Exploring the C^N^C theme: Synthesis and biological properties of tridentate cyclometalated gold(III) complexes.
Jürgens Sophie,Scalcon Valeria,Estrada-Ortiz Natalia,Folda Alessandra,Tonolo Federica,Jandl Christian,Browne Duncan L,Rigobello Maria Pia,Kühn Fritz E,Casini Angela
Bioorganic & medicinal chemistry
A family of cyclometalated Au(III) complexes featuring a tridentate C^N^C scaffold has been synthesized and characterized. Microwave assisted synthesis of the ligands has also been exploited and optimized. The biological properties of the thus formed compounds have been studied in cancer cells and demonstrate generally moderate antiproliferative effects. Initial mechanistic insights have also been gained on the gold complex [Au(C^N^C)(GluS)] (3), and support the idea that the thioredoxin system may be a target for this family of compounds together with other relevant intracellular thiol-containing molecules.
10.1016/j.bmc.2017.08.001
Design, synthesis, and anticancer activity of iridium(III) complex-peptide hybrids that contain hydrophobic acyl groups at the N-terminus of the peptide units.
Naito Kana,Yokoi Kenta,Balachandran Chandrasekar,Hisamatsu Yosuke,Aoki Shin
Journal of inorganic biochemistry
In previous work, we reported on that Ir complex-cationic peptide hybrids (IPHs) that contain three KKGG or KKKGG sequences (K: lysine, G: glycine) induce cell death in cancer cells by an intracellular Ca-dependent pathway and function as luminescent detectors in dead cells. To identify the target biomolecules by photoaffinity labeling, we designed and synthesized IPH that contains a photoreactive and hydrophobic 4-[3-(trifluotomethyl)-3H-diazirine-3-yl]benzoyl (TFDB) group and found that it has more potent cytotoxicity against Jurkat cells than the previously prepared compounds. Herein, we report on the preparation of some new IPHs that contain hydrophobic acyl groups at the N-terminus of the peptide portions of the molecules. Among them, an IPH containing a n-dodecanoyl group was found to have much more potent cancer cell death activity and superior selectivity for cancer cells (Jurkat cells) over normal cells. The results of mechanistic studies suggest that the cell death of Jurkat cells is induced via different pathway from that induced by the previously synthesized IPHs. The results of this study are described herein.
10.1016/j.jinorgbio.2019.110785
Cyclometalated Complexes of Platinum and Gold with Biological Properties: State-of-the-Art and Future Perspectives.
Jurgens Sophie,Kuhn Fritz E,Casini Angela
Current medicinal chemistry
BACKGROUND:The inherent problems accompanying chemotherapy necessitate the development of new anticancer approaches. The development of compounds that can disrupt cancerous cellular machinery by novel mechanisms, via interactions with proteins and non-canonical DNA structures (e.g. G-quadruplexes), as well as by alteration of the intracellular redox balance, is nowadays focus of intense research. In this context, organometallic compounds of the noble metals Pt and Au have become prominent experimental therapeutic agents. This review provides an overview of the Pt(II) and Au(III) cyclometalated compounds with a chelating ring containing a strong C-M σ -bond to improve the stability of the compounds with respect to ligand exchange reactions and biological reduction. Furthermore, these properties can be easily tuned by modification of either the anionic cyclometalated or the ancillary ligands. Special focus has been set to C^N, C^N^C, C^N^N and C^N^S platinum(II) and gold(III) pincer complexes regarding their synthesis and biological mechanisms of action as anticancer agents. METHODS:A structured search of both chemical and medicinal databases for peerreviewed research literature has been conducted. The quality of retrieved papers was appraised using standard tools. The synthesis as well as the chemical and biological properties of the described compounds were carefully reviewed and described. The findings were outlined using a conceptual framework. RESULTS:In this review we included 155 papers, the majority originating from high-impact papers on the synthesis and biological modes of platinum(II) and gold(III) compounds. Among them, 17 papers were highlighted to give an introduction to the use of Pt and Au compounds with medicinal properties, mainly focussing on coordination compounds. The synthesis and medicinal properties of organometallic compounds of various metals (such as Fe, Ru, Ti) were outlined in 51 papers. These compounds included metallocenes, metallo- arenes, metallo-carbonyls, metallo-carbenes (e.g. N-heterocyclic carbenes), and alkynyl complexes. The C^N, C^N^C, C^N^N and C^N^S pincer complexes of platinum( II) (46 papers) and gold(III) (44 papers) were discussed concerning their synthesis, stability and advantages to develop therapeutic compounds. We strove to show the consistent development of C^N, C^N^C, C^N^N and C^N^S platinum(II) and gold(III) pincer complexes regarding their synthesis and biological modes from the early beginnings to the most recent findings. CONCLUSION:This review supplies a profound overview of the development of organometallic compounds for medicinal purposes, setting special focus to the synthesis and stability of C^N, C^N^C, C^N^N and C^N^S pincer complexes of platinum(II) and gold(III) and their use as anticancer agents.
10.2174/0929867324666170529125229
Gold(I/III)-Phosphine Complexes as Potent Antiproliferative Agents.
Kim Jong Hyun,Reeder Evan,Parkin Sean,Awuah Samuel G
Scientific reports
The reaction of gold reagents [HAuCl•3HO], [AuCl(tht)], or cyclometalated gold(III) precursor, [C^NAuCl] with chiral ((R,R)-(-)-2,3-bis(t-butylmethylphosphino) quinoxaline) and non-chiral phosphine (1,2-Bis(diphenylphosphino)ethane, dppe) ligands lead to distorted Au(I), (1, 2, 4, 5) and novel cyclometalated Au(III) complexes (3, 6). These gold compounds were characterized by multinuclear NMR, microanalysis, mass spectrometry, and X-ray crystallography. The inherent electrochemical properties of the gold complexes were also studied by cyclic voltammetry and theoretical insight of the complexes was gained by density functional theory and TD-DFT calculations. The complexes effectively kill cancer cells with IC in the range of ~0.10-2.53 μΜ across K562, H460, and OVCAR8 cell lines. In addition, the retinal pigment epithelial cell line, RPE-Neo was used as a healthy cell line for comparison. Differential cellular uptake in cancer cells was observed for the compounds by measuring the intracellular accumulation of gold using ICP-OES. Furthermore, the compounds trigger early - late stage apoptosis through potential disruption of redox homeostasis. Complexes 1 and 3 induce predominant G1 cell cycle arrest. Results presented in this report suggest that stable gold-phosphine complexes with variable oxidation states hold promise in anticancer drug discovery and need further development.
