Also published as: An Y, Bai Y, Bark Y, Benabdelouahab Y, Chang Y, Chen Y, Choi Y, Chung Y, Cui Y, Dabiri Y, Deng Y, Ding Y, Du Y, Ellahioui Y, Fang Y, Feng Y, Fu Y, Gao Y, Garrosa-Miró Y, Geldmacher Y, Geng Y, Gibert Y, Gong Y, Gu Y, Gultekin Y, Guo Y, Han Y, He Y, Hong Y, Hou Y, Huang Y, Jian Y, Jiang Y, Jiao Y, Kang Y, Kim Y, Kolcuoğlu Y, Kong Y, Kuwatsuka Y, Lai Y, Lan Y, Li Y, Lin Y, Ling Y, Liu Y, Lu Y, Luo Y, Lussi Y, Ma Y, Miao Y, Mizuno Y, Ni Y, Nie Y, Nishida Y, Niu Y, Pan Y, Pang Y, Pechenyy Y, Peng Y, Praveen Kumar Y, Qian Y, Qin Y, Qiu Y, Qu Y, Ren Y, Rong Y, Sagara Y, Senkiv Y, Shao Y, Shen Y, Shi Y, Song Y, Su Y, Suh Y, Sun Y, Tan, Tristan T Y, Tang Y, Tantirungrotechai Y, Teraoka Y, Umemura Y, V V N Y, Wang Y, Wei Y, Wen Y, Wu Y, Xia Y, Xiang Y, Xiao Y, Xie Y, Xin Y, Xu Y, Xuan Y, Xue Y, Yakiyama Y, Yan Y, Yang Y, Yao Y, Yordanov Y, You Y, Yu Y, Yuan Y, Zeng Y, Zenke Y, Zhang Y, Zhao Y, Zheng Y, Zhong Y, Zhou Y, Zhu Y, Zuo Y
Previous studies on the neutral and cationic half-sandwich iridium(iii) and ruthenium(ii) complexes showed that the charge and the substitution pattern of the bidentate ligands, as well as the nature Show more
Previous studies on the neutral and cationic half-sandwich iridium(iii) and ruthenium(ii) complexes showed that the charge and the substitution pattern of the bidentate ligands, as well as the nature of the accompanying counteranion have a significant effect on their biological activities. In this contribution, a series of zwitterionic and cationic half-sandwich iridium(iii) and ruthenium(ii) complexes containing sulfonate groups have been prepared and characterized. The different locations of counteranions between these two kinds of complexes exert great influence on the cytotoxic activity towards cancer cells. The various possible mechanism of actions (MoAs) of the complexes were determined by flow cytometry. This work has shown for the first time the different biological activities between zwitterionic and cationic half-sandwich complexes. Show less
Ru(ii) polypyridine complexes which can undergo photo-induced ligand dissociation and subsequent DNA covalent binding may potentially serve as photoactivated chemotherapeutic (PACT) agents. In this pa Show more
Ru(ii) polypyridine complexes which can undergo photo-induced ligand dissociation and subsequent DNA covalent binding may potentially serve as photoactivated chemotherapeutic (PACT) agents. In this paper, three fluorinated dppz ligand coordinated Ru(ii) complexes (2-4) containing four monodentate pyridine ligands were studied. All complexes released one pyridine and covalently bound to DNA upon 470 nm irradiation. Compared with the parent complex [Ru(dppz)(py)4]2+ (1), 2-4 displayed enhanced phototoxicity but diminished dark cytotoxicity, more favorable for PACT application. Complex 3 is the most efficient one with IC50 values of about 8 μM toward HeLa and SKOV-3 cell lines, and also has a much higher IC50 value toward normal L-02 cells. Our results indicate that fluorination on the retaining ligand may be an efficient way to improve the drug activity of Ru(ii) PACT agents. Show less
Thioredoxin reductase (TrxR), a major component of the thioredoxin system, makes a critical role in regulating cellular redox signaling and is found to be overexpressed in many human cancer cells. Trx Show more
Thioredoxin reductase (TrxR), a major component of the thioredoxin system, makes a critical role in regulating cellular redox signaling and is found to be overexpressed in many human cancer cells. TrxR has become an attractive target for anticancer agents. In this work, three Ru(II) complexes with salicylate as ligand, [Ru(phen)2(SA)] (phen = 1,10-phenanthroline, SA = salicylate, 1), [Ru(dmb)2(SA)] (dmb = 4,4'-dimethyl-2,2'-bipyridine, 2) and [Ru(bpy)2(SA)] (bpy = 2,2'-bipyridine, 3), were synthesized and characterized. The anticancer effect exerted by them was evaluated. Complex 1 was found to exhibit obvious anticancer activity, in comparison with cisplatin, against cancer cell lines, while displaying low toxicity to