs. In this work, two near-infrared (NIR) emitting iridium(III)-NHC comple Show more
Metal N-Heterocyclic carbene (NHC) complexes are expected to be new opportunities for the development of anticancer metallodrugs. In this work, two near-infrared (NIR) emitting iridium(III)-NHC complexes Ir1 and Ir2 have been explored as mitochondria-targeted anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, and display higher cytotoxicity in the presence of 450 nm and 630 nm LED light. Colocalization and quantitative studies indicated that these complexes could specially localize to mitochondria. Mechanism studies show that these complexes increase intracellular reactive oxygen species (ROS) level, reduce mitochondrial membrane potential (MMP) and induce some degree of early apoptosis. Further studies found that Ir1could induce mitophagy at dark and necrocytosis under the irradiation of 630 nm LED light. The in vitro and in vivo photoxicity studies revealed that Ir1 is a promising photodynamic therapy (PDT) agent and could significantly inhibit tumor growth. Show less
Han, Yali, Tian, Zhenzhen, Zhang, Shumiao +6 more · 2018 · Journal of Inorganic Biochemistry
Han, Yali, Tian, Zhenzhen, Zhang, Shumiao, Liu, Xicheng, Li, Juanjuan, Li, Yanru, Liu, Yi, Gao, Min, Liu, Zhe Show less
Series of half-sandwich IrIIIN-heterocyclic carbene (NHC) antitumor complexes [(η5-Cp*)Ir(C^C)Cl] have been synthesized and characterized (Cp* is pentamethyl cyclopentadienyl, an Show more
Series of half-sandwich IrIIIN-heterocyclic carbene (NHC) antitumor complexes [(η5-Cp*)Ir(C^C)Cl] have been synthesized and characterized (Cp* is pentamethyl cyclopentadienyl, and C^C are four NHC chelating ligands containing phenyl rings at different positions). IrIII complexes showed potent antitumor activity with IC50 values ranged from 3.9 to 11.8 μM against A549 cells by the MTT assay. Complexes can catalyze the conversion of the coenzyme NADH to NAD+ and induce the production of reactive oxygen species (ROS), and bonding to BSA by static quenching mode. Complexes can arrest the cell cycle in G1 or S phase and reduce the mitochondrial membrane potential. Confocal microscopy test show complexes could target the lysosome and mitochondria in cells with the Pearson's colocalization coefficient of 0.82 and 0.21 after 12 h, respectively, and followed by an energy-dependent cellular uptake mechanism. Show less
Yang, Yuliang, Guo, Lihua, Ge, Xingxing +5 more · 2019 · Journal of Inorganic Biochemistry
Yang, Yuliang, Guo, Lihua, Ge, Xingxing, Shi, Shaopeng, Gong, Yuteng, Xu, Zhishan, Zheng, Xiaofeng, Liu, Zhe Show less
We herein report the synthesis, characterization, catalytic ability in converting coenzyme NADH to NAD+ and anticancer activity of half-sandwich iridium(III) complexes, [(η5-CpShow more
We herein report the synthesis, characterization, catalytic ability in converting coenzyme NADH to NAD+ and anticancer activity of half-sandwich iridium(III) complexes, [(η5-Cpxbiph)Ir(C^N)Cl]PF6-, where Cpxbiph = tetramethyl(biphenyl)cyclopentadienyl, C^N = varying imine-N-heterocyclic carbene ligands. The molecular structure of [(η5-Cpxbiph)Ir(L6)Cl]PF6 (complex Ir6), exhibiting the familiar "piano-stool" geometry, has been authenticated by X-ray crystallography. The anticancer activities of these complexes can be governed via substituent effects of three tunable domains and the ligand substituted variants offer an effective chelate ligand set that distinguishes anticancer activity and catalytic ability. Notably, complex Ir6 displays the greatest cytotoxic activities (IC50 = 0.85 μM), whose anticancer activity is more approximately 