- Email: [email protected]
Recent advances in endoplasmic reticulum targeting metal complexes
Coordination Chemistry Reviews 408 (2020) 213178
Contents lists available at ScienceDirect
Coordination Chemistry Reviews journal homepage: www.elsevier.com/locate/ccr
Review
Recent advances in endoplasmic reticulum targeting metal complexes Can Huang a, Tingxuan Li a, Jiayu Liang a, Huaiyi Huang a,⇑, Pingyu Zhang b,⇑, Samya Banerjee c,⇑ a
School of Pharmaceutical Science (Shenzhen), Sun Yat-sen University, Guangzhou 510275, PR China College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen 518060, PR China c Institute of Inorganic Chemistry, Georg-August-Universität Göttingen, Tammannstr. 4, 37077 Göttingen, Germany b
a r t i c l e
i n f o
Article history: Received 8 September 2019 Accepted 2 January 2020
Keywords: Endoplasmic reticulum Metal complexes Fluorescence imaging Anticancer Endoplasmic reticulum stress
a b s t r a c t Over the last few years, significant attention has been paid to develop metal complexes for different cellular organelle specific imaging agents and to achieve organelle targeting anticancer drugs. Endoplasmic reticulum (ER), the largest organelle in human cells is largely responsible for the synthesis of protein, lipid and hormones. ER is also crucial for protein folding and detoxification of cells. Cellular stress within the ER generates an ER stress leading to cell death. Several naturally occurring anticancer agents have been reported to induce ER stress response as a main mechanism of cell death. In spite of these facts, ER targeting synthetic small molecules are rare in the literature and research on the development of ER targeting metal complexes is only a few years old. In this review, we have discussed about the recent development in the ER targeting metal complexes which are used as ER imaging and ER targeting anticancer agents with detailed mechanism of action. Moreover, we also discussed about the difficulties and their possible solution in order to translate these kinds of molecules to clinic. Ó 2020 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Endoplasmic reticulum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Methods for detecting ER localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Metal complexes for ER stress generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Metal complexes for ER targeting anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.1. 3rd row transition metal complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.2. 2nd row transition metal complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.3. 1st row transition metal complexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 6. Metal complexes for probing ER polarity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 7. Future direction and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1. Introduction With around 8.2 million deaths and 14 million new diagnoses in 2012, cancer is the main cause of death worldwide [1]. Death caused by cancer is predicted to increase up to 70% by 2030 [1]. But, the commonly used Pt based chemotherapeutics are now ⇑ Corresponding authors. E-mail addresses: [email protected] (H. Huang), [email protected]. cn (P. Zhang), [email protected] (S. Banerjee). https://doi.org/10.1016/j.ccr.2020.213178 0010-8545/Ó 2020 Elsevier B.V. All rights reserved.
not effective for various cancers [1,2]. These chemotherapeutics also suffer from several undesirable side effects and drug resistance [1,2]. For this reason, new cancer drugs with novel mechanisms are one of the high-priority needs to save life, reduce drugs’ side-effects and overcome acquired drug resistance. Metal complexes have a great potential as next generation anticancer agents and can increase the effectiveness of chemotherapeutic drugs [3]. The concepts of metal based anticancer drugs with new mechanism of actions are only a few years old and need to be explored with more details [1–14].
2
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 1. Structures of the gliberclamide and commercial organic ER-Tracker.
Fig. 2. Structure of the complex 1 (a) and its ability to generate perinuclear vacuole (b). The figures are reproduced from Ref. [53] with the permission.
For a successful drug design, understanding the target sites in cells and effects on biological pathways are of high importantance. Strategies for the discovery of next-generation metalloanticancer drugs with novel mechanisms of action include targeting cellular organelles. Over the last few years, designing molecules to target different cellular organelles such as nucleus, mitochondria and lysosomes have attracted significant attention to develop specific cellular organelle imaging agents and nextgeneration organelle targeting cancer therapy [15–24]. Metal complexes often exhibit significant larger Stokes shifts compared to organic organelle targeting dyes. The small Stokes shifts of organic dyes can lead to significant self-quenching (homo trans-
Fig. 3. (a) The ER stress inducing gold(III)–phosphine complex viz., [(C,N,C)2Au2(mdppp)](CF3SO3)2 (2) (b) Mechanism of anticancer action of 2 by inducing ER stress. The figures are adopted from Ref. [57] with the permission.
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
3
Fig. 4. Structure and mechanism of action of ER stress inducing organoruthenium complexes namely RAS-1H (3) and RAS-1 T (4). The figure is adopted from Ref. [58] with the permission.
Fig. 5. The ER stress inducing Ru(II)-arene based complexes (5–8) of Schiff-Base containing iminoquinoline chelate ligands and their mode of ER stress induction. The figure is adopted from Ref. [59] with the permission.
fer) when the dyes are at high concentration or when a biomolecule is multiply labeled with the dye [15]. The positive charge of metal complexes can enhance water solubility. Additionally,
metal complexes exhibit better photo- and chemo-stability during long-term light irradiation, allowing intracellular tracking the physiological dynamic of organelles [25].
4
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 6. Three FDA-approved drugs for various diseases are also known as ER stress inducer and are currently under reinvestigation as anticancer agents.
The endoplasmic reticulum (ER) is an absolutely necessary cellular organelle [26–34] and ER targeting anticancer metal complexes are of recent origin. Small molecules induced stress in the ER (termed as ER Stress) to effect cell death [36–39]. The interaction of small molecules with the ER and subsequent generation of ER stress can be studied by techniques such as: (i) transmission electron microscopy (TEM) which utilizes high energy electrons to provide morphological information of the stressed ER or cells; (ii) fluorescence microscopy, that uses ER staining dyes to study the morphological changes of the stained ER during ER stress generation; (iii) microarray analysis for genes expression study; (iv) reserve transcriptase-polymerase chain reaction to study RNA expression levels after ER stress induction and (v) western blot analysis, an antibody based technique, of different ER stress biomarkers such as CHOP, IRE1a, phopho-IRE1a, peif2a, PERK
and phospho-PERK to determine their levels after the generation of ER stress. In this review, we have discussed the advancements of the ER targeting and ER stress generating metal complexes for anticancer application in the light of recent literatures.