the normal cell line BEAS-2B. The mechanism of complex 1 cancer cell growth suppress was investigated in A549 cells. Complex 1 exerted its anticancer through inducing apoptosis and triggering cell cycle arrest at the G0/G1 phase. Complex 1 can selectively inhibit TrxR activity and thus promote the generation and accumulation of reactive oxygen species (ROS), which subsequently trigger mitochondrial dysfunction and DNA damage, activate oxidative stress-sensitive mitogen activated protein kinase (MAPK), and suppress the protein kinase B (PKB or AKT) signal pathway, resulting in apoptosis in A549 cells. Show less
Near-IR-emitting and/or efficiently photodynamic water-soluble Ru(II) complexes that hold great application potentials as photodynamic therapy and/or photodetection agents for cancers have been poorly Show more
Near-IR-emitting and/or efficiently photodynamic water-soluble Ru(II) complexes that hold great application potentials as photodynamic therapy and/or photodetection agents for cancers have been poorly explored. In this paper, the solvatochromism, calf thymus DNA binding, and singlet oxygen generation properties of a known ruthenium(II) complex of visible-emitting [Ru(bpy)2(dtdpq)](ClO4)2 (Ru1) and a new homoleptic complex of near-IR-emitting [Ru(dtdpq)3](ClO4)2 (Ru2) (bpy = 2,2'-bipyridine, dtdpq = 2,3-bis(thiophen-2-yl)pyrazino[2,3-f][1,10]phenanothroline) in water are reported. Moreover, DNA photocleavage, singlet oxygen generation in HeLa cells, cellular uptake/localization, and in vitro photodynamic therapy for cancer cells of water-soluble Ru1 are described in detail. The results show that Ru1 acted as potent photodynamic cancer therapy and mitochondrial imaging agents. Ru2 exhibited very strong solvatochromism from a visible emission maximum at 588 nm in CH2Cl2 to the near-IR region at 700 nm in water and singlet oxygen generation yield in water (23%) and DNA binding properties (intercalative DNA binding constant on the order of 106 M-1) comparable to those of Ru1, which should make Ru2 attractive for the aforementioned applications of Ru1 if the water solubility of Ru2 can be improved enough for the studies above. Show less
Ru(ii) polypyridyl complexes which can undergo photo-induced ligand dissociation and DNA covalent binding are considered as potential photoactivated chemotherapeutic (PACT) agents. Herein four pyridin Show more
Ru(ii) polypyridyl complexes which can undergo photo-induced ligand dissociation and DNA covalent binding are considered as potential photoactivated chemotherapeutic (PACT) agents. Herein four pyridine-2-sulfonate (py-SO3-) ligand based Ru(ii) complexes [Ru(N-N)2(py-SO3)]+ (1-4) were synthesized and studied. All the complexes can undergo fast py-SO3- ligand dissociation and DNA covalent binding upon visible light irradiation. However, only complex 4 exhibited high photo-induced anticancer activities towards a series of cancer cells, with half maximal inhibitory concentration (IC50) values in 100-300 nM regions and phototoxicity index (PI) values of about 100. In particular, complex 4 can also kill cisplatin resistant SKOV-3 and A549 cancer cells with IC50 values in 200-400 nM regions and PI values of about 50, which should be the first report of Ru(ii) based PACT agents that are also effective towards cisplatin resistant cancer cells. Complex 4 exhibited much higher cell uptake and nuclear accumulation levels, which may be the main reasons for its high anticancer activities. The in vivo anticancer experiments indicated that complex 4 can inhibit tumor growth significantly with fewer side effects. Our results may provide guidelines for developing novel photoactivatable Ru(ii) anticancer agents. Show less
Human acute promyelocytic leukemia (APL) is the most malignant form of acute leukemia. The fusion of PML and RARα genes is responsible for over 98% of cases of APL. In this work, we found that a Ru(ii Show more