10.1038/s41598-019-48584-5
A Gold(III) Pincer Ligand Scaffold for the Synthesis of Binuclear and Bioconjugated Complexes: Synthesis and Anticancer Potential.
Bertrand Benoît,O'Connell Maria A,Waller Zoë A E,Bochmann Manfred
Chemistry (Weinheim an der Bergstrasse, Germany)
Cyclometalated (C^N^C)Au complexes bearing functionalized N-heterocyclic carbene (NHC) ligands provide a high-yielding, modular route to bioconjugated and binuclear complexes. This methodology has been applied to the synthesis of bioconjugated complexes presenting biotin and 17α-ethynylestradiol vectors, as well as to the synthesis of bimetallic Au /Au complexes. The in vitro antiproliferative activities of these compounds against various cancer cells lines depend on the linker length, with the longer linker being the most potent. The estradiol conjugate AuC Estra proved to be more toxic against the estrogen receptor positive (ER+) cancer cells than against the ER- cancer cells and non-cancer cells. The bimetallic complex AuC Au was more selective for breast cancer cells with respect to a healthy cell standard than the monometallic complex AuNHC. The metal uptake study on cells expressing or not biotin and estrogen receptors revealed an improved and targeted delivery of gold for both the bioconjugated complexes AuC Biot and AuC Estra compared to the non-vectorised analogue AuNHC. The investigations of the interaction of the bioconjugates and bimetallic complexes with human telomeric G-quadruplex DNA using FRET-melting techniques revealed a reduced ability to stabilize this DNA structure with respect to the non-vectorised analogue AuNHC.
10.1002/chem.201705902
Amphiphilic Gemini Iridium(III) Complex as a Mitochondria-Targeted Theranostic Agent for Tumor Imaging and Photodynamic Therapy.
Yi Sili,Lu Zhen,Zhang Jin,Wang Jun,Xie Zenghong,Hou Linxi
ACS applied materials & interfaces
Clinical diagnostics and therapeutics of tumors are significantly benefitted by the development of multifunctional theranostic agents, which integrate tumor targeting, imaging, and therapeutics. However, the integration of imaging and therapy functionalities to a unimolecular framework remains a great challenge. Herein, a family of amphiphilic gemini iridium(III) complexes (GIC), Ir1-Ir6, are synthesized and characterized. The presence of quaternary ammonium (QA) groups endows GIC with adjustable water solubility and excellent self-assembly properties. Spectroscopic and computational results reveal that introducing QA groups into cyclometalating ligands (ĈN ligands) can overcome the drawback of aggregation-caused emission quenching and ensure Ir1-Ir3 with high emission intensity and excellent singlet oxygen (O) generation ability in aqueous media. Cell-based assays indicate that Ir3 shows higher cellular uptake efficiency and localizes specifically in the mitochondria, as well as exhibits outstanding photostability and an impressive phototoxicity index with satisfactory performance in mitochondria-targeted imaging and photodynamic therapy (PDT) of tumor cells. Furthermore, in vivo studies further prove that Ir3 possesses excellent antitumor activity and remarkably inhibits the growth of the HepG2 cells under PDT treatment. Consequently, this study presents a promising strategy for designing clinical application potential multifunctional iridium complex theranostic agents for mitochondria-targeted imaging and PDT in a single molecular framework.
10.1021/acsami.9b01205
Phosphorescent iridium(iii) complexes capable of imaging and distinguishing between exogenous and endogenous analytes in living cells.
Zhang Kenneth Yin,Zhang Taiwei,Wei Huanjie,Wu Qi,Liu Shujuan,Zhao Qiang,Huang Wei
Chemical science
Many luminescent probes have been developed for intracellular imaging and sensing. During cellular luminescence sensing, it is difficult to distinguish species generated inside cells from those internalized from extracellular environments since they are chemically the same and lead to the same luminescence response of the probes. Considering that endogenous species usually give more information about the physiological and pathological parameters of the cells while internalized species often reflect the extracellular environmental conditions, we herein reported a series of cyclometalated iridium(iii) complexes as phosphorescent probes that are partially retained in the cell membrane during their cellular uptake. The utilization of the probes for sensing and distinguishing between exogenous and endogenous analytes has been demonstrated using hypoxia and hypochlorite as two examples of target analytes. The endogenous analytes lead to the luminescence response of the intracellular probes while the exogenous analytes are reported by the probes retained in the cell membrane during their internalization.
10.1039/c8sc02984a
Triphenylamine-appended cyclometallated iridium(III) complexes: Preparation, photophysical properties and application in biology/luminescence imaging.
Liu Xicheng,Hao Hailong,Ge Xingxing,He Xiangdong,Liu Yifei,Wang Yan,Wang Haojie,Shao Mingxiao,Jing Zhihong,Tian Laijin,Liu Zhe
Journal of inorganic biochemistry
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.
10.1016/j.jinorgbio.2019.110757
Cyclometallated ruthenium catalyst enables late-stage directed arylation of pharmaceuticals.
Simonetti Marco,Cannas Diego M,Just-Baringo Xavier,Vitorica-Yrezabal Iñigo J,Larrosa Igor
Nature chemistry
Biaryls are ubiquitous core structures in drugs, agrochemicals and organic materials that have profoundly improved many aspects of our society. Although traditional cross-couplings have made practical the synthesis of many biaryls, C-H arylation represents a more attractive and cost-effective strategy for building these structural motifs. Furthermore, the ability to install biaryl units in complex molecules via late-stage C-H arylation would allow access to valuable structural diversity, novel chemical space and intellectual property in only one step. However, known C-H arylation protocols are not suitable for substrates decorated with polar and delicate functionalities, which are commonly found in molecules that possess biological activity. Here we introduce a class of ruthenium catalysts that display a unique efficacy towards late-stage arylation of heavily functionalized substrates. The design and development of this class of catalysts was enabled by a mechanistic breakthrough on the Ru(II)-catalysed C-H arylation of N-chelating substrates with aryl (pseudo)halides, which has remained poorly understood for nearly two decades.