2. Endoplasmic reticulum Compared to the other subcellular targets, endoplasmic reticulum (ER) is not well explored as the target for anticancer agents, due to its complex role in human cells [26]. The largest organelle in human cells, endoplasmic reticulum has a crucial role in the synthesis of protein, lipid and hormones [26–31]. ER is also important for cellular sensing, signaling and detoxification, and is of high importance for protein folding and post-translational modifica-
Fig. 7. (a) The ER targeting luminescent platinum(II)-carbene complexes (9–17) (b) ER localization of complex 11 as was evident from the co-staining with ER tracker. The figures are reproduced from Ref. [61] with the permission.
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
5
Fig. 8. Pathway of cell death induced by the ER targeting complex 11. The figure is reproduced from Ref. [61] with the permission.
Fig. 9. (a) The ER targeting anticancer red emissive Ir(III) complexes (18–20). (b) ER localization of complex 20 as was evident from the co-staining with ER tracker. The figures are reproduced from Ref. [62] with the permission.
tions of proteins, contributing about 30% of the total proteome [32–34]. Any perturbation of the ER’s protein-folding ability leads to the generation of ER stress and causes cell death [35–39]. For this hitherto less explored mechanism of cell death, selective disruption of ER function by ER-targeting molecules in cancer cells has opened up a gate of next-generation anticancer drug development [1,40–42]. In this direction, a very recent trend is the devel-
opment of synthetic ER targeting metal complexes for ER stress induction in cancer cells, leading to cell death. Metal complexes, with tuneable coordination geometry, are very attractive small molecules to achieve tumor targeting anticancer activity or selectivity towards the ER. The metal complexes have three main advantages over the organic small molecule viz., (i) attachment of pendent tumor targeting/recognizing moieties on the ligand
Fig. 10. The ORTEP diagram of complex 21 with 50% thermal ellipsoids and all atoms labeling. The figures are reproduced from Ref. [63] with the permission.
6
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 11. (a) The ER targeting bridged dinuclear Ir(III) complexes 22 and 23. (b) Live HeLa cells imaging showing the ER localization of complex 23. The figures are reproduced from Ref. [64] with the permission.
does not require very trivial and sophisticated synthetic route (ii) just by changing the ligand systems or attaching hydrophilic/hydrophobic group to the ligand, the liphophilicity can be easily tuned to direct the complex to a particular cellular organelle (iii) an emissive pendent moiety can be attached very easily to track the complex in cells by microscopy. Moreover, dual action metal complexes for imaging and therapy are easy to synthesize than organic small molecules with the same functions. Generation of ER stress is known to alter the ER polarity and irregular ER morphology [43,44]. To visualize such changes in live cells, design and synthesis of ER imaging agents is becoming a hot area of research for many active research groups across the globe [45–49]. In this minireview, we focus on the recent development of metal complexes as ER imaging agents as well as ER targeting anticancer agents with detailed mechanism of drug action.
include ER-TrackerTM Blue-White DPX (Fig. 1) with a broad emission between 430 and 640 nm. However, as shortcoming for other the organic dyes, the fluorescence signal sometimes significantly reduced after fixing the cells or under continuous irradiation, limiting their application for cellular imaging rather than the important long-term organelle dynamic tracking.
3. Methods for detecting ER localization With the development of laser scanning confocal microscopy, the cellular organelle in live cells can now be visualized via commercial organelle-targeting agents. Despite a large majority of fluorescent probes produced, there are limited reports for ER targeting, partly due to the challenge in controlling ER selectivity [50]. The commercial fluorescent dyes ER-Tracker TM Green and ERTrackerTM Red both contain the ‘‘glibenclamide” segment to target sulphonylurea receptors of ATP-sensitive K+ channels [51] that are prominent on ER (Fig. 1) [52]. Moreover, fluorescence dyes labelled calreticulin, which is abundant in non-muscular tissues and the principal calcium-binding proteins in the ER can also be used for ER immunofluorescence. However, it is important to point out that ‘‘glibenclamide” segment of the commercial fluorescent dyes for ER imaging may perturb other cellular activity during imaging upon long exposure. Few other ER staining organic dyes are also commercially available. DiOC6(3) (Fig. 1) is a cell permeable, green fluorescent, lipophilic dye traditionally used for the ER imaging. However, high concentration of working solution of DiOC6(3) results in toxicity to living cells. Other commercial organic dyes for ER imaging
Fig. 12. The ER Localized Ir(III) based photosensitizer (24–27) as efficient PDT agents. The figure is reproduced from Ref. [65] with the permission.
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
7
Fig. 13. (a) The ER targeting complex, 26, induced dimerization of biotin-phenol (BP) in presence of 100 mW cm2 light studied by MALDI-MS. (b) Cartoon representation showing the procedure of detection of 26 induced photo-oxidized proteins of by mass spectral analysis. The figures are reproduced from Ref. [65] with the permission.
The co-localization assay with ER imaging dyes, or dyes labeledproteins can be used to confirm the ER localization of the metal complexes. Transition metals such as iridium, gold are exogenous elements within the living cells. The amount of exogenous metals in the cells can be quantified by inductively coupled plasma mass spectrometry (ICP-MS). 4. Metal complexes for ER stress generation The first breakthrough came in 2013. Che and colleagues reported an anticancer active ytterbium(III) porphyrin complex viz., [Yb(Por)(m-OH)]2 [Por = octaethylporphyrinato (1)] with sub-micromolar half maximal inhibitory concentration (IC50) (Fig. 2a) [53]. The complex exists as a hydroxyl-bridged dimer, [Yb2(Por)2(m-OH)2] in solid state, but as monomer viz., [Yb(Por) (DMSO)(OH)(OH2)] in H2O/DMSO solution. This complex induced apoptotic death of cancer cells and interestingly before the apoptosis generated perinuclear vacuole (Fig. 2b). While most of anti-
cancer lanthanide complexes are known to target DNA for their anticancer effect [54–56], this complex showed anti-cancer effect which was highly associated with the ER stress pathway as was confirmed by microarray analysis, connectivity map analyses and western blotting analysis. In the same year, they also reported a stable gold(III)–phosphine complex viz., [(C,N,C)2Au2(m-dppp)](CF3SO3)2 [2, HC,N, CH = 2,6-diphenylpyridine; dppp = bis(diphenylphosphino)pro pane] with excellent in-vitro cytotoxicity against a range of cancers and significant inhibition of tumor growth in nude mice and beagle dogs (Fig. 3a) [57]. This complex is a potent inhibitor of thioredoxin reductase (TrxR) and simultaneously induced ER stress. They also identified TRAIL, a ligand for death receptor 5 (DR5), as a synergistic agent for the anti-cancer activity of 2. Taken together, the reasons behind the excellent anticancer activity of 2 were the TrxR inhibition, ER stress generation and a death-receptor-dependent apoptosis via the activation of the apoptotic cascade (Fig. 3b).
