Publications by authors named "Xingxing Ge"

22 Publications

  • Page 1 of 1

Triphenylamine/carbazole-modified ruthenium(ii) Schiff base compounds: synthesis, biological activity and organelle targeting.

Dalton Trans 2020 Jul 18;49(25):8774-8784. Epub 2020 Jun 18.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.

Four triphenylamine/carbazole-modified half-sandwich ruthenium(ii) compounds [(η-p-cymene)Ru(N/O^N)Cl] with Schiff base chelating ligands (N/O^N) are synthesized and characterized. The introduction of Schiff base units effectively increases the antitumor activity of these compounds (IC: 1.70 ± 0.56-17.75 ± 3.10 μM), which, meanwhile, can inhibit the metastasis of tumor cells effectively. These compounds follow an energy-dependent cellular uptake mechanism, mainly accumulate in lysosomes to destroy their integrity, and then eventually promote apoptosis. In addition, these compounds can induce an increase of intracellular reactive oxygen species (ROS) levels and provide an antitumor mechanism of oxidation, which is confirmed by the decrease of mitochondrial membrane potential (MMP) and the catalytic oxidation of the coenzyme nicotinamide-adenine dinucleotide (NADH). All these indicate that these ruthenium(ii) compounds are expected to be dual-functional antitumor agents: anti-metastasis and lysosomal damage.
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http://dx.doi.org/10.1039/d0dt01547dDOI Listing
July 2020

Fluorescent iridium(iii) coumarin-salicylaldehyde Schiff base compounds as lysosome-targeted antitumor agents.

Dalton Trans 2020 May;49(18):5988-5998

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.

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.
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http://dx.doi.org/10.1039/d0dt00627kDOI Listing
May 2020

Imidazole and Benzimidazole Modified Half-Sandwich Iridium -Heterocyclic Carbene Complexes: Synthesis, Anticancer Application, and Organelle Targeting.

Front Chem 2020 17;8:182. Epub 2020 Mar 17.

The Key Laboratory of Life-Organic Analysis, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Institute of Anticancer Agents Development and Theranostic Application, Qufu Normal University, Qufu, China.

Herein, we report the synthesis, characterization and anticancer activity of a series of half-sandwich iridium imidazole and benzimidazole -heterocyclic carbene (NHC) anticancer complexes, and the general formula of which can be expressed as [(η-Cp)Ir(CN)Cl]Cl (Cp: pentamethylcyclopentadienyl (Cp) or biphenyl derivatives (Cp); CN: imidazole and benzimidazole NHC chelating ligands). Compared with -platin, these complexes showed interesting antitumor activity against A549 cells. Complexes could bind to bovine serum albumin (BSA) by means of static quenching mode, catalyze the oxidation of nicotinamide adenine dinucleotide (NADH) and increase the levels of reactive oxygen species (ROS). Meanwhile, these complexes could arrest the cell cycles of A549 cells and influence the mitochondrial membrane potential significantly. Due to the inherent luminescence property, laser confocal test show that complexes could enter cells followed an energy-dependent mechanism and effectively accumulate in lysosome (the value of Pearson's co-localization coefficient is 0.70 after 1 h), further destroy lysosome integrity and induce apoptosis.
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http://dx.doi.org/10.3389/fchem.2020.00182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090125PMC
March 2020

Dual functions of iridium(III) 2-phenylpyridine complexes: Metastasis inhibition and lysosomal damage.

J Inorg Biochem 2020 04 8;205:110983. Epub 2020 Jan 8.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

Six N-phenylcarbazole/triphenylamine-appended half-sandwich iridium(III) 2-phenylpyridine complexes ([(η-Cp*)Ir(C^N)Cl]) were prepared and characterized. Compared with cisplatin, these complexes exhibited potential antitumor activity against A549 and HeLa tumor cells, with IC values (half-maximum inhibitory concentration) that changed from 2.8 ± 0.8 μM to 39.5 ± 2.7 μM, and could block the migration of tumor cells. These complexes also effectively bound to protein (binding constant: ~10 M) and were transported through serum proteins, catalyzed the oxidation of coenzyme nicotinamide-adenine dinucleotide. Additionally, laser confocal microscopy and flow cytometry confirmed that these complexes possessed a non-energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (Pearson colocalization coefficient: ~0.74), damaged the integrity of acidic lysosomes, led to a change in the mitochondrial membrane potential, disrupted the cell cycle (G/G phase), and eventually induced apoptosis. Above all, these complexes are potential antitumor agents with dual functions: metastasis inhibition and lysosomal damage.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110983DOI Listing
April 2020

Fluorescent COFs with a highly conjugated structure for visual drug loading and responsive release.