Human acute promyelocytic leukemia (APL) is the most malignant form of acute leukemia. The fusion of PML and RARα genes is responsible for over 98% of cases of APL. In this work, we found that a Ru(ii) arene complex, [(η6-p-bip)Ru(en)Cl][PF6] (Ru-1), can selectively react with PML, leading to zinc-release and protein unfolding. Consequently, the degradation of the fusion protein PML-RARα occurs, which causes the differentiation of APL cells. In addition, Ru-1 can also bind to DNA and trigger apoptosis of APL cells. Therefore, Ru-1 acts as a dual functional agent that inhibits the growth of APL cells and induces cell differentiation. In contrast, the other non-selective Ru(ii) compound, though also highly reactive to PML, does not exhibit anti-APL activity. The selectivity of Ru-1 to PML suggests a new strategy for the development of anti-APL drugs using ruthenium agents. Show less
Ru(ii) polypyridyl complexes, containing a morpholine moiety, and possessing two-photon absorption properties and pH dependent singlet oxygen production were used for stepwise lysosomes-to-mitochondri Show more
Ru(ii) polypyridyl complexes, containing a morpholine moiety, and possessing two-photon absorption properties and pH dependent singlet oxygen production were used for stepwise lysosomes-to-mitochondria photodamage of cancer cells. 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
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
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
Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine Show more
Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity than cisplatin and they can effectively localize to mitochondria. Among them, complexes Ir3 and Ir4 with dipyrido[3,2- a:2',3'- c]phenazine (dppz) ligands can bind to DNA tightly in vitro, intercalate to mtDNA in situ, and induce mtDNA damage. Ir3- and Ir4-impaired mitochondria exhibit decline of mitochondrial membrane potential, disability of adenosine triphosphate generation, disruption of mitochondrial energetic and metabolic status, which subsequently cause protective mitophagy, G0/G1 phase cell cycle arrest, and apoptosis. In vivo antitumor evaluations also show that Ir4 can inhibit tumor xenograft growth effectively. Overall, our work proves that targeting the mitochondrial genome may present an effective strategy to develop metal-based anticancer agents to overcome cisplatin resistance. Show less
Eight novel Ir(III) complexes listed as [Ir(H-P)2(P)]PF6 (PyP-Ir), [Ir(H-P)2(dMP)]PF6 (PydMP-Ir), [Ir(H-P)2(MP)]PF6 (Show more
Eight novel Ir(III) complexes listed as [Ir(H-P)2(P)]PF6 (PyP-Ir), [Ir(H-P)2(dMP)]PF6 (PydMP-Ir), [Ir(H-P)2(MP)]PF6 (PyMP-Ir), [Ir(H-P)2(tMP)]PF6 (PytMP-Ir), [Ir(MPy)2(P)]PF6 (MPyP-Ir), [Ir(MPy)2(dMP)]PF6 (MPydMP-Ir), [Ir(MPy)2(MP)]PF6 (MPyMP-Ir), [Ir(MPy)2((tMP)]PF6 (MPytMP-Ir) with 2-phenylpyri-dine (H-P) and 3-methyl-2-phenylpyridine (MPy) as ancillary ligands and pyrido-[3,2-a]-pyrido[1',2':1,2]imidazo[4,5-c]phenazine (P), 12,13-dimethyl pyrido-[3,2-a]-pyrido[1',2':1,2]-imidazo-[4,5-c]-phenazine (dMP), 2-methylpyrido [3,2-a]-pyrido-[1',2':1,2]-imidazo-[4,5-c]-phenazine (MP), and 2,12,13-trimethylpyrido-[3,2-a]-pyrido-[1',2':1,2]-imidazo-[4,5-c]-phenazine (tMP) as main ligands, respectively, were designed and synthesized to fully characterize and explore the effect of their toxicity on cancer cells. Cytotoxic mechanism studies demonstrated that the eight Ir(III) complexes exhibited highly potent antitumor activity selectively against cancer cell lines NCI-H460, T-24, and HeLa, and no activity against HL-7702, a noncancerous cell line. Among the eight Ir(III) complexes, MPytMP-Ir exhibited the highest cytotoxicity with an IC50 = 5.05 ± 0.22 nM against NCI-H460 cells. The antitumor activity of MPytMP-Irin vitro could be contributed to the steric or electronic effect of the methyl groups, which induced telomerase inhibition and damaged mitochondria in NCI-H460 cells. More importantly, MPytMP-Ir displayed a superior inhibitory effect on NCI-H460 xenograft in vivo than cisplatin. Our work demonstrates that MPytMP-Ir could potentially be developed as a novel potent Ir-based antitumor drug. Show less