8
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
platin, and 5-fluorouracil. The p-acidity of the chelating ligand was found to alter the stability, ROS generation ability and ER stress induction efficiency of the complex. Moreover, this p-acidity played an important role in the switching between ROS-induced ER stress activation and ROS-independent ER stresses activation. These complexes have the potential as anticancer agents for the drug resistance cancers and suitable tuning of the ligand was expected to improve the drug efficacy. Moreover, auranofin, nelfinavir and sorafenib (Fig. 6), the FDAapproved drugs for various diseases are also known as ER stress inducer and are currently under reinvestigation as anticancer agents [60].
5. Metal complexes for ER targeting anticancer activity 5.1. 3rd row transition metal complexes
Fig. 14. Mechanistic pathway for the photoactivated anticancer activity of complexes (24–27). The figure is reproduced from Ref. [65] with the permission.
Multidrug resistance (MDR) is one of the major problems in cancer therapy to overcome [1–14]. MDR generally resist malignant cells to cellular apoptosis. Most of the current cancer drugs act via apoptosis and are suffering from the drug resistance issue. In order to combat this problem, compounds that can induce other forms of programmed cell death are of current interest to bypass MDR. In this line of research, W. H. Ang and C. Gaiddon and other coworkers in 2016 reported two organo-ruthenium complexes namely RAS-1H (3) and RAS-1T (4) (Fig. 4) which induced non-apoptotic programmed cell death by ER stress pathways [58]. Although the complexes shared similar chemical structure but their modes of drug action were completely different. RAS-1T (4) induced ROS-mediated ER stress and thereafter XBP-1s splicing while the mechanism of action for RAS-1H (3) was ROSindependent and via XBP-1s splicing. Both of them were more effective against apoptosis-resistant cells while comparing to oxaliplatin. For the first time they opened up the lock for metal complex induced ER stress modulation to bypass apoptosis related resistance. Another report from Prof. W. H. Ang laboratory presented a new class of ER stress-inducing and highly cytotoxic Ru(II)-arene based complexes (5–8) of Schiff-Base containing iminoquinoline chelate ligands (Fig. 5) [59]. The complexes showed high efficacies towards both the drug-sensitive (ovarian cancer; A2780, gastric cancer; AGS, colorectal cancers; HT29 and HCT116) and cisplatin resistant (ovarian cancer; A2780cisR and colorectal cancers; HCT116 p53/) cancer types with nano molar IC50 values. The complexes were also active against multidrug-resistant colorectal cancer TC7 with micromolar IC50 values. Interestingly, the complexes were multiple times more potent than the clinical drugs cisplatin, oxali-
A report from the C.M. Che group in 2013 demonstrated the ability of a series of luminescent platinum (II) complexes (9–17) (Fig. 7a) containing bidentate N-heterocyclic carbene ligands for ER targeting photo-toxicity [61]. The complex 11 selectively localized in the ER which was proved by co-staining with ER-TrackerTM (Fig. 7b). The complexes showed potent anticancer activity against a wide range of cancer cell lines including HeLa, breast cancer (MCF-7), nasopharyngeal carcinoma (HONE1, SUNE1), lung carcinoma (HCC827, H1975), hepatocellular carcinoma (HepG2). Complex 11 was the highly active in this series with the IC50 values ranging from 0.45 mM to 1.59 mM. Interestingly 11 was 5.3–60 times more potent than cisplatin against the above-mentioned cell lines and was significantly less toxic to non-tumorigenic liver cell line (MIHA). Complex 11 also generated ER stress after accumulating in the ER as was probed by the dramatic up-regulation of the expressions of phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK), phosphorylated eukaryotic initiation factor 2a (eIF2a) and C/EBP homologous protein (CHOP). Moreover, 11 induced mitochondrial dysfunction and ultimately produced apoptosis as the mode of cell death. The activity of the complexes 9–17 was further enhanced by 5.6- to 33.1-fold upon irradiation (2.8 mWcm2 visible light for 1 h) compared to that in the dark. The complex 11 generated 1O2 very efficiently in the ER on visible light irradiation. The generated 1O2 caused ER stress which leads to photo-cytotoxicity. Overall, the reported complexes specifically selectively targeted the ER and induced mitochondrial dysfunction and ER stress, which ultimately lead to the cell apoptosis (Fig. 8). A few months later, Cao et al. reported synthesis of a series of red emissive cationic iridium(III) complexes viz., [Ir(ppy)2(N,N)]+ (ppy: 1-phenyl-pyridine; N,N = 2,20 -bipyridine (18) or phenanthroline (19) or 4,7-diphenyl-1,10- phenanthroline (20)) (Fig. 9a) [62]. The highly hydrophobic complex 20 showed highest quantum yields, lipophilicity and intracellular uptake. All these complexes were effective as anticancer agents against HeLa, MCF-7 and A549 cells. Complex 20 was the most cytotoxic among these complexes and was also much efficient than that of cisplatin under identical experimental conditions (24 h drug incubation). Complex 20 was accumulated mostly to the ER (Fig. 9b) and caused ER stress in cancer cells. Notably, for the first time, the authors have tried to draw a co-relation between ER localization with the physiochemical properties of the complex and have mentioned the strong hydrophobic nature as the main factor that might drive the accumulation of 20 in the ER. Complex 20 induced stress in the ER and during the stress, fast cytosolic release of calcium from the stressed ER was found to disturb the mitochondrial morphology and function and ultimately initiate cellular apoptosis via the intrinsic pathway. In this context, a better understanding of the cell death mechanism would be helpful for structure-activity optimiza-
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
9
Fig. 15. (a) The cyclometallated Ir(III) complexes (28–30) for ER targeting photocytotoxicty. (b) Confocal images showing the intracellular Ca2+ level at differentconcentrations of complex 29. BF: Bright field; Scale bars: 20 lm. The figure is reproduced from Ref. [67] with the permission.