Chem Commun (Camb) 2020 Jan 11;56(4):519-522. Epub 2019 Dec 11.

The Key Laboratory of Life-Organic Analysis, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. and Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810001, P. R. China.

For the first time, a facile solvothermal method to synthesize covalent organic frameworks (COFs) with a nanosized structure and bright fluorescence was reported to monitor drug loading with the naked eye and realize responsive release.
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http://dx.doi.org/10.1039/c9cc08217dDOI Listing
January 2020

The Fluorine Effect in Zwitterionic Half-Sandwich Iridium(III) Anticancer Complexes.

Inorg Chem 2020 Jan 6;59(1):748-758. Epub 2019 Dec 6.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering , Qufu Normal University , Qufu 273165 , People's Republic of China.

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 η-Cp ring. The molecular structures for complexes - and were determined by single-crystal X-ray crystallography techniques. Notably, the asymmetrically substituted fluoro complexes and 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 η-Cp 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 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.
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http://dx.doi.org/10.1021/acs.inorgchem.9b03006DOI Listing
January 2020

Ferrocene-Appended Iridium(III) Complexes: Configuration Regulation, Anticancer Application, and Mechanism Research.

Inorg Chem 2019 Oct 27;58(20):14175-14184. Epub 2019 Sep 27.

Institute of Anticancer Agents Development and Theranostic Application, Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering , Qufu Normal University , Qufu 273165 , China.

A series of ferrocene-appended half-sandwiched iridium(III) phenylpyridine complexes have been designed and synthesized. These complexes show better anticancer activity than cisplatin widely used in clinic under the same conditions. Meanwhile, complexes could effectively inhibit cell migration and colony formation. Complexes could interact with protein and transport through serum protein, effectively catalyzing the oxidation of nicotinamide-adenine dinucleotid and inducing the accumulation of reactive oxygen species (ROS, O), which confirmed the anticancer mechanism of oxidation. Furthermore, laser scanning confocal detection indicates that these complexes can enter cells followed by a non-energy-dependent cellular uptake mechanism, effectively accumulating in the lysosome (Pearson's colocalization coefficient: ∼0.90), leading to lysosome damage, and reducing the mitochondrial membrane potential (MMP). Taken together, ferrocene-appended iridium(III) complexes possess the prospect of becoming a new multifunctional therapeutic platform, including lysosome-targeted imaging and anticancer drugs.
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http://dx.doi.org/10.1021/acs.inorgchem.9b02227DOI Listing
October 2019

Theranostic Lysosomal Targeting Anticancer and Antimetastatic Agents: Half-Sandwich Iridium(III) Rhodamine Complexes.

ACS Omega 2019 Sep 3;4(12):15240-15248. Epub 2019 Sep 3.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.

Two rhodamine-modified half-sandwich Ir(III) complexes with the general formula [(Cp)Ir(ĈN) Cl] were synthesized and characterized, where Cp is 1-biphenyl-2,3,4,5-tetramethylcyclopentadienyl (Cp). Both complexes showed potent anticancer activity against A549, HeLa, and HepG2 cancer cells and normal cells, and altered ligands had an effect on proliferation resistance. The complex enters cells through energy dependence, and because of the different ligands, not only could it affect the anticancer ability of the complex but also could affect the degree of complex lysosome targeting, lysosomal damage, and further prove the antiproliferative mechanism of the complex. Excitingly, antimetastatic experiments demonstrated that complex has the ability to block the migration of cancer cells. Furthermore, although the complex did not show a stronger ability to interfere with the coenzyme NAD/NADH pair by transfer hydrogenation, the intracellular reactive oxygen species (ROS) content has shown a marked increase. NF-κB activity is increased by ROS regulation, and the role of ROS-NF-κB signaling pathway further induces apoptosis. Moreover, cell flow experiments also demonstrated that complex blocked the cell cycle in S phase, but the complex did not cause significant changes in the mitochondrial membrane potential.
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http://dx.doi.org/10.1021/acsomega.9b01863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751730PMC
September 2019

Triphenylamine-appended cyclometallated iridium(III) complexes: Preparation, photophysical properties and application in biology/luminescence imaging.

J Inorg Biochem 2019 10 27;199:110757. Epub 2019 Jun 27.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

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 IC 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 (K: 10Ms), disturb cell cycle at G/G 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.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110757DOI Listing
October 2019

Design, synthesis, and evaluation of phosphorescent Ir(III) complexes with anticancer activity.