10.1038/s41557-018-0062-3
Selective targeting of PARP-1 zinc finger recognition domains with Au(iii) organometallics.
Wenzel Margot N,Meier-Menches Samuel M,Williams Thomas L,Rämisch Eberard,Barone Giampaolo,Casini Angela
Chemical communications (Cambridge, England)
The binding of Au(iii) complexes to the zinc finger domain of the anticancer drug target PARP-1 was studied using a hyphenated mass spectrometry approach combined with quantum mechanics/molecular mechanics (QM/MM) studies. Competition experiments were carried out, whereby each Au complex was exposed to two types of zinc fingers. Notably, the cyclometallated Au-C^N complex was identified as the most selective candidate to disrupt the PARP-1 zinc finger domain, forming distinct adducts compared to the coordination compound Auphen.
10.1039/c7cc08406d
Rollover Cyclometalated Bipyridine Platinum Complexes as Potent Anticancer Agents: Impact of the Ancillary Ligands on the Mode of Action.
Babak Maria V,Pfaffeneder-Kmen Martin,Meier-Menches Samuel M,Legina Maria S,Theiner Sarah,Licona Cynthia,Orvain Christophe,Hejl Michaela,Hanif Muhammad,Jakupec Michael A,Keppler Bernhard K,Gaiddon Christian,Hartinger Christian G
Inorganic chemistry
Platinum-based anticancer coordination compounds are widely used in the treatment of many tumor types, where they are very effective but also cause severe side effects. Organoplatinum compounds are significantly less investigated than the analogous coordination compounds. We report here rollover cyclometalated Pt compounds based on 2,2'-bipyridine which are demonstrated to be potent antitumor agents both in vitro and in vivo. Variation of the co-ligands on the Pt(2,2'-bipyridine) backbone resulted in the establishment of structure-activity relationships. They showed that the biological activity was in general inversely correlated with the reaction kinetics to biomolecules as shown for amino acids, proteins, and DNA. The less stable compounds caused higher reactivity with biomolecules and were shown to induce p53-dependent DNA damage. In contrast, the presence of bulky PTA and PPh ligands was demonstrated to cause lower reactivity and increased antineoplastic activity. Such compounds were devoid of DNA-damaging activity and induced ATF4, a component of the endoplasmic reticulum (ER) stress pathway. The lead complex inhibited tumor growth similar to oxaliplatin while showing no signs of toxicity in test mice. Therefore, we demonstrated that it is possible to fine-tune rollover-cyclometalated Pt(II) compounds to target different cancer pathways and be a means to overcome the side effects associated with cisplatin and analogous compounds in cancer chemotherapy.
10.1021/acs.inorgchem.7b03210
Towards Novel Photodynamic Anticancer Agents Generating Superoxide Anion Radicals: A Cyclometalated Ir Complex Conjugated to a Far-Red Emitting Coumarin.
Novohradsky Vojtech,Rovira Anna,Hally Cormac,Galindo Alex,Vigueras Gloria,Gandioso Albert,Svitelova Marie,Bresolí-Obach Roger,Kostrhunova Hana,Markova Lenka,Kasparkova Jana,Nonell Santi,Ruiz José,Brabec Viktor,Marchán Vicente
Angewandte Chemie (International ed. in English)
Although cyclometalated Ir complexes have emerged as promising photosensitizers for photodynamic therapy, some key drawbacks still hamper clinical translation, such as operability in the phototherapeutic window and reactive oxygen species (ROS) production efficiency and selectivity. In this work, a cyclometalated Ir complex conjugated to a far-red-emitting coumarin, Ir -COUPY, is reported with highly favourable properties for cancer phototherapy. Ir -COUPY was efficiently taken up by HeLa cells and showed no dark cytotoxicity and impressive photocytotoxicity indexes after irradiation with green and blue light, even under hypoxia. Importantly, a clear correlation between cell death and intracellular generation of superoxide anion radicals after visible light irradiation was demonstrated. This strategy opens the door to novel fluorescent photodynamic therapy agents with promising applications in theragnosis.
10.1002/anie.201901268
Cyclometalated Gold(III) Complexes Containing N-Heterocyclic Carbene Ligands Engage Multiple Anti-Cancer Molecular Targets.
Fung Sin Ki,Zou Taotao,Cao Bei,Lee Pui-Yan,Fung Yi Man Eva,Hu Di,Lok Chun-Nam,Che Chi-Ming
Angewandte Chemie (International ed. in English)
Metal N-heterocyclic carbene (NHC) complexes are a promising class of anti-cancer agents displaying potent in vitro and in vivo activities. Taking a multi-faceted approach employing two clickable photoaffinity probes, herein we report the identification of multiple molecular targets for anti-cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and in vivo anti-tumor activities in mice bearing xenografts of human cervical and lung cancers. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB-1, accompanied by expected downstream mechanisms of action. Additionally, Pt and Pd analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal-NHC scaffold in the design of anti-cancer metal medicines with multiple molecular targets.
10.1002/anie.201612583
Cyclometalated Iridium(III)-Complex-Based Micelles for Glutathione-Responsive Targeted Chemotherapy and Photodynamic Therapy.
Xiang Huijing,Chen Hongzhong,Tham Huijun Phoebe,Phua Soo Zeng Fiona,Liu Jin-Gang,Zhao Yanli
ACS applied materials & interfaces
The integration of chemotherapy and photodynamic therapy (PDT) in a single delivery system is highly desirable for enhancing anticancer therapeutic efficacy. Herein, two cyclometalated Ir(III) complex-constructed micelles FIr-1 and FIr-2 were demonstrated for glutathione (GSH) activated targeted chemotherapy and PDT. The cyclometalated Ir(III) complexes were prepared by conjugating phosphorescent Ir(III) compounds with chemotherapeutic drug camptothecin (CPT) through GSH responsive disulfide bond linkages, and the Ir(III) complexes were then assembled with amphiphilic surfactant pluronic F127 via noncovalent encapsulation to afford micelles. The surfaces of the micelles were further decorated with folic acid as a targeting group. The micelles showed intense fluorescence that renders them with excellent real-time imaging capability. The release of free anticancer drug CPT from the micelles was realized through GSH-activated disulfide bond cleavage in tumor cells. In addition, the micelles were capable of generating singlet oxygen used for PDT upon visible light irradiation. On account of having folic acid targeting ligand, the micelles displayed greater cellular accumulation in folate receptor (FR) overexpressed HeLa cells than FR low-expressed MCF-7 cells, leading to selective cancer cell killing effect. As compared with solo therapeutic systems, the micelles with targeted combinational chemotherapy and PDT presented superior potency and efficacy in killing tumor cells at a low dosage. On the basis of these findings, the multifunctional micelles could serve as a versatile theranostic nanoplatform for cancer cell targeted imaging and combinational therapy.