25-fold higher than that of cisplatin. The initial cell death mechanistic insight displays that this group of iridium(III) complexes exerts anticancer effects via cell cycle arrest, apoptosis induction and loss of the mitochondrial membrane potential. In addition, the confocal microscopy imaging shows that the complex Ir6 can damage lysosome. Overall, preliminary structure-activity relationships study and understanding of the cell death mechanism perhaps provide a rational strategy for enhancing anticancer activity of this family of complexes. Show less
Liu, Xicheng, Shao, Mingxiao, Liang, Congcong +6 more · 2021 · ChemBioChem
Liu, Xicheng, Shao, Mingxiao, Liang, Congcong, Guo, Jinghang, Wang, Guangxuan, Yuan, Xiang‐Ai, Jing, Zhihong, Tian, Laijin, Liu, Zhe Show less
A series of half-sandwich structural iridium(III) phenanthroline (Phen) complexes with halide ions (Cl- , Br- , I- ) and pyridine leaving groups ([(η5 -CpShow more
A series of half-sandwich structural iridium(III) phenanthroline (Phen) complexes with halide ions (Cl- , Br- , I- ) and pyridine leaving groups ([(η5 -CpX )Ir(Phen)Z](PF6 )n , Cpx : electron-rich cyclopentadienyl group, Z: leaving group) have been prepared. Target complexes, especially the Cpxbiph (biphenyl-substituted cyclopentadienyl)-based one, showed favourable anticancer activity against human lung cancer (A549) cells; the best one (Ir8) was almost five times that of cisplatin under the same conditions. Compared with complexes involving halide ion leaving groups, the pyridine-based one did not display hydrolysis but effectively caused lysosomal damage, leading to accumulation in the cytosol, inducing an increase in the level of intracellular reactive oxygen species and apoptosis; this indicated an anticancer mechanism of oxidation. Additionally, these complexes could bind to serum albumin through a static quenching mechanism. The data highlight the potential value of half-sandwich iridium(III) phenanthroline complexes as anticancer drugs. Show less
Liu, Xicheng, He, Xiangdong, Zhang, Xiaojing +7 more · 2019 · ChemBioChem
Liu, Xicheng, He, Xiangdong, Zhang, Xiaojing, Wang, Yongling, Liu, Jiaying, Hao, Xiujuan, Zhang, Yue, Yuan, Xiang‐Ai, Tian, Laijin, Liu, Zhe Show less
Iridium(III) complexes have attracted more and more attention in the past few years because of their potential antineoplastic activity. In this study, four IrIII complexes of the types [(η< Show more
Iridium(III) complexes have attracted more and more attention in the past few years because of their potential antineoplastic activity. In this study, four IrIII complexes of the types [(η5 -Cpx )Ir(N^N)Cl]PF6 (complexes 1 and 2) and [Ir(Phpy)2 (N^N)]PF6 (complexes 3 and 4) have been synthesized and characterized. They exhibit potential antineoplastic activity towards A549 cells, especially in the case of complex 1 [IC50 =(3.56±0.5) μm], which was nearly six times as effective as cisplatin [(21.31±1.7) μm]. Additionally, these complexes show some selectivity towards cancer cells over normal cells. They could be transported by serum albumin (binding constants were changed from 0.37×105 to 81.71×105 m-1 ). IrIII complexes 1 and 2 could catalyze the transformation of nicotinamide adenine dinucleotide reduced form (NADH) into NAD+ (turnover numbers 43.2, 11.9] and induce the accumulation of reactive oxygen species, thus confirming their antineoplastic mechanism of oxidation, whereas the cyclometalated complexes 3 and 4 were able to target the lysosome [Pearson co-localization coefficient (PCC)=0.73], cause lysosomal damage, and induce apoptosis. Understanding the mechanism of action would help further structure-activity optimization on these IrIII complexes as emerging cancer therapeutics. Show less