J Inorg Biochem 2019 08 4;197:110703. Epub 2019 May 4.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.

A range of phosphorescent Ir(III) complexes containing four diverse P^P-chelating ligands of the type [Ir(ppy)(L)][PF], (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.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110703DOI Listing
August 2019

Serendipitous Synthesis of Five-Coordinated Half-Sandwich Aminoimine Iridium(III) and Ruthenium(II) Complexes and Their Application as Potent Anticancer Agents.

Inorg Chem 2019 May 15;58(9):5956-5965. Epub 2019 Apr 15.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering , Qufu Normal University , Qufu 273165 , China.

Stable five-coordinated (16-electron) half-sandwich iridium(III) and ruthenium(II) complexes are rarely reported, and their biological evaluations have not been considered to date. Herein, in an experiment designed to synthesize six-coordinated half-sandwich iridium(III) and ruthenium(II) complexes containing N,N-chelated α-keto-β-diimine ligands, we observed the serendipitous formation of half-sandwich aminoimine iridium(III) and ruthenium(II) complexes via solvent-involved rearrangement reaction. These unsaturated 16-electron complexes had sufficient stability in DMSO-water solution. Moreover, no reaction with two-electron donors (CO and PPh) and nucleobase (9-MeA and 9-EtG) was observed. Most of the complexes show good anticancer activities toward A549, HeLa, and HepG2 cancer cells, which are higher than the clinical drug cisplatin. The investigation of mechanism by flow cytometry showed that the complexes exert their anticancer efficacy by inducing apoptosis or necrosis, and increasing the intracellular ROS level. In addition, fluorescence property of these complexes makes it possible to investigate the microscopic mechanism by confocal microscopy. Notably, the complexes Ir3 and Ru1 enter A549 cancer cells through an energy-independent pathway, and they are mainly located in mitochondria and lysosomes.
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http://dx.doi.org/10.1021/acs.inorgchem.9b00282DOI Listing
May 2019

Zwitterionic and cationic half-sandwich iridium(iii) ruthenium(ii) complexes bearing sulfonate groups: synthesis, characterization and their different biological activities.

Dalton Trans 2019 Mar 18;48(10):3193-3197. Epub 2019 Feb 18.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.

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.
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http://dx.doi.org/10.1039/c9dt00259fDOI Listing
March 2019

Half-sandwich iridium(III) complexes with α-picolinic acid frameworks and antitumor applications.

J Inorg Biochem 2019 03 24;192:52-61. Epub 2018 Dec 24.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

Eight half-sandwich iridium (Ir) complexes of the general formula [(η-Cp)Ir(O^N)Cl] (Cp 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 Ir 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. Ir 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. Ir 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.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.12.012DOI Listing
March 2019

Ferrocenyl-Triphenyltin Complexes as Lysosome-Targeted Imaging and Anticancer Agents.

Inorg Chem 2019 Jan 28;58(2):1710-1718. Epub 2018 Dec 28.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering , Qufu Normal University , Qufu 273165 , China.

In this paper, two ferrocenyl-triphenyltin complexes were synthesized and characterized. Complex 2 is constructed as new multifunctional therapeutic platform for lysosome-targeted imaging and displayed much higher cytotoxicity than its analogue 1 by the introduction of a methyl group instead of a hydrogen atom in acylhydrazone. The cyclic voltammograms and reaction with GSH (glutathione) further confirmed that complex 1 has a reversible redox peak and can react with GSH, which indicate that complex 1 might lose its anticancer effect by undergoing reaction with GSH once it enters the cancer cell. Complex 2 could effectively catalyze the oxidation of NADH (the reduced form of nicotinamide adenine dinucleotide) to NAD and induce the production of reactive oxygen species (ROS), lead to caspase-dependent apoptosis through damaged mitochondria, simultaneously, accounting for the mitochondrial vacuolization and karyorrhexis. The caspase-3 activation and cytoplasmic vacuolation karyorrhexis induced by complex 2 revealed that the A549 cell lines might undergo cell death primarily mediated by apoptosis and oncosis; however, 1 cannot reproduce this effect. Taken together, these results indicated that complex 2 has more potential for evolution as a new bioimaging and anticancer agent.
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http://dx.doi.org/10.1021/acs.inorgchem.8b03305DOI Listing
January 2019

Design, synthesis, and evaluation of fluorine and Naphthyridine-Based half-sandwich organoiridium/ruthenium complexes with bioimaging and anticancer activity.