10.1021/acsami.7b09506
Iridium(iii) complexes with five-membered heterocyclic ligands for combined photodynamic therapy and photoactivated chemotherapy.
Wu Na,Cao Jian-Jun,Wu Xiao-Wen,Tan Cai-Ping,Ji Liang-Nian,Mao Zong-Wan
Dalton transactions (Cambridge, England : 2003)
Organometallic iridium complexes have emerged as potent anticancer agents in recent years. In this work, three cyclometalated iridium(iii) complexes Ir1-Ir3 containing monodentate five-membered heterocyclic ligands have been synthesized and characterized. Upon visible light (425 nm) irradiation, the five-membered heterocyclic ligands will dissociate from the metal centre. Moreover, Ir1-Ir3 can also act as effective singlet oxygen photosensitizers. Thus, Ir1-Ir3 can exert their light-mediated activation of anticancer effects by dual modes including ligand exchange reactions and generation of singlet oxygen (O) upon visible light irradiation. Notably, Ir1 displays a high phototoxicity index of 61.7 against human cancer cells. Further studies show that light-mediated anticancer properties exerted by Ir1-Ir3 occur through reactive oxygen species (ROS) generation, caspase activation, and eventually apoptosis induction. Our study demonstrates that these complexes can act as novel dual-mode light-mediated anticancer agents.
10.1039/c7dt02477k
Guanidine-modified cyclometalated iridium(III) complexes for mitochondria-targeted imaging and photodynamic therapy.
Song Xing-Dong,Chen Bing-Bing,He Shu-Fen,Pan Nan-Lian,Liao Jia-Xin,Chen Jia-Xi,Wang Guan-Hai,Sun Jing
European journal of medicinal chemistry
PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425 nm. Notably, Ir1 conferred almost no dark toxicity (IC > 100 μM) to HepG2 cells, but the value decreased by 387-fold to 0.36 μM following 10 min of light irradiation (425 nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425 nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development.
10.1016/j.ejmech.2019.06.045
Cycloplatinated(II) Derivatives of Mercaptopurine Capable of Binding Interactions with HSA/DNA.
Aseman Marzieh Dadkhah,Aryamanesh Shiva,Shojaeifard Zahra,Hemmateenejad Bahram,Nabavizadeh S Masoud
Inorganic chemistry
In this study, two new bis-cyclometalated Pt(II) complexes, [Pt(C^N)(S^N)] [S^N = deprotonated 6-mercaptopurine (6-MP) and C^N = deprotonated 2-phenylpyridine (ppy), ; C^N = deprotonated benzo[]quinoline (bhq), ], are synthesized by the reaction of [PtR(SMe)(C^N)] (R = Me or -MeCH) with 1 equiv of 6-mercaptopurine (6-HMP) at room temperature. The complexes are fully characterized using H and C NMR spectroscopies, electrospray ionization mass spectrometry, and elemental analysis. Biomolecular interaction of complex with human serum albumin (HSA) is studied by fluorescence, UV-vis, and circular dichroism (CD) spectroscopies. The binding constants () and number of binding sites () are evaluated using the Stern-Volmer equation. The intrinsic fluorescence of protein is quenched by a static quenching mechanism, with a binding constant of ∼ 10 reflecting a high affinity of complex for HSA. The thermodynamic parameters (Δ°, Δ°, and Δ°) indicate that the interaction is a spontaneous process and hydrophobic forces play a main role in the reaction. The displacement experiments demonstrate that the reactive binding sites of HSA to complex are mainly located within its hydrophobic cavity in subdomain IIA (site I). Synchronous fluorescence spectra reveal that complex affected the microenvironment of tryptophan-214 residues in subdomain IIA of HSA. In the case of interaction of complex and HSA, because of overlapping of the emission spectra of complex with HSA, chemometric approaches are applied. The results indicate significant interaction between the tryptophan residue of HSA and complex . Moreover, the binding of Pt(II) complexes and causes a reduction of the α-helix content of HSA, as obtained by far-UV CD spectroscopy. The average binding distance () between Pt(II) complexes and HSA is obtained by Förster's resonance energy-transfer theory. Also, a molecular docking simulation reveals that π-π-stacking and hydrophobic interactions between these complexes and HSA are significant. Furthermore, the interactions of platinum complexes, , with calf-thymus DNA (CT-DNA) are investigated. The UV-vis results and ethidium bromide competitive studies support an intercalative interaction of both Pt(II) complexes with DNA. The new complexes are also screened for anticancer activities. The results show that complexes exhibit significant anticancer activity against the K562 (chronic myelogenous leukemia) cell line.
10.1021/acs.inorgchem.9b02696
Dual Functions of Cyclometalated Iridium(III) Complexes: Anti-Metastasis and Lysosome-Damaged Photodynamic Therapy.
Wang Fang-Xin,Chen Mu-He,Lin Yan-Nan,Zhang Hang,Tan Cai-Ping,Ji Liang-Nian,Mao Zong-Wan
ACS applied materials & interfaces
Four phosphorescent cyclometalated iridium(III) complexes containing benzimidazole moiety have been designed and synthesized. These Ir(III) complexes can effectively inhibit several cancerous processes, including cell migration, invasion, colony formation, and angiogenesis. Interestingly, they show a much higher singlet oxygen quantum yield in an acidic solution than in a neutral solution. Upon irradiation at 425 nm with low energy (1.2 J cm), they can induce apoptosis through lysosomal damage, evaluation of reactive oxygen species level, and activation of caspase-3/7. The highest phototoxicity index is >476, with almost no dark cytotoxicity observed for Ir4. Ir4 can also inhibit tumor growth effectively in nude mice in vivo after photodynamic therapy. An in vitro assay against 70 kinases indicates that maternal embryonic leucine zipper kinase (MELK), PIK3CA, and AMPK are the possible molecular targets. The half maximal inhibitory concentration of Ir4 toward MELK is 1.27 μM. Our study demonstrates that these Ir(III) complexes are promising anticancer agents with dual functions, including metastasis inhibition and lysosome-damaged photodynamic therapy.