Zhang, Pingyu, Huang, Huaiyi, Banerjee, Samya +4 more · 2019 · Angewandte Chemie International Edition
Zhang, Pingyu, Huang, Huaiyi, Banerjee, Samya, Clarkson, Guy J., Ge, Chen, Imberti, Cinzia, Sadler, Peter J. Show less
An organoiridium-albumin bioconjugate (Ir1-HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1-HSA was enhanced significantly compared t Show more
An organoiridium-albumin bioconjugate (Ir1-HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1-HSA was enhanced significantly compared to parent complex Ir1. The long phosphorescence lifetime and high 1 O2 quantum yield of Ir1-HSA are highly favorable properties for photodynamic therapy. Ir1-HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC50 ; 0.8-5 μm, photo-cytotoxicity index PI=40-60), while remaining non-toxic to normal cells and normal cell spheroids, even after photo-irradiation. This nucleus-targeting organoiridium-albumin is a strong candidate photosensitizer for anticancer photodynamic therapy. Show less
Yip, Alex Man‐Hei, Lai, Calvin Kin‐Ho, Yiu, Ken Shek‐Man +1 more · 2022 · Angewandte Chemie International Edition
Yip, Alex Man‐Hei, Lai, Calvin Kin‐Ho, Yiu, Ken Shek‐Man, Lo, Kenneth Kam‐Wing Show less
The dual functionality of 1,2,4,5-tetrazine as a bioorthogonal reactive unit and a luminescence quencher has shaped tetrazine-based probes as attractive candidates for luminogenic labeling of biomolec Show more
The dual functionality of 1,2,4,5-tetrazine as a bioorthogonal reactive unit and a luminescence quencher has shaped tetrazine-based probes as attractive candidates for luminogenic labeling of biomolecules in living systems. In this work, three cyclometalated iridium(III) complexes featuring two tetrazine units were synthesized and characterized. Upon photoexcitation, the complexes were non-emissive but displayed up to 3900-fold emission enhancement upon the inverse electron-demand Diels-Alder (IEDDA) [4+2] cycloaddition with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) substrates. The rapid reaction kinetics (k2 up to 1.47×104 M-1 s-1 ) of the complexes toward BCN substrates allowed effective peptide labeling. The complexes were also applied as live cell bioimaging reagents and photocytotoxic agents. One of the complexes was utilized in the preparation of luminescent nanosized hydrogels that exhibited interesting cargo delivery properties. Show less
Li, Steve Po‐Yam, Liu, Hua‐Wei, Zhang, Kenneth Yin +1 more · 2010 · Chemistry – A European Journal
Li, Steve Po‐Yam, Liu, Hua‐Wei, Zhang, Kenneth Yin, Lo, Kenneth Kam‐Wing Show less
We report the synthesis, characterization, and photophysical properties of a new class of luminescent cyclometalated iridium(III) polypyridine poly(ethylene glycol) (PEG) complexes [Ir(N--C)(2)(N--N)] Show more
We report the synthesis, characterization, and photophysical properties of a new class of luminescent cyclometalated iridium(III) polypyridine poly(ethylene glycol) (PEG) complexes [Ir(N--C)(2)(N--N)](PF(6)) (HN--C=Hppy (2-phenylpyridine), N--N=bpy-CONH-PEG1 (bpy=2,2'-bipyridine; 1a), bpy-CONH-PEG3 (1b); HN--C=Hpq (2-phenylquinoline), N--N=bpy-CONH-PEG1 (2a), bpy-CONH-PEG3 (2b); HN--C=Hpba (4-(2-pyridyl)benzaldehyde), N--N=bpy-CONH-PEG1 (3)) and their PEG-free counterparts (N--N=bpy-CONH-Et, HN--C=Hppy (1c); HN--C=Hpq (2c)). The cytotoxicity and cellular uptake of these complexes have been investigated by the MTT assay, ICPMS, laser-scanning confocal microscopy, and flow cytometry. The results showed that the complexes supported