Eur J Med Chem 2019 Feb 12;163:830-839. Epub 2018 Dec 12.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmech.2018.12.021DOI Listing
February 2019

Fluorescence turn-off Ag/fluorinated graphene composites with high NIR absorption for effective killing of cancer cells and bacteria.

J Mater Chem B 2018 Dec 14;6(47):7926-7935. Epub 2018 Nov 14.

The Key Laboratory of Life-Organic Analysis, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. China.

The unique structure and special chemical surface make fluorinated graphene-silver (FG-Ag) hold great promise in many biological fields. However, the synthesis of this nano-composite has not yet been achieved mostly due to the strong hydrophobicity and inertness of C-F bonds. Herein, we demonstrate an interesting concept of multifunctional FG-Ag and integrate it as a highly effective targeted drug carrier, photothermal therapy (PTT) and antibacterial agent. To achieve this, the F-sacrificing method is first employed to enrich FG with oxygen groups (FGO), which then serve as necessary and active reaction sites for controlled deposition of Ag nanoparticles (AgNPs) and modification of cancer targeting molecules. Interestingly, AgNPs well quench FGO's fluorescence, and FGO-Ag then acts as another effective quencher for the anticancer drug doxorubicin, all of which guarantee it as a novel sensor to visually monitor drug loading by "turn-off" fluorescence. More importantly, this nano-composite also possesses special targeting toward cancer cells; it exhibits high near-infrared absorption for PTT and shows effective antibacterial activity. This study establishes FGO-Ag as a novel nanocarrier with good targeting efficiency, high NIR absorption and drug loading and demonstrates its first application in antibacterial and cancer chemo-photothermal treatments.
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http://dx.doi.org/10.1039/c8tb02211aDOI Listing
December 2018

Triphenyltin(IV) acylhydrazone compounds: Synthesis, structure and bioactivity.

J Inorg Biochem 2019 02 24;191:194-202. Epub 2018 Nov 24.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

Four new triphenyltin(IV) acylhydrazone compounds of the type PhSnCHCHCONHN=R (where Ph = phenyl; R = isopropyl, isobutyl, cyclopentyl and cyclooctyl) were synthesized and characterized by elemental analysis, infrared spectrum (IR), nuclear magnetic resonance spectrum (NMR) and mass spectrum (MS). The crystal structures were determined and showed that tin atoms were four-coordinated and adopted a pseudo-tetrahedron configuration. Tin(IV) compounds show excellent bovine serum albumin (BSA) binding properties, and can oxidize nicotinamide-adenine dinucleotid (NADH) to generate reactive oxygen species (ROS), which inducing apoptosis effectively. Bioassay results indicated that tin(IV) compounds have stronger cytotoxic activity against A549 human lung cancer cells compared with cis-platin used clinically, and showing some selectivity.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.11.011DOI Listing
February 2019

Structure-activity relationships for highly potent half-sandwich organoiridium(III) anticancer complexes with C^N-chelated ligands.

J Inorg Biochem 2019 02 10;191:1-7. Epub 2018 Nov 10.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

We herein report the synthesis, characterization, catalytic ability in converting coenzyme NADH to NAD and anticancer activity of half-sandwich iridium(III) complexes, [(η-Cp)Ir(C^N)Cl]PF, where Cp = tetramethyl(biphenyl)cyclopentadienyl, C^N = varying imine-N-heterocyclic carbene ligands. The molecular structure of [(η-Cp)Ir(L6)Cl]PF (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 (IC = 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.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.11.007DOI Listing
February 2019

Half-sandwich Iridium(III) Benzimidazole-Appended Imidazolium-Based N-heterocyclic Carbene Complexes and Antitumor Application.

Chem Asian J 2018 Dec 31;13(23):3697-3705. Epub 2018 Oct 31.

Institute of Antitumor Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of, Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, China.