10.1021/acsami.7b10258
Inhibition of autophagic flux by cyclometalated iridium(iii) complexes through anion transportation.
Chen Mu-He,Zheng Yue,Cai Xiong-Jie,Zhang Hang,Wang Fang-Xin,Tan Cai-Ping,Chen Wen-Hua,Ji Liang-Nian,Mao Zong-Wan
Chemical science
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 (Hbiim, ) or 2-(1-imidazol-2-yl)pyridine (Hpyim, ) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on Hbiim and Hpyim, and display pH-dependent phosphorescence and can specifically image lysosomes. Both and can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for . Mechanism investigation shows that and can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As and 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.
10.1039/c8sc04520h
NF-κB hijacking theranostic Pt(ll) complex in cancer therapy.
Zhu Yingzhong,Zhang Mingzhu,Luo Lei,Gill Martin R,De Pace Cesare,Battaglia Giuseppe,Zhang Qiong,Zhou Hongping,Wu Jieying,Tian Yupeng,Tian Xiaohe
Theranostics
Platinum complexes have been used for anti-cancer propose for decades, however, their high side effects resulting from damage to healthy cells cannot be neglected and prevent further clinical utilisation. Here, we designed a cyclometalated platinum (II) complex that can bind the endogenous nuclear factor-κB (NF-κB) protein. Employing detailed colocalization studies in co-culture cell line models, we show that by binding to NF-κB, the platinum (II) complex is capable of upregulated nuclear translocation specifically in cancer but not normal cells, thereby impairing cancer proliferation without disturbing healthy cells. In a murine tumour model, the platinum (II) complex prevents tumour growth to a greater extent than cisplatin and with considerably lower side-effects and kidney damage. Considering its weak damage to normal cells combined with high toxicity to cancer cells, this NF-κB-binding platinum complex is a potential anti-cancer candidate and acts to verify the strategy of hijacking endogenous trans-nuclear proteins to achieve cancer-cell specificity and enhance therapeutic indices.
10.7150/thno.30886
A new C,N-cyclometalated osmium(ii) arene anticancer scaffold with a handle for functionalization and antioxidative properties.
Ortega Enrique,Yellol Jyoti G,Rothemund Matthias,Ballester Francisco J,Rodríguez Venancio,Yellol Gorakh,Janiak Christoph,Schobert Rainer,Ruiz José
Chemical communications (Cambridge, England)
A series of six osmium(ii) complexes of the type [(η6-p-cymene)Os(C^N)X] (X = chlorido or acetato) containing benzimidazole C^N ligands with an ester group as a handle for further functionalization have been synthesized. They exhibit IC50 values in the low micromolar range in a panel of cisplatin (CDDP)-resistant cancer cells (approximately 10× more cytotoxic than CDDP in MCF-7), decrease the levels of intracellular ROS and reduce the NAD+ coenzyme, and inhibit tubulin polymerization. This discovery could open the door to a new large family of osmium(ii)-based bioconjugates with diverse modes of action.
10.1039/c8cc06427j
Fluorinated cyclometalated iridium(iii) complexes as mitochondria-targeted theranostic anticancer agents.
Ouyang Miao,Zeng Leli,Huang Huaiyi,Jin Chengzhi,Liu Jiangping,Chen Yu,Ji Liangnian,Chao Hui
Dalton transactions (Cambridge, England : 2003)
Six cyclometalated iridium(iii) complexes bearing different numbers of fluorine atoms were synthesized. These complexes demonstrated much better anti-proliferation activities towards five tumour cell lines than the widely used clinical chemotherapeutic agent cisplatin. Moreover, the anti-proliferation activities were correlated to the number of substituted fluorine atoms. Colocalization and inductively coupled plasma-mass spectrometry (ICP-MS) indicated that this series of complexes could penetrate cell membranes rapidly and preferentially target mitochondria. Manifesting high selectivity between tumour cells and normal cells and remarkable sensitivity to a cisplatin-resistant cell line (A549R), complex Ir6 was successfully developed as a novel anticancer agent (with IC values of 0.5 ± 0.1 μM for HeLa, 1.1 ± 0.2 μM for HepG2, 1.5 ± 0.3 μM for BEL-7402, 0.8 ± 0.1 μM for A549, and 0.7 ± 0.2 μM for A549R cell lines). Further mechanism studies including mitochondrial membrane potential depolarization and caspase 3/7 activation revealed that Ir6 induced apoptosis via mitochondrial pathways. These results demonstrated that complex Ir6 might be a promising candidate as a mitochondria-targeted theranostic anticancer agent.
10.1039/c7dt01043e
Cyclometalated Gold(III) Complexes Bearing DACH Ligands.
Gukathasan Sailajah,Parkin Sean,Awuah Samuel G
Inorganic chemistry
The synthesis of a novel class of cyclometalated gold(III) complexes supported by benzoylpyridine, benzylpyridine, and (1,2)-(+)-1,2-diaminocyclohexane (DACH) ligands, along with their crystal structures, is reported. These compounds provide a new scaffold to investigate biological properties of gold(III) complexes. The six complexes were prepared and characterized, following reactions of (C,N) cyclometalated gold(III) scaffolds, [Au(C^N)Cl] with DACH, which yielded a new series of cyclometaled gold(III), -, of the type [Au(C^NH)(DACH)] and the nitrogen-substituted cyclometalated Au(III), -, of the type [Au(C^N)(DACH)]. Antiproliferative activity of these complexes in a panel of cancer cells showed promising results with IC in the micromolar range and selectivity over normal epithelial cells, MRC5. Whereas shows minimal interaction with superhelical DNA except at high gold concentrations of 500 μM, complex does not show interaction even at 1000 μM. The complexes display significant uptake in OVCAR8 cancer cells within 200-1200 pmol/million cells with the exception of complex . Differential cellular uptake was observed for the complexes; for example, while and display significant uptake, showed minimal uptake. The compounds proved to be stable under physiological conditions and were minimally affected by either glutathione or sodium ascorbate. Cell cycle studies reveal a G1 arrest induced by representative complexes. The results reveal that enhanced Au(III) stabilization promoted by combined cyclometalated and DACH ligands may offer ligand tuning insights for novel anticancer drug design.