by the water-soluble PEG can act as biological probes and labels with considerably reduced cytotoxicity. Because the aldehyde groups of complex 3 are reactive toward primary amines, the complex has been utilized as the first luminescent PEGylation reagent. Bovine serum albumin (BSA) and poly(ethyleneimine) (PEI) have been PEGylated with this complex, and the resulting conjugates have been isolated, purified, and their photophysical properties studied. The DNA-binding and gene-delivery properties of the luminescent PEI conjugate 3-PEI have also been investigated. Show less
Fan, Zhongxian, Xie, Jiaen, Sadhukhan, Tumpa +8 more · 2022 · Chemistry – A European Journal
Fan, Zhongxian, Xie, Jiaen, Sadhukhan, Tumpa, Liang, Chao, Huang, Can, Li, Wenqing, Li, Tingxuan, Zhang, Pingyu, Banerjee, Samya, Raghavachari, Krishnan, Huang, Huaiyi Show less
Four photo-catalysts of the general formula [Ir(CO6/ppy)2 (L)]Cl where CO6=coumarin 6 (Ir1-Ir3), ppy=2-phenylpyridine (Ir4), L=4'-(3,5-di-tert-butylphenyl)-2,2' : 6',2''-terpyridine (Ir1), Show more
Four photo-catalysts of the general formula [Ir(CO6/ppy)2 (L)]Cl where CO6=coumarin 6 (Ir1-Ir3), ppy=2-phenylpyridine (Ir4), L=4'-(3,5-di-tert-butylphenyl)-2,2' : 6',2''-terpyridine (Ir1), 4'-(3,5-bis(trifluoromethyl)phenyl)-2,2' : 6',2''-terpyridine (Ir2 and Ir4), and 4-([2,2' : 6',2''-terpyridin]-4'-yl)-N,N-dimethylaniline (Ir3) were synthesized and characterized. These photostable photo-catalysts (Ir1-Ir3) showed strong visible light absorption between 400-550 nm. Upon light irradiation (465 and 525 nm), Ir1-Ir3 generated singlet oxygen and induced rapidly photo-catalytic oxidation of cellular coenzymes NAD(P)H. Ir1-Ir3 showed time-dependent cellular uptake with excellent intracellular retention efficiency. Upon green light irradiation (525 nm), Ir2 provided a much higher photo-index (PI=793) than the clinically used photosensitizer, 5-aminolevulinicacid (5-ALA, PI>30) against HeLa cancer cells. The observed necro-apoptotic anticancer activity of Ir2 was due to the Ir2 triggered photo-induced intracellular redox imbalance (by NAD(P)H oxidation and ROS generation) and change in the mitochondrial membrane potential. Remarkably, Ir2 showed in vivo photo-induced catalytic anticancer activity in mouse models. Show less
Pracharova, Jitka, Vigueras, Gloria, Novohradsky, Vojtech +6 more · 2018 · Chemistry – A European Journal
Pracharova, Jitka, Vigueras, Gloria, Novohradsky, Vojtech, Cutillas, Natalia, Janiak, Christoph, Kostrhunova, Hana, Kasparkova, Jana, Ruiz, José, Brabec, Viktor Show less
A series of five kinetically inert bis-cyclometalated IrIII complexes of general formula [Ir(C^N)2 (N^N)][PF6 ] [C^N=2-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-benzo[d] Show more
A series of five kinetically inert bis-cyclometalated IrIII complexes of general formula [Ir(C^N)2 (N^N)][PF6 ] [C^N=2-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-benzo[d]imidazol-κN,C; N^N=1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3), benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn, 4), and dipyrido[3,2-a:2',3'-c]phenazine-10,11-imidazolone (dppz-izdo, 5)] were designed and synthesized to explore the effect of the degree of π conjugation of the polypyridyl ligand on their toxicity in cancer cells. We show that less-lipophilic complexes 1 and 2 exhibit the highest toxicity [sub-micromolar inhibitory concentration (IC50 ) values] in A2780, HeLa, and MCF-7 cancer cells, and they are markedly more efficient than clinically used platinum drugs. It is noteworthy that the investigated Ir agents display the capability to overcome acquired and