A series of half-sandwich iridium(III) benzimidazole-appended imidazolium-based N-heterocyclic carbene (NHC) antitumor complexes [(η -Cp )Ir(C^N)Cl]Cl, where Cp is pentamethylcyclopentadienyl (Cp*) or its biphenyl derivative (Cp ) and C^N is a NHC chelating ligand, were successfully synthesized and characterized. The Ir complexes showed potential antitumor activity against A549 cells, at most three times more potent than cis-platin under the same conditions. Complexes could bind to BSA by a static quenching mode, catalyzing the change of NADH to NAD and inducing the production of reactive oxygen species (maximum turnover number, 9.8), which play an important role in regulating cell apoptosis. Confocal microscopy showed that the complexes could specifically target lysosomes in cells with a Pearson's co-localization coefficient 0.76 and 0.72 after 1 h and 6 h, respectively, followed an energy-dependent cellular uptake mechanism and damaged the integrity of lysosomes. At the same time, complexes caused a marked loss of mitochondrial membrane potential.
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http://dx.doi.org/10.1002/asia.201801323DOI Listing
December 2018

Novel and Versatile Imine-N-Heterocyclic Carbene Half-Sandwich Iridium(III) Complexes as Lysosome-Targeted Anticancer Agents.

Inorg Chem 2018 Sep 22;57(17):11087-11098. Epub 2018 Aug 22.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering , Qufu Normal University , Qufu 273165 , China.

We, herein, report the synthesis, characterization, luminescence properties, anticancer, and antibacterial activities of a family of novel half-sandwich iridium(III) complexes of the general formula [(η-Cp)Ir(C^N)Cl]PF [Cp = pentamethylcyclopentadienyl (Cp*) or tetramethyl(biphenyl)-cyclopentadienyl (Cp)] bearing versatile imine-N-heterocyclic carbene ligands. In this complex framework, substituents on four positions could be modulated, which distinguishes this class of complex and provides a large amount of flexibility and opportunity to tune the cytotoxicity of complexes. The X-ray crystal structures of complexes 4 and 10 exhibit the expected "piano-stool" geometry. With the exception of 1, 2, and 11, each complex shows potent cytotoxicity, with IC (half-maximum inhibitory concentration) values ranging from 1.99 to 25.86 μM toward A549 human lung cancer cells. First, the effect of four positions bearing different substituents in the complex framework on the anticancer activity, that is, structure-activity relationship, was systematically studied. Complex 8 (IC = 1.99 μM) displays the highest anticancer activities, whose cytotoxicity is more than 10-fold higher than that of the clinical platinum drug cisplatin against A549 cancer cells. Second, their chemical reactivity including nucleobases binding, catalytic activity in converting coenzyme NADH to NAD, reaction with glutathione (GSH), and bovine serum albumin (BSA) binding is investigated. No reaction with nucleobase is observed. However, these iridium(III) complexes bind rapidly to GSH and can catalyze oxidation of NADH to NAD. In addition, they show moderate binding affinity to BSA and the fluorescence quenching of BSA by the iridium (III) complexes is due to the static quenching. Third, the mode of cell death was also explored through flow cytometry experiments, including cell cycle, apoptosis induction, reactive oxygen species (ROS) and mitochondrial membrane potential. It seems that cell cycle perturbation, apoptosis induction, increase of ROS level and loss of mitochondrial membrane potential together contribute to the anticancer potency of these complexes. Last, the use of confocal microscopy provides insights into the microscopic mechanism that the typical and most active complex 8 enters A549 lung cancer cells mainly through energy-dependent pathway and is located in lysosome. Furthermore, lysosome damage and nuclear morphology were detected by confocal microscopy. Nuclear condensation and apoptotic bodies may finally induce cells apoptosis. Interestingly, complex 8 also shows antibacterial activity against Gram-positive Staphylococcus aureus. This work may provide an alternative and effective strategy to smart design of potent organometallic half-sandwich iridium(III) anticancer drugs.
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http://dx.doi.org/10.1021/acs.inorgchem.8b01656DOI Listing
September 2018

Lysosome-Targeted Chemotherapeutics: Half-Sandwich Ruthenium(II) Complexes That Are Selectively Toxic to Cancer Cells.

Inorg Chem 2018 Sep 17;57(17):10498-10502. Epub 2018 Aug 17.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering , Qufu Normal University , Qufu 273165 , China.

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.
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http://dx.doi.org/10.1021/acs.inorgchem.8b01944DOI Listing
September 2018

Imine-N-Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p-Cymene Anticancer Complexes: A Structure-Activity Relationship Study.

Chem Asian J 2018 Oct 5;13(19):2923-2933. Epub 2018 Sep 5.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, China.

A family of novel imine-N-heterocyclic carbene ruthenium(II) complexes of the general formula [(η -p-cymene)Ru(C^N)Cl]PF (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 (IC =14.36 μm), with an approximately 1.5-fold better activity than the clinical platinum drug cisplatin (IC =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.
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http://dx.doi.org/10.1002/asia.201801058DOI Listing
October 2018