10.1021/acs.inorgchem.9b01031
New Variations on the Theme of Gold(III) CNN Cyclometalated Complexes as Anticancer Agents: Synthesis and Biological Characterization.
Carboni Silvia,Zucca Antonio,Stoccoro Sergio,Maiore Laura,Arca Massimiliano,Ortu Fabrizio,Artner Christian,Keppler Bernhard K,Meier-Menches Samuel M,Casini Angela,Cinellu Maria Agostina
Inorganic chemistry
A series of novel (CNN) cyclometalated Au complexes of general formula [Au(bipy-H)X][PF] (bipy-H = CNN cyclometalated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine) were prepared with a range of anionic ligands X in the fourth coordination position, featuring C (alkynyl)-, N-, O-, or S-donor atoms. The X ligands are varied in nature and include three coumarins, 4-ethynylaniline, saccharine, and thio-β-d-glucose tetraacetate, the tripeptide glutathione (GSH), and a coumarin-substituted amide derived from 4-ethynylaniline. The gold(I) complex [Au(CArNHCOQ)(PPh)] (HCArNHCOQ = N-(4-ethynylphenyl)-2-oxo-2 H-chromene-3-carboxamide) was also prepared for comparison. The new compounds were fully characterized by means of analytical techniques, including NMR, absorption, and emission spectroscopy. The crystal structures of three cyclometalated Au complexes and of the Au derivative were solved by single-crystal X-ray diffraction. The antiproliferative activity of the new Au cyclometalated derivatives was evaluated against cancer cells in vitro. According to the obtained results, only complexes 3-PF and 5-PF, featuring coumarins as ancillary ligands and endowed with high redox stability in solution, display antiproliferative effects, with 5-PF being the most potent, while all of the others are scarcely active to nonactive in the selected cell lines. In order to study the reactivity of the compounds with biomolecules, the interaction of complexes 3-PF and 5-PF with the protein cytochrome c and the amino acids cysteine and histidine was analyzed by electrospray ionization mass spectrometry (ESI MS), showing adduct formation only with Cys after at least 1 h incubation. Furthermore, the parent hydroxo complex [Au(bipy-H)(OH)][PF] (1OH-PF) was investigated in a competitive assay to determine the protein vs oligonucleotide binding preferences by capillary zone electrophoresis (CZE) coupled to ESI-MS. Of note, the compound was found to selectively form adducts with the oligonucleotide over the protein upon ligand exchange with the hydroxido ligand. Adduct formation occurred within the first 10 min of incubation, demonstrating the preference of 1OH-PF for nucleotides in this setup. Overall, the obtained results point toward the possibility to selectively target DNA with gold(III) organometallics.
10.1021/acs.inorgchem.8b02604
Cyclometalated iridium(iii) complexes induce mitochondria-derived paraptotic cell death and inhibit tumor growth in vivo.
He Liang,Wang Kang-Nan,Zheng Yue,Cao Jian-Jun,Zhang Ming-Fang,Tan Cai-Ping,Ji Liang-Nian,Mao Zong-Wan
Dalton transactions (Cambridge, England : 2003)
The development of iridium complexes as potent anticancer agents has received increasing attention in recent years. In this study, four cyclometalated Ir(iii) complexes with good photophysical properties and potent anticancer activity have been synthesized and characterized. They are taken up by human lung adenocarcinoma A549 cells very quickly and specifically target mitochondria. Mechanism studies reveal that one of them, namely IrM2, induces paraptosis accompanied by excessive mitochondria-derived cytoplasmic vacuoles. Meanwhile, IrM2 affects the ubiquitin-proteasome system (UPS) and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, IrM2 rapidly induces a series of mitochondria-related dysfunctional events, including the loss of mitochondrial membrane potential, cellular ATP depletion, mitochondrial respiration inhibition and reactive oxygen species (ROS) elevation. The rapid loss of mitochondrial functions, elevation of ROS and impairment of the UPS induced by IrM2 lead to the collapse of mitochondria and the subsequent cytoplasmic vacuolation before the cells are ready to start the mechanisms of apoptosis and/or autophagy. Among the ROS, superoxide anion radicals play a critical role in IrM2-mediated cell death. In vivo studies reveal that IrM2 can significantly inhibit tumor growth in a mouse model. This work gives useful insights into the design and anticancer mechanisms of new metal-based anticancer agents.
10.1039/c8dt00783g
Acridine-decorated cyclometallated gold(iii) complexes: synthesis and anti-tumour investigations.
Williams Morwen R M,Bertrand Benoît,Fernandez-Cestau Julio,Waller Zoë A E,O'Connell Maria A,Searcey Mark,Bochmann Manfred
Dalton transactions (Cambridge, England : 2003)
(C^N) and (C^N^C) cyclometalated Au(iii) represent a highly promising class of potential anticancer agents. We report here the synthesis of seven new cyclometalated Au(iii) complexes with five of them bearing an acridine moiety attached via (N^O) or (N^N) chelates, acyclic amino carbenes (AAC) and N-heterocyclic carbenes (NHC). The antiproliferative properties of the different complexes were evaluated in vitro on a panel of cancer cells including leukaemia, lung and breast cancer cells. We observed a trend between the cytotoxicity and the intracellular gold uptake of some representative compounds of the series. Some of the acridine-decorated complexes were demonstrated to interact with ds-DNA using FRET-melting techniques.
10.1039/c8dt02507j
Light-Up Mitophagy in Live Cells with Dual-Functional Theranostic Phosphorescent Iridium(III) Complexes.
Chen Mu-He,Wang Fang-Xin,Cao Jian-Jun,Tan Cai-Ping,Ji Liang-Nian,Mao Zong-Wan
ACS applied materials & interfaces
Phosphorescent Ir(III) complexes are expected to be new multifunctional theranostic platforms that enable the integration of imaging capabilities and anticancer properties. Mitophagy is an important selective autophagic process that degrades dysfunctional mitochondria. Until now, the regulation of mitophagy is still poorly understood. Herein, we present two phosphorescent cyclometalated iridium(III) complexes (Ir1 and Ir2) that can accumulate in mitochondria and induce mitophagy. Because of their intrinsic phosphorescence, they can specially image mitochondria and track mitochondrial morphological alterations. Mechanism studies show that Ir1 and Ir2 induce mitophagy by depolarization of mitochondrial membrane potential, depletion of cellular ATP, perturbation in mitochondrial metabolic status, and induction of oxidative stress. Moreover, no sign of apoptosis is observed in Ir1- and Ir2-treated cells under the same conditions that an obvious mitophagic response is initiated. We demonstrate that Ir1 is a promising theranostic agent that can induce mitophagy and visualize changes in mitochondrial morphology simultaneously.