The rational design by the introduction of fluorine into a compound has achieved success in the development of organic anticancer drugs. However, the fluorine effect in metal-based anticancer complexe Show more
The rational design by the introduction of fluorine into a compound has achieved success in the development of organic anticancer drugs. However, the fluorine effect in metal-based anticancer complexes has rarely been reported. In this contribution, we report the synthesis, characterization, chemical reactivity, and biological activity of a series of half-sandwich zwitterionic iridium(III) complexes containing different substituents in the η5-CpR ring. The molecular structures for complexes Ir1-Ir4 and Ir7 were determined by single-crystal X-ray crystallography techniques. Notably, the asymmetrically substituted fluoro complexes Ir4 and Ir6 in solution show two conformational isomers. These complexes have sufficient stability, exhibit fluorescence emission, and show potent catalytic activity in converting NADH to NAD+. The effect of the substituents in the η5-CpR ring for these zwitterionic complexes on their anticancer activity was systematically investigated. Surprisingly, the presence of fluorinated substituents gives rise to a significant increase in the anticancer activity. The lipophilicity and cellular uptake levels of these complexes appeared to be the primary factors for their cytotoxicity in this system. A microscopic mechanism study showed that the typical complex Ir4 entered A549 cancer cells through an energy-dependent pathway and was mainly located in lysosomes. Furthermore, an increase in ROS level, apoptosis induction, and cell-cycle perturbation together contribute to the anticancer potency of these zwitterionic complexes. Show less
Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remain Show more
Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remains to be explored. In this work, two phosphorescent cyclometalated Ir(iii) complexes containing 2-phenylpyridine (ppy) as the cyclometalated ligand, and 2,2'-biimidazole (H2biim, Ir1) or 2-(1H-imidazol-2-yl)pyridine (Hpyim, Ir2) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on H2biim and Hpyim, Ir1 and Ir2 display pH-dependent phosphorescence and can specifically image lysosomes. Both Ir1 and Ir2 can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for Ir1. Mechanism investigation shows that Ir1 and Ir2 can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As Ir1 and Ir2 can alkalinize lysosomes through anion disturbance, they can inhibit autophagic flux. Our work provides a novel anticancer mechanism of metal complexes, which gives insights into the innovative structure-based design of new metallo-anticancer agents. Show less
A mitochondria-targeted photodynamic therapy (PDT) agent was designed and synthesized. Upon light irradiation, it can produce photoacid and its photolysis products can further sensitize 1O2 generation Show more
A mitochondria-targeted photodynamic therapy (PDT) agent was designed and synthesized. Upon light irradiation, it can produce photoacid and its photolysis products can further sensitize 1O2 generation, causing dual-mode (oxygen-independent and oxygen-dependent) photodynamic damage in mitochondria and killing cancer cells effectively even under hypoxic conditions. Show less
Lysosomes play a critical role in the autophagy process. The impairment of lysosomes can affect the degradation of autophagic cargo, leading to the blockage of autophagy at the lysosomal stage and sub Show more
Lysosomes play a critical role in the autophagy process. The impairment of lysosomes can affect the degradation of autophagic cargo, leading to the blockage of autophagy at the lysosomal stage and subsequent cell death. Herein, two phosphorescent Re(i) tricarbonyl complexes (Re1 and Re2) bearing β-carboline derivatives have been synthesized and characterized. Both complexes show pH-dependent phosphorescence, which can be used to specifically image the lysosomes. Cytotoxicity assay shows that they exhibit high anticancer activity and are able to overcome cross-resistance to cisplatin. Re2 can induce autophagy, which is blocked at the lysosomal stage due to lysosomal dysfunction, such as the decrease of cathepsin B activity, subsequently leading to both autophagy and apoptosis dependent cell death. In vivo studies revealed that it could significantly inhibit tumor growth. Show less