inherent resistance to conventional cisplatin (in A2780cisR and MCF-7 cells, respectively). We demonstrate that the Ir complexes, unlike clinically used platinum antitumor drugs, do not kill cells through DNA-damage response. Rather, they kill cells by inhibiting protein translation by targeting preferentially the endoplasmic reticulum. Our findings also reveal that the toxic effect of the Ir complexes can be significantly potentiated by irradiation with visible light (by more than two orders of magnitude). The photopotentiation of the investigated Ir complexes can be attributed to a marked increase (≈10-30-fold) in intracellular reactive oxygen species. Collectively, these data highlight the functional diversity of antitumor metal-based drugs and the usefulness of a mechanism-based rationale for selecting candidate agents that are effective against chemoresistant tumors for further preclinical testing. Show less
Laws, Kristine, Eskandari, Arvin, Lu, Chunxin +1 more · 2018 · Chemistry – A European Journal
Laws, Kristine, Eskandari, Arvin, Lu, Chunxin, Suntharalingam, Kogularamanan Show less
The cancer stem cell (CSC) toxicity and mechanism of action of a series of iridium(III) complexes bearing polypridyl and charged 1-methyl-2-(2-pyridyl)pyridinium ligands, 1-4 is reported. The most eff Show more
The cancer stem cell (CSC) toxicity and mechanism of action of a series of iridium(III) complexes bearing polypridyl and charged 1-methyl-2-(2-pyridyl)pyridinium ligands, 1-4 is reported. The most effective complex (containing 1,10-phenanthroline), 3, kills CSCs and bulk cancer cells with equal potency (in the micromolar range), indicating that it could potentially remove heterogenous tumour populations with a single dose. Encouragingly, 3 also inhibits mammopshere formation to a similar extent as salinomycin, a well-established anti-CSC agent. This complex induces CSC apoptosis by mitochondrial membrane depolarization, inhibition of mitochondrial metabolism, and intracellular reactive oxygen species (ROS) generation. To the best of our knowledge, this is the first study to investigate the anti-CSC properties of iridium complexes. Show less
Thomas, Samuel J., Balónová, Barbora, Cinatl, Jindrich +4 more · 2020 · ChemMedChem
Thomas, Samuel J., Balónová, Barbora, Cinatl, Jindrich, Wass, Mark N., Serpell, Christopher J., Blight, Barry A., Michaelis, Martin Show less
Thiourea and guanidine units are found in nature, medicine, and materials. Their continued exploration in applications as diverse as cancer therapy, sensors, and electronics means that their toxicity Show more
Thiourea and guanidine units are found in nature, medicine, and materials. Their continued exploration in applications as diverse as cancer therapy, sensors, and electronics means that their toxicity is an important consideration. Iridium complexes present new opportunities for drug development and imaging in terms of structure and photoactivity. We have systematically synthesised a set of thiourea and guanidine compounds and iridium complexes thereof, and elucidated structure-activity relationships for cellular toxicity in three ovarian cancer cell lines and their cisplatin-resistant sub-lines. We have been able to use the intrinsic luminescence of iridium complexes to visualise the effect of both structure alteration and cellular resistance mechanisms. These findings provide starting points for the development of new drugs and consideration of safety issues for novel thiourea-, guanidine-, and iridium-based materials. Show less
Redrado, Marta, Miñana, Miriam, Coogan, Michael P. +2 more · 2022 · ChemMedChem