10.1021/acsami.7b01735
Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes.
Chemical science
Mitochondria generate energy but malfunction in many cancer cells, hence targeting mitochondrial metabolism is a promising approach for cancer therapy. Here we have designed cyclometallated iridium(iii) complexes, containing one TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) spin label [CHNOIr·PF]˙ () and two TEMPO spin labels [CHNOIr·PF]˙ (). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units in . Both and showed bright luminescence with long lifetimes ( 35-160 ns); while displayed monoexponential decay kinetics, the biexponential decays measured for indicated the presence of more than one energetically-accessible conformation. This observation was further supported by density functional theory (DFT) calculations. The antiproliferative activity of towards a range of cancer cells was much greater than that of , and also the antioxidant activity of is much higher against A2780 ovarian cancer cells when compared with . Most notably was particularly potent towards PC3 human prostate cancer cells (IC = 0.53 μM), being 8× more active than the clinical drug cisplatin, and 15× more selective towards cancer cells normal cells. Confocal microscopy showed that both and localise in the mitochondria of cancer cells.
10.1039/c7sc03216a
Mixed-ligand iridium(iii) complexes as photodynamic anticancer agents.
Zheng Yue,He Liang,Zhang Dong-Yang,Tan Cai-Ping,Ji Liang-Nian,Mao Zong-Wan
Dalton transactions (Cambridge, England : 2003)
Many phosphorescent iridium complexes are potent candidates as photodynamic therapeutic agents. In this work, a series of mixed-ligand phosphorescent iridium complexes (Ir1: [Ir(L)(bpy)Cl](PF); Ir2: [Ir(L)(ppy)Cl](PF); Ir3: [Ir(L)(bpy)Cl](PF); Ir4: [Ir(L)(ppy)Cl](PF). L = 2,6-bis(2-benzimidazolyl)pyridine; bpy = 2,2'-bipyridine; L = 2,6-bis(1-methyl-benzimidazol-2-yl)pyridine; ppy = 2-phenylpyridine) have been synthesized and characterized. These complexes display high luminescence quantum yields and long phosphorescence lifetimes. All the complexes are resistant to hydrolysis in aqueous solutions, and can produce singlet oxygen (O) effectively upon irradiation. Ir1 and Ir2 show pH-sensitive emission properties. Interestingly, higher cellular uptake efficiency is observed for Ir2 and Ir4 with the cyclometalated ppy ligand in human lung adenocarcinoma A549 cells. Ir2 with pH-sensitive emission properties can selectively image lysosomes, and Ir4 can specifically target mitochondria. Both Ir2 and Ir4 exhibit potent photodynamic therapy (PDT) effects, with Ir2 displaying a higher phototoxicity index (PI) especially in A549 cells (PI > 54). Mechanism studies indicate that Ir2 and Ir4 can induce apoptosis through reactive oxygen species (ROS) generation and caspase activation upon visible light (425 nm) irradiation. As expected, Ir2 can damage lysosomes more effectively with a pH-sensitive singlet oxygen (O) yield, while Ir4 tends to impair mitochondrial function. Nevertheless, the practical application of Ir2 and Ir4 for PDT may be limited to superficial tumors due to the short excitation wavelength (425 nm). Our study gives insights into the design and anticancer mechanisms of new metal-based PDT anticancer agents.
10.1039/c7dt02273e
Cyclometalated iridium(III)-guanidinium complexes as mitochondria-targeted anticancer agents.
Song Xing-Dong,Kong Xia,He Shu-Fen,Chen Jia-Xi,Sun Jing,Chen Bing-Bing,Zhao Jin-Wu,Mao Zong-Wan
European journal of medicinal chemistry
Guanidinium-functionalized molecules are commonly studied for their use as pharmaceutically active compounds and drugs carriers. Herein, four cyclometalated iridium(III) complexes containing guanidinium ligands have been synthesized and characterized as potential anticancer agents. These complexes exhibit moderate antitumor activity in HeLa, MCF-7, HepG2, CNE-2, and A549 human tumor cells. Interestingly, all complexes showed higher cytotoxicity than cisplatin against a cisplatin-resistant cell line A549R, and less cytotoxicity on the nontumorigenic LO2 cells. Intracellular distribution studies suggest that these complexes are selectively localized in the mitochondria. Mechanism studies indicate that these complexes arrested the cell cycle in the G0/G1 phase and can influence mitochondrial integrity, inducing cancer cell death through reactive oxygen species (ROS)-dependent pathways.
10.1016/j.ejmech.2017.06.038
(C^N^C)Au complexes of acyclic carbene ligands: synthesis and anticancer properties.
Williams Morwen,Green Adam I,Fernandez-Cestau Julio,Hughes David L,O'Connell Maria A,Searcey Mark,Bertrand Benoît,Bochmann Manfred
Dalton transactions (Cambridge, England : 2003)
A series of cyclometallated gold(iii) complexes supported by pyrazine-based (C^N^C)-type pincer ligands were synthesized via two different pathways. Nucleophilic attack on the isocyanide complex [(C^N^C)Au(C[triple bond, length as m-dash]NCHMe-2,6)]SbF (2) gave [(C^N^C)Au(ACC)]SbF complexes with aniline (4·SbF), adamantylamine (5), glycine ethyl ester (6), alanine methyl ester (7), valine methyl ester (8), phenylglycine methyl ester (9) and methionine methyl ester (10) substituents (ACC = acyclic carbene). The pathway via isocyanide insertion into gold-amide bonds was also investigated; e.g. the reaction of xylyl isocyanide with (C^N^C)AuNHPh followed by protonation with HBF·OEt gave the acyclic carbene complex 4·BF. To the best of our knowledge compounds 6-10 represent the first examples of gold(iii) acyclic carbene complexes bearing amino acid functions. The compounds provide a versatile platform for the study of the anti-proliferative properties of gold(iii) complexes. Tests against human adenoma-type lung cancer cells identified 5, 6, 7 and 10 as particularly promising and demonstrate the synthetic flexibility of acyclic carbene complexes and the potential of that class of compounds for anticancer applications. Compared to cisplatin, amino ester-containing ACC complexes showed improved selectivity for MCF-7 breast cancer cells over that for healthy fibroblasts.