tion to develop next generation ER targeting Ir(III) based cancer therapeutics. In 2014, S. Mandal and co-workers reported a very similar ER targeting heteroleptic phosphorescent cyclometalated Ir(III) complex (21) with the same [(ppy)2Ir(pipt)] (pipt = 2-phenyl-(1H-imi dazo[4,5–f][1,10]-phenanthroline) co-ordination core site (Fig. 10) [63]. The complex exhibited high luminescence in the endoplasmic reticulum and on 405 nm light irradiation for 1 h gave membrane blebbing and cell death in MCF-7 cancer cells by generating ROS. Interesting authors proved that the indication of 20 -OH group in the phenyl ring of complex 21 with the imidazolyl N is very crucial for its ER localization and luminescence. T. F. Anjong and co-workers reported two Ir(III) based bridged (by conjugated aromatic ligand, tppz) dinuclear complexes viz., [(bhq)2Ir(tppz)Ir(bhq)2] (22) and [(ppy)2Ir(tppz)Ir(ppy)2] (23) where bhq is benzo(h)quinolone, ppy is phenyl-pyridine and tppz istetrapyrido-[3,2-a:20 ,30 -c:300 ,200 -h:2000 ,3000 -j]phenazine (Fig. 11a) [64]. The complexes effectively interacted with liposomes indicating their possible intracellular localization within lipid-rich organelles in live cells. Complex 23 interacted with the liposomes more strongly than complex 22. The complex was cytotoxic to the HeLa cervical cancer cells with the IC50 of 15.6 mM for 22 and 18.2 mM for 23 respectively upon 24 h incubation. The photostable complexes showed primarily ER localization in the HeLa cells indicating their possible applications as imaging agent and ER tracker in the live cells (Fig. 11b).
In 2018, Tae-Hyuk Kwon and co-workers designed and synthesized ER Localized Ir(III) based photosensitizer (24–27) as efficient PDT agents (Fig. 12) [65]. The complexes were designed via ligand tuning to achieve efficient ROS generation, accounted for appropriate energy levels and high emission quantum yields. The ER localized complexes even at a low concentration (2 lM) and very less light energy (1 Jcm2) triggered cancer cells death by spatiotemporal cell killing activity via efficient ROS generation. Complex 26 also showed potent anticancer activity by 860 nm two photon irradiation. The complexes damaged protein via both protein crosslink formation and protein oxidation. Photo-induced protein cross-links formation by metal complexes commonly occurred through coupling with the tyrosyl radicals, present over the protein surfaces. They employed a tyrosine residue containing biotinphenol (BP) to confirm the covalent dimerization by in vitro cross-linking upon photoactivation of the complexes. Matrixassisted laser desorption ionization mass spectrometry (MALDIMS) was used to study the BP cross-links formation, induced by the complexes (Fig. 13a). They mainly focused on the proteins modifications that contain oxidized methionine residues such as mono-oxidized methionine (O-Met) and used methionine sulfoxide antibody to identify such protein modification (Fig. 13b). Proteins damage in live cells was mainly in proteins near to the ER and mitochondria. Mitochondria and the ER are within a few nanometers distance at the ER- mitochondria-tethered junction [66]. As the complexes generate 1O2 on photo-irradiation in the
10
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 16. (a) The ER targeting cytotoxic binuclear Ru(II) complex 31. (b) Co-staining of MCF-7 cells with complex 31 and ER-localized calnexin protein (visualized by immunofluorescence; FITC-conjugated secondary antibody). The figures are reproduced from Ref. [68] with the permission.
Fig. 17. (a) The complex 32. (b) Localization of the complex 32 in the ER and Lysosomes. The figures are reproduced from Ref. [69] with the permission.
ER, a fraction of generated 1O2 can reach the mitochondrial space from the ER via the outer mitochondrial membrane and ultimately damage both proximal ER and mitochondrial proteins. Complex 23 induced aggregation of mitochondria, a signature of mitochondrial pathway of apoptosis. Overall, these ER targeting Ir(III) based com-
plexes efficiently acted as a photosensitizer for PDT application through effective protein disablement (Fig. 14). Recently in 2019, Chao et al., developed three cyclometallated Ir (III) complexes (28–30) for ER-targeted PDT with a gradually enhanced conjugation area in the ligand (Fig. 15a) [67]. The
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
11
A549R, L02, HeLa, HepG2). Interestingly, their singlet oxygen quantum yields and cytotoxicity increase with the enhancement of the conjugation in ligands. Very interestingly, the photo-induced ERstress leads to the efflux of Ca2+ from the ER in A549 cells (Fig. 15b). They have confirmed the release Ca2+ from the ER using Fluo-4 AM as the fluorogenic probe. Fluo-4 AM, after internalization in the cells converted to Fluo-4 via hydrolysis by the intracellular esterase. This Fluo-4 on binding to the released and free Ca2+ turns its green fluorescence on. As depicted in Fig. 15, the green fluorescence intensity of Fluo-4 increases with the gradual enhancement complex 29 concentrations, indicating a significant increase of intracellular Ca2+ level. No significant fluorescence was observed under the dark which indicated light activation was the triggering factor for the anticancer activity of this complex. As the ER is an indispensable organelle for synthesis and export of proteins and membrane lipids, any interference to the ER redox signaling leads to the apoptosis via ER-stress. Considering this, all these above reports indicate the promising potential of 5d complexes as the ER targeting next generation chemo/photochemotherapeutics for the effective treatment of cancer. 5.2. 2nd row transition metal complexes
Fig. 18. (a) Oxovanadium(IV) complex 33 which localized in the ER. (b) Photoinduced apoptotic cell death by ER targeting complex 33. Coordinate (1) represents percentage of live cells; Coordinate (2), percentage of early apoptotic cells; Coordinate (3), percentage of late apoptotic cells and Coordinate (4), percentage of necrotic cells. The figures are reproduced from Refs. [70,71] with the permission.