Half-sandwich metal-based anticancer complexes suffer from uncertain targets and mechanisms of action. Herein we report the observation of the images of half-sandwich iridium and ruthenium complexes i Show more
Half-sandwich metal-based anticancer complexes suffer from uncertain targets and mechanisms of action. Herein we report the observation of the images of half-sandwich iridium and ruthenium complexes in cells detected by confocal microscopy. The confocal microscopy images showed that the cyclopentadienyl iridium complex 1 mainly accumulated in nuclei in A549 lung cancer cells, whereas the arene ruthenium complex 3 is located in mitochondria and lysosomes, mostly in mitochondria, although both complexes entered A549 cells mainly through energy-dependent active transport. The nuclear morphological changes caused by Ir complex 1 were also detected by confocal microscopy. Ir complex 1 is more potent than cisplatin toward A549 and HeLa cells. DNA binding studies involved interaction with the nucleobases 9-ethylguanine, 9-methyladenine, ctDNA, and plasmid DNA. The determination of bovine serum albumin binding was also performed. Hydrolysis, stability, nucleobase binding, and catalytic NAD+/NADH hydride transfer tests for complexes 1 and 3 were also carried out. Both complexes activated depolarization of mitochondrial membrane potential and intracellular ROS overproduction and induced cell apoptosis. Complex 3 arrested the cell cycle at the G0/G1 phase by inactivation of CDK 4/cyclin D1. This work paves the way to track and monitor half-sandwich metal complexes in cells, shines a light on understanding their mechanism of action, and indicates their potential application as theranostic agents. Show less
In this study, six half-sandwich luminescent iridium (Ir) and ruthenium (Ru) anticancer complexes bearing P^P-chelating ligands 1,2-bis(diphenylphosphino)benzene (dppbz) and 1,8-bis(diphenylphosphino) Show more
In this study, six half-sandwich luminescent iridium (Ir) and ruthenium (Ru) anticancer complexes bearing P^P-chelating ligands 1,2-bis(diphenylphosphino)benzene (dppbz) and 1,8-bis(diphenylphosphino)naphthalene (dppn) were synthesized and characterized via1H-NMR spectroscopy, 31P-NMR spectroscopy, mass spectrometry, elemental analysis and X-ray crystallography. All the complexes displayed more potent anticancer activity than cisplatin towards A549 lung cancer cells and HeLa cervical cancer cells, especially the most potent iridium complex Ir3, which was 73 times more potent than cisplatin against A549 cells. Different from cisplatin, no nucleobase adducts of Ir3 were detected. With the help of the self-luminescence of complex Ir3 and confocal microscopy, it was observed that Ir3 efficiently penetrated into the A549 cells via energy-dependent active transport, and specifically accumulated in lysosomes, affected the permeabilization of the lysosomal membranes and induced caspase-dependent cell death through lysosomal damage. Both apoptosis and autophagy of the A549 cells were observed. The reactive oxygen species (ROS) elevation, reduction of the mitochondrial membrane potential and cell cycle arrest at the G0/G1 phase also contributed to the observed cytotoxicity of Ir3. We demonstrate that these half-sandwich Ir and Ru anticancer complexes have different anticancer mechanism of action from that of cisplatin, which can be developed as potential multifunctional theranostic platforms that combine bioimaging and anticancer capabilities. Show less
A family of novel imine-N-heterocyclic carbene ruthenium(II) complexes of the general formula [(η6 -p-cymene)Ru(C^N)Cl]PF6- (where C^N is an imine-N-heterocyclic carb Show more