Redrado, Marta, Miñana, Miriam, Coogan, Michael P., Concepción Gimeno, M., Fernández‐Moreira, Vanesa Show less
Bioactive and luminescent cyclometallated Ir(III) complexes [Ir(ppy)2 L1]Cl (1) and [Ir(ppy)2 L2]Cl (2) containing a benzimidazole derivative (L1/L2) as auxiliary mimic of a nucl Show more
Bioactive and luminescent cyclometallated Ir(III) complexes [Ir(ppy)2 L1]Cl (1) and [Ir(ppy)2 L2]Cl (2) containing a benzimidazole derivative (L1/L2) as auxiliary mimic of a nucleotide have been synthesised. The emissive properties of both complexes are conditioned by the nature of L1 and L2, rendering an orange and a green emitter respectively. Both are highly emissive with quantum yield increasing in absence of oxygen up to 0.26 (1) and 0.36 (2), suggesting their phosphorescent character. Antiproliferative activity against lung cancer A549 cells increased up to 15 times upon irradiation conditions, reaching IC50 values in the nanomolar range (0.3±0.09 μM (1) and 0.26±0.14 μM (2)) and pointing them as good PSs candidates for photodynamic therapy via 1 O2 generation. Cellular biodistribution analysis by fluorescence microscopy suggest the lysosomes as the preferential accumulation organelle. Time-resolved studies showed a greatly increased cellular emission lifetime compared to the solution values, indicating binding to macromolecules or cellular structures and restriction of collision and vibrational quenching. Show less
Liu, Zhe, Habtemariam, Abraha, Pizarro, Ana M. +8 more · 2011 · Journal of Medicinal Chemistry
Liu, Zhe, Habtemariam, Abraha, Pizarro, Ana M., Fletcher, Sally A., Kisova, Anna, Vrana, Oldrich, Salassa, Luca, Bruijnincx, Pieter C. A., Clarkson, Guy J., Brabec, Viktor, Sadler, Peter J. Show less
The low-spin 5d(6) Ir(III) organometallic half-sandwich complexes [(η(5)-Cp(x))Ir(XY)Cl](0/+), Cp(x) = Cp*, tetramethyl(phenyl)cyclopentadienyl (Cp(xph)), or tetramethyl(biphenyl)cyclopentadienyl (Cp( Show more
The low-spin 5d(6) Ir(III) organometallic half-sandwich complexes [(η(5)-Cp(x))Ir(XY)Cl](0/+), Cp(x) = Cp*, tetramethyl(phenyl)cyclopentadienyl (Cp(xph)), or tetramethyl(biphenyl)cyclopentadienyl (Cp(xbiph)), XY = 1,10-phenanthroline (4-6), 2,2'-bipyridine (7-9), ethylenediamine (10 and 11), or picolinate (12-14), hydrolyze rapidly. Complexes with N,N-chelating ligands readily form adducts with 9-ethylguanine but not 9-ethyladenine; picolinate complexes bind to both purines. Cytotoxic potency toward A2780 human ovarian cancer cells increases with phenyl substitution on Cp*: Cp(xbiph) > Cp(xph) > Cp*; Cp(xbiph) complexes 6 and 9 have submicromolar activity. Guanine residues are preferential binding sites for 4-6 on plasmid DNA. Hydrophobicity (log P), cell and nucleus accumulation of Ir correlate with cytotoxicity, 6 > 5 > 4; they distribute similarly within cells. The ability to displace DNA intercalator ethidium bromide from DNA correlates with cytotoxicity and viscosity of Ir-DNA adducts. The hydrophobicity and intercalative ability of Cp(xph) and Cp(xbiph) make a major contribution to the anticancer potency of their Ir(III) complexes. Show less
Cao, Rui, Jia, Junli, Ma, Xiaochuan +2 more · 2013 · Journal of Medicinal Chemistry
Cao, Rui, Jia, Junli, Ma, Xiaochuan, Zhou, Ming, Fei, Hao Show less
The cellular behavior and toxicity effect of organometallic complexes depend largely on their peripheral ligands. In this study, we have synthesized a series of novel luminescent cationic iridium(III) Show more