complexes showed preferential uptake and localization in the ER and induced apoptosis on PDT treatment (405 nm, 6 Jcm2) via an ER stress mechanism in different cancer cell lines (A549,
Thomas et al., reported a highly lipophilic and ER-targeting dinuclear ruthenium(II) complex, [{Ru(DIP)2}2(tpphz)]4+ (31) where DIP is 4,7-diphenyl-1,10-phenanthroline and tpphz is tetrapyrido [3,2-a:20 ,30 -c:300 ,200 -h:2000 ,3000 -j]phenazine (Fig. 16a) [68]. They confirmed the ER localization by the immunofluorescent co-staining with the antibodies for ER specific proteins such as calnexin (Fig. 16b). In order to explain the affinity of this complex for ER, they have proposed that due to the strong lipophilic character, the complex interact very strongly with the lipid-dense organelle, the ER. This explanation is in the same direction with what Cao et al has proposed and indicates that hydrophobicity and lipophilicity of a molecule may have a direct relation with its ER affinity. This complex also demonstrated marked cytotoxicity towards both MCF-7 and HeLa cell lines. 5.3. 1st row transition metal complexes Arion and co-workers reported a green fluorescent dimeric zinc complex, [Zn2(MeOOCLCOO)(CH3COO)2] (32) (Fig. 17a) (MeOOCLCOO = Diethyl-2,20 -((3-(((5H-indolo[3,2–c]quinolin-6(11H)-ylidene)-hyd razono)methyl)-2-hydroxy-5 methylbenzyl)azanediyl)-diacetate) which was cytotoxic to the A549 (nonsmall cell lung carcinoma),
Fig. 19. (a) The ER targeting photocytotoxic Fe(III) complexes 34 and 35. The figures are reproduced from Ref. [72] with the permission.
12
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 20. The ER targeting biotinylated zinc(II) phthalocyanine (36). The figure is reproduced from Ref. [73] with the permission.
Fig. 21. (a) Representation of pH dependent sulphonamide ligation in europium complex 37. (b) Changes in the Eu emission intensity ratio and excited state lifetimes (t) for 37 as a function of pH. The figures are reproduced from Ref. [76] with the permission.
CH1 (ovarian carcinoma), and SW480 (colon adenocarcinoma) in micromolar concentrations [69]. Very interestingly this complex was localized both in the ER and lysosomes (Fig. 17b). The oxovanadium(IV) vitamin-B6 Schiff base complex of formulation [VO(HL1)(acdppz)]Cl (33) (acdppz is 11-(9-acridinyl) dipyrido[3,2-a:20 ,30 -c]phenazine and H2L1∙HCl is 3-hydroxy-5-(hy droxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyri din-1-ium chloride) reported by Chakravarty and co-workers
showed tumor selective ER targeting photocytotoxicity (Fig. 18a) [70,71]. The complex was highly stable in cellular medium and was photo-stability under 400–700 nm visible light irradiation. Preferential uptake of this complex to MCF-7 and HeLa cancer cells over MCF-10A normal cells was due to the vitamin-B6 transporting membrane carrier (VTC) mediated entry of the complex. The complex with acdppz moiety acted as an excellent photosensitizer for photodynamic therapy (PDT) with nano-molar IC50 upon light irra-
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
diation (400–700 nm, 1 h) while was not toxic even treated with up to 40 mM of 33 in the dark and also to the normal MCF-10A cells both upon light irradiation and under the dark. Importantly, photocytotoxicity of the complex was 10 times higher compared to the FDA approved drug PDT drug PhotofrinÒ. Fluorescence microscopy revealed that the complex localized in the ER and thereafter generates reactive oxygen species (ROS) upon photo-irradiation. The ER localization of the complex and generation of ROS resulted in cell apoptosis possibility by triggering ER stress response (Fig. 18b). Another report from the same group indicated the ability of Iron (III) complexes of vitamin B6 with the general formulae [Fe(B)(L)] NO3 (34, 35) (B: (anthracen-9-yl)-N,N-bis((pyridin-2-yl)methyl)m ethanamine in 2; (pyren-1-yl)-N,N-bis((pyridin-2-yl)-methyl)met hanamine in 3 and H2L is 3-hydroxy-5-(hydroxymethyl)-4-(((2-h ydroxyphenyl)imino)methyl)-2-methylpyridine) as ER targeting visible light photocytotoxicity agents for PDT application (Fig. 19) [72]. Complexes were 10-fold more potent as anticancer agents when irradiated with visible light of 400–700 nm for 1 h than that of the dark. A report by L. Yu et al., in 2018 showed the potential of a glutathione (GSH)-responsive biotinylated zinc(II) phthalocyanine as a targeted photodynamic therapeutic agent [73]. The biotinylated zinc(II) phthalocyanine (36) (Fig. 20) localized in the ER and its fluorescence and singlet oxygen generation ability were silenced due to presence of 2,4-dinitrobenzenesulfonyl moiety. The complex shows ca. 3 times higher uptake in human hepatocarcinoma cells (HepG2 cells; known for higher biotin receptor expression) compared to the Chinese hamster ovary (CHO cells with lower biotin receptor expression), indicating the tumor selective nature of the complex. Under high GSH concentration, the complex restored its
13
photosensitizing ability in phosphate buffered saline and inside cancer cells. In HepG2 cells, it gave a nanomolar photocytotoxicity (IC50 = 0.1 mM; 2 h incubation, 20 min illumination, Light source: 300 W halogen lamp, Newport, cut-on 610 nm, total fluence: 21.6 Jcm2) by generating ER stress. All these 3d metals-based ER targeting anticancer complexes indicate the future potential of 3d metal complexes for the next generation ER targeting anticancer drug development. As most of the 3d metals are essential elements of human life, 3d metal complexes are expected to have less side effects or inherent metal toxicity compared to the heavy 4d/5d metals [74,75]. Moreover, considering the availability and cost of these 3d metals, it is expected that any 3d metal based anticancer drug will be much less expensive compared to the platinum based chemotherapeutics. 6. Metal complexes for probing ER polarity The pursuit of non-invasive, responsive optical probes which target specific organelles for the real time bioactive species tracking in live cells remain a challenging area of research. In particular, reliable probes that represent change of intracellular pH have potential to monitor several pathological and physiological processes. David Parker and et al., in 2013 reported a europium based probe (37) to monitor the change in pH within the endoplasmic reticulum of live cells (Fig. 21a) [76]. Earlier works by Kim et al., and J. Lopis et al., indicated that significant communication occurs with the homeostatic mechanism that controls cytosolic pH due to the large proton permeability of the ER membrane [77,78]. Based
Fig. 22. (a) Structure of the complex 39 for probing polarity in the ER. (b) Confocal microscopy images of the live A549 cells incubated with 39 alone (10 lM) at different time points. (c) Confocal microscopy images of the live A549 cells incubated with both the complex 32 and ER stress stimulus tunicamycin (Tm, 50 lg mL1) at different time points. The figures are reproduced from Ref. [79] with the permission. In this minireview, the recent development in the endoplasmic reticulum (ER) imaging and ER targeting anticancer 1st–3rd row metal complexes are detailed discussed.