A family of novel imine-N-heterocyclic carbene ruthenium(II) complexes of the general formula [(η6 -p-cymene)Ru(C^N)Cl]PF6- (where C^N is an imine-N-heterocyclic carbene chelating ligand with varying substituents) have been prepared and characterized. In this imine-N-heterocyclic carbene chelating ligand framework, there are three potential sites that can be modified, which distinguishes this class of ligand and provides a body of flexibilities and opportunities to tune the cytotoxicity of these ruthenium(II) complexes. The influence of substituent effects of three tunable domains on the anticancer activity and catalytic ability in converting coenzyme NADH to NAD+ is investigated. This family of complexes displays an exceedingly distinct anticancer activity against A549 cancer cells, despite their close structural similarity. Complex 9 shows the highest anticancer activity in this series against A549 cancer cells (IC50 =14.36 μm), with an approximately 1.5-fold better activity than the clinical platinum drug cisplatin (IC50 =21.30 μm) in A549 cancer cells. Mechanistic studies reveal that complex 9 mediates cell death mainly through cell stress, including cell cycle arrest, inducing apoptosis, increasing intracellular reactive oxygen species (ROS) levels, and depolarization of the mitochondrial membrane potential (MMP). Furthermore, lysosomal damage is also detected by confocal microscopy. Show less
A range of fluorine and naphthyridine-based half-sandwich iridium (III) and ruthenium (II) complexes were synthesized. The iridium complexes possessed excellent antiproliferative properties, a substan Show more
A range of fluorine and naphthyridine-based half-sandwich iridium (III) and ruthenium (II) complexes were synthesized. The iridium complexes possessed excellent antiproliferative properties, a substantial improvement over cisplatin, especially the best 1C containing the fluorine atom and 2C containing the naphthyridine. On the contrary, the ruthenium complexes displayed much less antiproliferative activity. Two X-ray crystal structures were determined. The cytotoxicity of the complexes can be changed flexible by regulating the metal center and the ancillary ligands. The best complex 1C was chose to study further on the mechanism of action. The chemical reactivity such as hydrolysis, reaction with nucleobases, glutathione and catalytic conversion of NADH to NAD+, were investigated. Complex 1C can react with 9-ethylguanine (9-EtG) and catalyze oxidation of NADH. In addition, the self-luminescence of the complex 1C was also successfully used in confocal microscopy images for elucidating the subcellular localization. Complex 1C specifically targeted to lysosomes in A549 cancer cells and caused lysosomal damages and promote cathepsin B released. Flow cytometry studies confirmed that the biological effects of this type of complexes induced apoptosis, especially late apoptosis. Our results suggested that changes in the mitochondria membrane potential were responsible for apoptosis. The chemistry and biological studies has showed that this class of metal complexes are worthy of further exploration for the design of novel anticancer drugs. Show less
The aim of this study was to encapsulate a ruthenium complex [Ru(ttbpy)2PIP](ClO4)2 (Ru) in liposomes to enhance their antitumor effect on human cervical c Show more
Aim
The aim of this study was to encapsulate a ruthenium complex [Ru(ttbpy)2PIP](ClO4)2 (Ru) in liposomes to enhance their antitumor effect on human cervical cancer.
Methods
The Ru-loaded PEGylated liposomes (Ru-Lip) were prepared using thin-film hydration method. The mechanism of action was studied.
Results
A novel Ru was successfully synthesized. Ru-Lip showed stronger cytotoxic activity against HeLa cells than Ru. Ru-Lip demonstrated a more significant increase in apoptosis, reactive oxygen species production and apoptosis-associated processes (intracellular calcium concentration, cytochrome c release and activation of Bax and caspase-3) than Ru. Ru-Lip exhibited greater blockade efficacy in the cell cycle G1 phase and greater DNA damage than Ru.