10.1039/c7dt02804k
Anticancer Cyclometalated Iridium(III) Complexes with Planar Ligands: Mitochondrial DNA Damage and Metabolism Disturbance.
Cao Jian-Jun,Zheng Yue,Wu Xiao-Wen,Tan Cai-Ping,Chen Mu-He,Wu Na,Ji Liang-Nian,Mao Zong-Wan
Journal of medicinal chemistry
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, G/G 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.
10.1021/acs.jmedchem.8b01704
Cyclometalated iridium(iii) N-heterocyclic carbene complexes as potential mitochondrial anticancer and photodynamic agents.
Li Yi,Liu Bing,Lu Xin-Ran,Li Meng-Feng,Ji Liang-Nian,Mao Zong-Wan
Dalton transactions (Cambridge, England : 2003)
Metal N-heterocyclic carbene (NHC) complexes represent a promising class of anticancer therapeutic agents. In this work, four cyclometalated iridium(iii) complexes (Ir1-Ir4) containing N-heterocyclic carbene ligands have been explored as mitochondrial anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, can quickly penetrate into A549 cells and are mainly localized in the mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by increasing the intracellular ROS level, reducing the mitochondrial membrane potential (MMP) and inducing apoptosis. Additionally, Ir1-Ir4 exhibited two orders of magnitude higher cytotoxicity upon irradiation at 450 nm LED light. Our work provides a strategy for the design of highly effective anticancer photodynamic therapeutic agent based phosphorescent iridium complexes.
10.1039/c7dt01903c
Alkyl chain-modified cyclometalated iridium complexes as tunable anticancer and imaging agents.
Laha Paltan,De Umasankar,Chandra Falguni,Dehury Niranjan,Khullar Sadhika,Kim Hyung Sik,Patra Srikanta
Dalton transactions (Cambridge, England : 2003)
Five mononuclear cyclometalated iridium complexes [1](PF6)-[5](PF6) were prepared using imidazole-based ligands of varying alkyl chain length. The complexes were characterised by various analytical techniques. The single crystal X-ray structures of [2](PF6), [3](PF6) and [4](PF6) revealed the expected distorted Oh structures around the metal centre; however, the chain length was found to play a crucial role in deciding the overall geometry. Theoretical investigations demonstrated that the HOMOs were mainly contributed by iridium and cyclometalated ligands, whereas the LUMOs were constituted from bpy/phen units. The complexes were found to be luminescent with a moderate emission quantum yield and lifetime in CH3CN. The in vitro growth inhibition assay of the complexes with a shorter alkyl chain ([4]+ and [5]+) displayed higher anticancer activity (IC50 < 0.5 μM) compared to the complexes with a longer alkyl chain ([1]+-[3]+) (IC50 < 30 μM) against human breast cancer (MCF-7) cells. The complexes [4]+ and [5]+ also displayed moderate cancer cell selectivity (∼3 times) over normal breast (MCF-10) cells. The flow cytometry assay and fluorescence microscopy analysis suggested that cellular accumulation was primarily responsible for the variation in anticancer activity. Interestingly, without possessing any anticancer activity or toxicity ((IC50 > 50 μM), the complex [1]+ mainly accumulated near the cell membrane outside the cell and displayed a clear image of the cell membrane. The light microscopy images and western blot analysis reveal that complex [4]+ induced combined apoptosis and paraptosis. Thus, tuning the anticancer activity and cellular imaging property mediated by the alkyl chain would be of great importance and would be useful in anticancer research.
10.1039/c8dt02461h
Influence of substituents on DNA and protein binding of cyclometalated Ir(iii) complexes and anticancer activity.
Mukhopadhyay Sujay,Singh Roop Shikha,Paitandi Rajendra Prasad,Sharma Gunjan,Koch Biplob,Pandey Daya Shankar
Dalton transactions (Cambridge, England : 2003)
Synthesis of terpyridyl based ligands 3-([2,2':6',2''-terpyridin]-4'-yl)-7-methoxy-2-(methylthio)-quinolone, (L1); 3-([2,2':6',2''-terpyridin]-4'-yl)-6-methoxyquinolin-2(1H)-one, (L2); 3-([2,2'-:6',2''-terpyridin]-4'-yl)-6-methylquinolin-2(1H)-one (L3) and cyclometalated iridium(iii) complexes [[Ir(ppy)L1]PF (1), [Ir(ppy)L2]PF (2), [Ir(ppy)L3]PF (3) (2-phenylpyridine = Hppy)] involving these ligands has been described. The ligands L1-L3 and complexes 1-3 have been thoroughly characterized by elemental analyses, spectral studies (IR, H, C NMR, UV/vis and fluorescence) ESI-MS, and the structure of 3 has been unambiguously authenticated by single crystal X-ray analyses. UV/vis, fluorescence and circular dichroism spectroscopic studies showed rather efficient binding of 1 with CT-DNA (calf thymus DNA) and BSA (bovine serum albumin) relative to 2 and 3. Molecular docking studies unveiled binding of 1-3 with minor groove of CT-DNA via van der Waal's forces and electrostatically with the hydrophobic moiety of HSA (human serum albumin). The ligands and complexes exhibited moderate cytotoxicity towards MDA-MB-231 (breast cancer cell line) and significant influence on HeLa (cervical cancer cell line) cells. Cytotoxicity, morphological changes, and apoptosis have been followed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay, Hoechst 33342/PI (PI = propidium iodide) staining, cell cycle analysis by FACS (fluorescence activated cell sorting), and ROS (reactive oxygen species) generation by DCFH-DA (dichlorodihydrofluorescein diacetate) dye. Confocal microscopy images revealed that the drug efficiently initiates apoptosis in the cell cytosol. The IC values showed superior cytotoxicity of 1-3 against the HeLa cell line relative to cisplatin, and their ability to induce apoptosis is in the order 1 > 2 > 3.
10.1039/c7dt01015j