14
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
on the unique fluorescent property of europium complex, timegated spectral imaging microscope was applied to measure the pH via intensity ratio of emission bands or the variation of excited state lifetime. Notably, each method was independent of complex concentration. Such imaging technology effectively enhanced signal-to-noise ratio by filtrating the short-lived background autofluorescence and light scattering from the surrounding biological environment. The value of ER pH was measured to be 7.15, like that found within the cytoplasm (7.1, Fig. 21b). In addition to pH, the polarity of ER is the feedback of a series of complicated mechanisms that establish and maintain functionality of particular domains. Many cellular processes involved in the spatial arrangement and protein composition such as differentiation, localized membrane growth, activation of the immune response, directional cell migration, and vectorial transport of molecules across cell layers may lead to change and development of ER polarity. Zhang and colleagues reported sensitively tracked the changes in the ER micro-environmental polarity using an iridium(III) complex 38 (Fig. 22) as fluorescent probe [79]. This probe exclusively targeted the ER and successfully tracked the polarity variations during ER stress in live cells in situ. Importantly, this complex 38 can also be used to monitor the blood polarity of diabetes. In the presence of blood from diabetic mice 38 exhibited distinguished phosphorescence compared with that from normal mice.
7. Future direction and conclusion As over the past decades, researchers are highly interested to develop metal based anticancer drugs with reduced side effects and drug resistance as the potential alternative of FDA proved and widely used platinum-based chemotherapeutics [5–20], ER targeting anticancer drug development is now a very hot area of research. The ER, so far, compared to the other cellular organelles is not well documented as a cancer drug target, but selective disruption of ER function by ER-targeting molecules in cancer cells has the potential to unlock a new gate of next-generation cancer drug development and cancer treatment [26,40–42]. To this direction all the above reported literatures are very much valuable to extend and broaden this research to reach the ultimate goal- ‘‘ER targeting anticancer drugs for clinical use”. Moreover, few of the above complexes (9–39) indicate that suitable metal-based ER tracker is indeed possible to develop for biological research. Complexes 37 and 39 indicate the potential of metal-based probes for monitoring change in the ER polarity during ER stress in live cells. The complexes discussed in this review did not show distinct structure-activity relationship to target the ER mainly due to a very limited no of ER-targeting metal complexes for comparison, thus the observations of ER localization of the above complexes were serendipitous in nature. When we tried to develop a statures activity relationship based on the literature reports, we see ER-targeting complexes have some common features like: (i) positively charged (ii) liphophilic (iii) molecular weight >500 g/mol. Overall, this new and hot area of research is highly exciting considering the facts that this might introduce triple action (imaging, polarity probe and therapy) metal complexes in cancer therapy. But ‘‘miles to go” for this newly born research for it’s translation from laboratory to clinic. A few very important issues need to be addressed such as (i) How to design selectively ER targeting metal complexes? Few studies indicated that the strong hydrophobicity of a molecule is one of its main driving forces for its selective accumulation in the ER, but it’s not a very straight forward guidance for developing ER targeting molecules. (ii) How to develop tumor recognizing and simultaneously ER targeting metal complexes? To achieve this goal ER targeting metal complexes probably have to attach with tumor recognizing moieties such as biotin, peptides,
folic acid etc. (iii) How to improve therapeutic efficacy of such ER targeting complexes? Probably the ER targeting metal complexes which can target specifically cancer cells over normal cells and generate ER stress will have the potential to address this issue. In this context, biocompatible metal such as iron, copper, zinc complexes will be interesting candidates as by using such metal, the inherent metal toxicity can be minimized. Moreover ER targeting photoactive complexes can provide both the temporal and spatial control over the anticancer drug action as such photoactive complexes will only be anticancer active at the target tumor site upon light irradiation. Using such design the issues of drug side effect and drug resistance can be overcome. Design of water soluble ER targeting metal complexes potentially can increase the in-vivo bioavailability of the drug. Moreover, ER targeting, cancer cells specific, photoactive and catalytic metal complexes which can alter the intracellular redox balance via catalytic mode of action only after photo-irradiation will have the potential as clinical ER targeting anticancer drugs. Acknowledgements We appreciate the financial support of the Sun Yat-sen University Startup fund 75110-18841213 and the Sun Yat-sen University Undergraduate Teaching ‘‘Quality Engineering” project 7511018842502 and the Fundamental Research Funds for the Central Universities project 75110-31610005 for H.H.; the National Natural Science Foundation of China (NSFC, 21701113); the Natural Science Foundation of SZU (2018036) and Peacock Talent Fund (827-000389) for P.Z. Declaration of Competing Interest The author declares no competing financial interests. References [1] K.D. Mjos, C. Orvig, Chem. Rev. 114 (2014) 4540–4563. [2] T.C. Johnstone, K. Suntharalingam, S.J. Lippard, Chem. Rev. 116 (2016) 3436– 3486. [3] A. Terenzi, C. Pirker, B.K. Keppler, W. Berge, J. Inorg. Biochem. 