Conclusion
Ru-Lip significantly elevates the anticancer effect via reactive oxygen species-mediated mitochondrial dysfunctional pathway. Show less
In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium-8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halog Show more
In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium-8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells. Show less
Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellu Show more
Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellular uptake and DNA-binding activity. Both types of organometallics triggered ligand dependent efficient cytotoxic effects against tumor cells with the rhodium(I) NHC derivatives causing stronger effects than the ruthenium (II) NHC analogues. Antiproliferative effects could also be observed against several pathogenic Gram-positive bacterial strains, whereas the growth of Gram-negative bacteria was not substantially affected. Cellular uptake was confirmed by atomic absorption spectroscopy as well as by fluorescence microscopy indicating a general ligand dependent accumulation in the cells. An in-depth study on the interaction with DNA confirmed insertion of the naphthalimide moiety between the planar bases of B-DNA via an intercalation mechanism, as well as its stacking on top of the quartets of G-quadruplex structures. Furthermore, additional coordinative binding of the organometallic complexes to the model DNA base 9-ethylguanine could be detected. The studied compounds thus represent promising bioorganometallics featuring strong pharmacological effects in combination with excellent cellular imaging properties. Show less
In this study, four polypyridyl ruthenium(II) complexes, namely, [(L1)2RuL2]·2ClO4 (1: L1 = phen, L2 = o-TFPIP, 2: L1 = bpy Show more
In this study, four polypyridyl ruthenium(II) complexes, namely, [(L1)2RuL2]·2ClO4 (1: L1 = phen, L2 = o-TFPIP, 2: L1 = bpy, L2 = o-TFPIP, 3: L1 = phen, L2 = o-MOPIP, and 4: L1 = bpy, L2 = o-MOPIP), were synthesized with different phenanthroimidazole derivatives, and their inhibitory activities were tested against various cancer cells. Among the Ru(II) complexes, 1 excellently inhibited the proliferation and induced the apoptosis of HepG2 cell. Importantly, 1 was mainly distributed in the cell mitochondria and markedly induced the dissipation of mitochondrial membrane potential, possibly attributing to DNA damage induced by the Ru(II) complexes. Synthetic Ru(II) complexes can suppress the growth of tumor cells in zebrafish xenograft model with low toxicity at effective concentrations. These results inspired us to further develop polypyridyl ruthenium(II) complexes as potential potent inhibitors against liver cancer. Show less
Poor selectivity between cancer cells and normal cells is one of the major limitations of cancer chemotherapy. Lysosome-targeted ruthenium-based complexes target tumor cells selectively, only displayi Show more
Poor selectivity between cancer cells and normal cells is one of the major limitations of cancer chemotherapy. Lysosome-targeted ruthenium-based complexes target tumor cells selectively, only displaying rather weak cytotoxicity or inactivity toward normal cells. Confocal microscopy was employed for the first time to determine the cellular localization of the half-sandwich Ru complex. Show less
Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic c Show more
Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic carbene (NHC) fragments [Cl2(p-cymene)Ru(μ-dppm)Au(NHC)]ClO4 was conceived to combine the known antiproliferative and cytotoxic properties of Au-NHC-based compounds and the antimigratory, antimetastatic, and antiangiogenic characteristic of specific Ru-based compounds. Following recent studies of the anticancer efficacies of these Ru-Au-NHC complexes with promising potential as chemotherapeutics against colorectal, and renal cancers in vitro, we report here on the mechanism of a selected compound, [Cl2(p-cymene)Ru(μ-dppm)Au(IMes)]ClO4 (RANCE-1, 1). The studies were carried out in vitro using a human clear cell renal carcinoma cell line (Caki-1). These studies indicate that bimetallic compound RANCE-1 (1) is significantly more cytotoxic than the Ru (2) or Au (3) monometallic derivatives. RANCE-1 significantly inhibits migration, invasion, and angiogenesis, which are essential for metastasis. RANCE-1 was found to disturb pericellular proteolysis by inhibiting cathepsins, and the metalloproteases MMP and ADAM which play key roles in the etiopathogenesis of cancer. RANCE-1 also inhibits the mitochondrial protein TrxR that is often overexpressed in cancer cells and facilitates apoptosis evasion. We found that while auranofin perturbed migration and invasion to similar degrees as RANCE-1 (1) in Caki-1 renal cancer cells, RANCE-1 (1) inhibited antiangiogenic formation and VEGF expression. We found that auranofin and RANCE-1 (1) have distinct proteolytic profiles. In summary, RANCE-1 constitutes a very promising candidate for further preclinical evaluations in renal cancer. Show less