The cellular behavior and toxicity effect of organometallic complexes depend largely on their peripheral ligands. In this study, we have synthesized a series of novel luminescent cationic iridium(III) complexes by tuning the ancillary N(∧)N ligand based on a structure [Ir(ppy)2(N(∧)N)](+) (ppy = 1-phenyl-pyridine; N(∧)N = 2,2'-bipyridine (bpy, 1) or phenanthroline (phen, 2) or 4,7-diphenyl-1,10- phenanthroline (DIP, 3)). As the size of coordinated N(∧)N ligand increases, absorbance/emission efficiency, quantum yields, lipophilicity, and cell uptake rates of the complexes also increase, in a general order: 3 > 2 > 1. All three complexes display anticancer activity, with 3 exhibiting the highest cellular uptake efficiency and the greatest cytotoxic activities in several cancer cell lines with IC50s lower than that of cisplatin. Because of its strong hydrophobic nature, the death inducer 3 was found to accumulate favorably to endoplasmic reticulum (ER) and to cause ER stress in cells. The fast cytosolic release of calcium from stressed ER disturbed the morphology and function of mitochondria, initiating an intrinsic apoptotic pathway. Understanding of the cell death mechanism would help further structure-activity optimization on these novel Ir(III) complexes as emerging cancer therapeutics. Show less
Liu, Cong, Liu, Xicheng, Ge, Xingxing +8 more · 2020 · Dalton Transactions
Liu, Cong, Liu, Xicheng, Ge, Xingxing, Wang, Qinghui, Zhang, Lei, Shang, Wenjing, Zhang, Yue, Yuan, Xiang Ai, Tian, Laijin, Liu, Zhe, You, Jinmao Show less
Six fluorescent half-sandwich iridium(iii) coumarin-salicylaldehyde Schiff base (O^N) compounds ([(η5-Cp*)Ir(O^N)Cl]) were prepared and characterized. The introduction of a coumarin unit increased the Show more
Six fluorescent half-sandwich iridium(iii) coumarin-salicylaldehyde Schiff base (O^N) compounds ([(η5-Cp*)Ir(O^N)Cl]) were prepared and characterized. The introduction of a coumarin unit increased the antitumor activity (IC50: 9.9 ± 0.1 μM-40.7 ± 12.9 μM) of these compounds, the best of which was nearly two times that of clinical cisplatin. The results of laser confocal microscopy demonstrated that these compounds possessed an energy-dependent cellular uptake mechanism, accumulated in the lysosomes (Pearson co-localization coefficient: ∼0.7), damaged the integrity of the lysosomes, and induced apoptosis. The compounds could also decrease the mitochondrial membrane potential, catalyze the oxidation of the coenzyme (nicotinamide-adenine dinucleotide) and improve the levels of the intracellular reactive oxygen species, following an antitumor mechanism of oxidation. Additionally, these compounds could block the metastasis of tumor cells. Above all, these iridium(iii) compounds show potential as antitumor agents with dual functions: lysosomal damage and anti-metastasis. Show less
Liu, Li-Juan, Lu, Lihua, Zhong, Hai-Jing +4 more · 2015 · Journal of Medicinal Chemistry
Liu, Li-Juan, Lu, Lihua, Zhong, Hai-Jing, He, Bingyong, Kwong, Daniel W. J., Ma, Dik-Lung, Leung, Chung-Hang Show less
A novel iridium(III) complex was synthesized and evaluated for its ability to target JMJD2 enzymatic activity. The iridium(III) complex 1 can inhibit JMJD2 activity and was selective for JMJD2 activit Show more
A novel iridium(III) complex was synthesized and evaluated for its ability to target JMJD2 enzymatic activity. The iridium(III) complex 1 can inhibit JMJD2 activity and was selective for JMJD2 activity over JARID, JMJD3, and HDAC activities. Moreover, 1 suppressed the trimethylation of the p21 promoter on H3K9me3 and interrupted the JMJD2D-H3K9me3 interactions in human cells, suggesting that it could act as an epigenetic modulator. To our knowledge, 1 represents the first metal-based JMJD2 inhibitor reported in the literature. Show less