165 (2016) 71– 79. [4] M. Wenzel, A. Casini, Coord. Chem. Rev. 352 (2017) 432–460. [5] K. Laws, G. Bineva-Todd, A. Eskandari, C. Lu, N. O’Reilly, K. Suntharalingam, Angew. Chem. Int. Ed. 57 (2018) 287–291. [6] Z. Liu, P.J. Sadler, Acc. Chem. Res. 47 (2014) 1174–1185. [7] M. Patra, G. Gasser, Nat. Rev. Chem. 1 (2017) 0066. [8] B. Albada, N. Metzler-Nolte, Chem. Rev. 116 (2016) 11797–11839. [9] J.P.C. Coverdale, I. Romero-Canelón, C. Sanchez-Cano, G.J. Clarkson, A. Habtemariam, M. Wills, P.J. Sadler, Nat. Chem. 10 (2018) 347–354. [10] A.K. Renfrew, N.S. Bryce, T. Hambley, Chem. Eur. J. 21 (2015) 15224–15234. [11] S. Banerjee, J.J. Soldevila-Barreda, J.A. Wolny, C.A. Wootton, A. Habtemariam, I. Romero-Canelón, F. Chen, G.J. Clarkson, I. Prokers, L. Song, P.B. O’Connor, V. Schünemann, P.J. Sadler, Chem. Sci. 9 (2018) 3177–3185. [12] H. Huang, S. Banerjee, P.J. Sadler, ChemBioChem. 19 (2018) 1574–1589. [13] S.H.C. Askes, S. Bonnet, Nat. Rev. Chem. 2 (2018) 437–452. [14] S. Bonnet, Dalton Trans. 47 (2018) 10330–10343. [15] K. Qiu, Y. Chen, T.W. Rees, L. Ji, H. Chao, Coord. Chem. Rev. 378 (2019) 66–86. [16] S. Banerjee, A.R. Chakravarty, Acc. Chem. Res. 48 (2015) 2075–2083. [17] P. Zhang, H. Huang, Dalton Trans. 47 (2018) 14841–14854. [18] K.K.W. Lo, Acc. Chem. Res. 48 (2015) 2985–2995. [19] C. Imberti, P. Zhang, H. Huang, P.J. Sadler, Angew. Chem. Int. Ed. 132 (2020) 61–73. [20] P. Zhang, H. Huang, S. Banerjee, G.J. Clarkson, C. Ge, C. Imberti, P.J. Sadler, Angew. Chem. Int. Ed. 131 (2019) 2372–2376. [21] T. Sarkar, S. Banerjee, S. Mukherjee, A. Hussain, Dalton Trans. 45 (2016) 6424– 6438. [22] T. Sarkar, S. Banerjee, A. Hussain, RSC Adv. 5 (2015) 16641–16653. [23] L. He, C.P. Tan, R.R. Ye, Y.Z. Zhao, Y.H. Liu, Q. Zhao, L.N. Ji, Z.W. Mao, Angew. Chem. Int. Ed. 53 (2014) 12137–12141. [24] W. Zhou, X. Wang, M. Hu, C. Zhu, Z. Guo, Chem. Sci. 5 (2014) 2761–2770. [25] H. Huang, L. Yang, P. Zhang, K. Qiu, J. Huang, Y. Chen, J. Diao, J. Liu, L. Ji, J. Long, H. Chao, Biomaterials 83 (2016) 321–331. [26] J.R. Cubillos-Ruiz, S.E. Bettigole, L.H. Glimcher, Cell 168 (2017) 692–706. [27] J. Mandl, T. Mészáros, G. Bánhegyi, L. Hunyady, M. Csala, Trends. Endocrin. Met. 20 (2009) 194–201.
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178 [28] D.W. Reid, C.V. Nicchitta, Nat. Rev. Mol. Cell. Bio. 16 (2015) 221–231. [29] L.M. Westrate, J.E. Lee, W.A. Prinz, G.K. Voeltz, Annu. Rev. Biochem. 84 (2015) 791–811. [30] T.A. Rapoport, Nature 450 (2007) 663–669. [31] D.N. Hebert, S.C. Garman, M. Molinari, Trends. Cell. Biol. 15 (2005) 364–370. [32] C.H. Jan, C.C. Williams, J.S. Weissman, Science 346 (2014) 1257521. [33] D.S. Schwarz, M.D. Blower, Cell. Mol. Life. Sci. 73 (2016) 79–94. [34] M. Wang, R.J. Kaufman, Nature 529 (2016) 326–335. [35] E. Bahar, J.Y. Kim, H. Yoon, Cancers 11 (2019) 338. [36] R.K. Yadav, S.W. Chae, H.R. Kim, H.J. Chae, J. Cancer. Prev. 19 (2014) 75–88. [37] R. Sano, J.C. Reed, BBA-Mol. Cell. Res. 1833 (2013) 3460–3470. [38] S.J. Marciniak, FEBS. J. 286 (2019) 228–231. [39] K. Nowotny, J.P. Castro, M. Hugo, S. Braune, D. Weber, M. Pignitter, V. Somoza, J. Bornhorst, T. Grune, Free. Radical. Bio. Med. 120 (2018) 102–113. [40] J.C. Simard, I. Durocher, D. Girard, Apoptosis 21 (2016) 1279–1290. [41] M. Wang, R.J. Kaufman, Nat. Rev. Cancer 14 (2014) 581–597. [42] S. Banerjee, W. Zhang, ChemBioChem 19 (2018) 2341–2343. [43] J.D. Malhotra, R.J. Kaufman, Antioxid. Redox, Sign. 9 (2007) 2277–2294. [44] B. Bhandary, A. Marahatta, H.R. Kim, H.J. Chae, Int. J. Mol. Sci. 14 (2012) 434– 456. [45] Q. Rao, M. Yang, G. Liu, H. Zhang, H. Xu, J. Wang, Y. Tian, J. Yu, A. Wang, H. Zhou, Dyes. Pigments. 169 (2019) 60–65. [46] H. Xiao, R. Zhang, C. Wu, P. Li, W. Zhang, B. Tang, Sensor. Actuat. B-Chem. 273 (2018) 1754–1761. [47] H. Xiao, X. Liu, C. Wu, Y. Wu, P. Li, X. Guo, B. Tang, Biosen. Bioelectron. 91 (2017) 449–455. [48] P. Shen, S. Ohta, S. Inasawa, Y. Yamaguchi, Chem. Commun. 47 (2011) 8409– 8411. [49] C. Ghosh, A. Nandi, S. Basu, Nanoscale 11 (2019) 3326–3335. [50] L. McDonald, B. Liu, A. Taraboletti, K. Whiddon, L.P. Shriver, M. Konopka, Q. Liu, Y. Pang, J. Mater. Chem. B 4 (2016) 7902–7908. [51] A. Hambrock, C. Löffler-Walz, U. Quast, Br. J. Pharmacol. 136 (2002) 995–1004. [52] A.J. Smith, T.K. Taneja, J. Mankouri, A. Sivaprasadarao, Expert Rev. Mol. Med. 9 (2007) 1–17. [53] W.L. Kwong, R.W.Y. Sun, C.N. Lok, F.M. Siu, S.Y. Wong, K.H. Low, C.M. Che, Chem. Sci. 4 (2013) 747–754. [54] A. Hussain, K. Somyajit, B. Banik, S. Banerjee, G. Nagaraju, A.R. Chakravarty, Dalton Trans 42 (2013) 182–195. [55] A. Hussain, A.R. Chakravarty, J. Chem. Sci. 124 (2012) 1327–1342. [56] R. Jastrza˛b, M. Nowak, M. Skroban´ska, A. Tolin´ska, M. Zabiszak, M. Gabryel, Ł. Marciniak, M.T. Kaczmarek, Coordin, Chem. Rev. 382 (2019) 145–159.