A mutifunctional ruthenium-based conjugate Ru-BSe was designed and synthesized. The Ru complex with favorable bioimaging function was covalently linked with a cancer-targeted molecule that could be ef Show more
A mutifunctional ruthenium-based conjugate Ru-BSe was designed and synthesized. The Ru complex with favorable bioimaging function was covalently linked with a cancer-targeted molecule that could be effectively internalized by the tumor to realize enhanced theranostic effects. The pH-response of the Ru conjugate in tumor acidic microenvironment causes ligand substitution and release of therapeutic complex. This activated complex remains inert to the reducing biomolecule-glutathione and terminally locates in mitochondria, in which it triggers oxidative stress, and activates intrinsic apoptosis. Real-time monitoring reveals that this Ru conjugate could selectively accumulate in tumor tissue in vivo, which significantly suppresses tumor progression and alleviate the damage to normal organs, realizing the precise cancer theranosis. Show less
Polypyridine Ru(II) complexes have long been deemed to excellent antitumor agents that inhibit the proliferation of breast cancer cells. Nevertheless, their effects on the metastatic potency of breast Show more
Polypyridine Ru(II) complexes have long been deemed to excellent antitumor agents that inhibit the proliferation of breast cancer cells. Nevertheless, their effects on the metastatic potency of breast cancer cells need further research. Herein, a class of polypyridine Ru(II) complexes coordinated with phenazine derivates (DPPZ) ([Ru(bpy)2(DPPZ-R)](ClO4)2, Ru(bpy)2DPPZ: R = -H, Ru(bpy)2BrDPPZ: R = -Br, Ru(bpy)2MDPPZ: R = -CH3, Ru(bpy)2BnDPPZ: R = -acene, Ru(bpy)2BEDPPZ: R = -C ≡ C(C6H5)) was synthesized by introducing different substituent groups to regulate the electron cloud density and planarity of the main ligands. Results indicated that this class of DPPZ-based Ru(II) complexes exhibited promising inhibitory effect against MDA-MB-231 triple-negative breast cancer cells, especially for Ru(bpy)2BEDPPZ, which is comparable with that of cisplatin. In addition, Ru(bpy)2BEDPPZ effectively inhibited the migration and invasion of MDA-MB-231 cells in vitro and suppressed focal adhesion and stress fiber formation. Moreover, it effectively blocked MDA-MB-231 cell metastasis in blood vessels and restrained angiogenesis formation in a zebrafish xenograft breast cancer model. Further studies showed that the mechanisms may involve DNA damage-mediated apoptosis probably due to Ru(bpy)2BEDPPZ, which was enriched in the cell nucleus and induced DNA damage. All these results suggested that the DPPZ-based Ru(II) complexes can act as potent anti-metastasis agents. Show less
The chemical structures of Ru (II) complexes are known to affect their cellular behavior and toxicity. In this study, three new luminescent Ru (II) complexes, [Ru(bpy)2(HIPMP)](ClO4Show more
The chemical structures of Ru (II) complexes are known to affect their cellular behavior and toxicity. In this study, three new luminescent Ru (II) complexes, [Ru(bpy)2(HIPMP)](ClO4)2 (Ru1, bpy = 2,2'-bipyridine, HIPMP = 2-(1H-imidazo-[4,5-f] [1,10] phenanthrolin-2-yl)-4-methylphenol), [Ru(phen)2(HIPMP)](ClO4)2 (Ru2, phen = 1,10-phenanthroline), [Ru(dmb)2(HIPMP)](ClO4)2 (Ru3, dmb = 4,4'-dimethyl-2,2'-bipyridine), were synthesized, and their anticancer activities were examined. All three complexes displayed anticancer activities against various cancer cells, with Ru2 exhibiting the highest cytotoxic activities. Ru2 was shown to accumulate specifically in the endoplasmic reticulum (ER) and induce ER stress-mediated apoptosis. In addition, Ru2 could generate reactive oxygen species (ROS) and trigger mitochondrial membrane potential depolarization. These results demonstrated that Ru2 induced apoptosis in HeLa cells through ER stress and ROS production. 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