15
[57] R.W.Y. Sun, C.N. Lok, T.T.H. Fong, C.K.L. Li, Z.F. Yang, T. Zou, A.F.M. Siu, C.M. Che, Chem. Sci. 4 (2013) 1979–1988. [58] M.J. Chow, C. Licona, G. Pastorin, G. Mellitzer, W.H. Ang, C. Gaiddon, Chem. Sci. 7 (2016) 4117–4124. [59] M.J. Chow, M.V. Babak, K.W. Tan, M.C. Cheong, G. Pastorin, C. Gaiddon, W.H. Ang, Mol. Pharmaceut. 15 (2018) 3020–3031. [60] P. Zou, M. Chen, J. Ji, W. Chen, X. Chen, S. Ying, J. Zhang, Z. Zhang, Z. Liu, S. Yang, G. Liang, Oncotarget 6 (2015) 36505–36521. [61] T. Zou, C.N. Lok, Y.M.E. Fung, C.M. Che, Chem. Commun. 49 (2013) 5423–5425. [62] R. Cao, J. Jia, X. Ma, M. Zhou, H. Fei, J. Med. Chem. 56 (2013) 3636–3644. [63] S. Mandal, D.K. Poria, R. Ghosh, P.S. Ray, P. Gupta, Dalton Trans. 43 (2014) 17463–17474. [64] T.F. Anjong, G. Kim, H.Y. Jang, J. Yoon, J. Kim, New J. Chem. 41 (2017) 377–386. [65] J.S. Nam, M.G. Kang, J. Kang, S.Y. Park, S.J.C. Lee, H.T. Kim, J.K. Seo, O.H. Kwon, M.H. Lim, H.W. Rhee, T.H. Kwon, J. Am. Chem. Soc. 138 (2016) 10968–10977. [66] A.A. Rowland, G.K. Voeltz, Nat. Rev. Mol. Cell. Biol. 13 (2012) 607–625. [67] B. Yuan, J. Liu, R. Guan, C. Jin, L. Ji, H. Chao, Dalton Trans. 48 (2019) 6408–6415. [68] M.R. Gill, D. Cecchin, M.G. Walker, R.S. Mulla, G. Battaglia, C. Smythe, J.A. Thomas, Chem. Sci. 4 (2013) 4512–4519. [69] M.F. Primik, S. Göschl, S.M. Meier, N. Eberherr, M.A. Jakupec, E.A. Enyedy, G. Novitchi, V.B. Arion, Inorg. Chem. 52 (52) (2013) 10137–10146. [70] S. Banerjee, A. Dixit, R.N. Shridharan, A.A. Karande, A.R. Chakravarty, Chem. Commun. 50 (2014) 5590–5592. [71] S. Banerjee, A. Dixit, A.A. Karande, A.R. Chakravarty, Dalton Trans. 45 (2016) 783–796. [72] U. Basu, I. Pant, A. Hussain, P. Kondaiah, A.R. Chakravarty, Inorg. Chem. 54 (2019) 3748–3758. [73] L. Yu, Q. Wang, K.W. Yeung, W.P. Fong, P.C. Lo, Chem-Asian. J. 13 (2018) 3509– 3517. [74] A. Jan, M. Azam, K. Siddiqui, A. Ali, I. Choi, Q. Haq, Int. J. Mol. Sci. 16 (2015) 29592–29630. [75] S.M. Page, S.R. Boss, P.D. Barker, Future Med. Chem. 1 (2009) 541–559. [76] B.K. McMahon, R. Pal, D. Parker, Chem. Commun. 49 (2013) 5363–5365. [77] J.H. Kim, L. Johannes, B. Goud, C. Antony, C.A. Lingwood, R. Daneman, S. Grinstein, Proc. Natl. Acad. Sci. USA 95 (1998) 2997–3002. [78] J. Llopis, J.M. McCaffery, A. Miyawaki, M.G. Farquhar, R.Y. Tsien, Proc. Natl. Acad. Sci. USA 95 (1998) 6803–6808. [79] Q. Tang, X. Zhang, H. Cao, G. Chen, H. Huang, P. Zhang, Q. Zhang, Dalton Trans. 48 (2019) 7728–7734.
Contents lists available at ScienceDirect
Coordination Chemistry Reviews journal homepage: www.elsevier.com/locate/ccr
Review
Recent advances in endoplasmic reticulum targeting metal complexes Can Huang a, Tingxuan Li a, Jiayu Liang a, Huaiyi Huang a,⇑, Pingyu Zhang b,⇑, Samya Banerjee c,⇑ a
School of Pharmaceutical Science (Shenzhen), Sun Yat-sen University, Guangzhou 510275, PR China College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen 518060, PR China c Institute of Inorganic Chemistry, Georg-August-Universität Göttingen, Tammannstr. 4, 37077 Göttingen, Germany b
a r t i c l e
i n f o
Article history: Received 8 September 2019 Accepted 2 January 2020
Keywords: Endoplasmic reticulum Metal complexes Fluorescence imaging Anticancer Endoplasmic reticulum stress
a b s t r a c t Over the last few years, significant attention has been paid to develop metal complexes for different cellular organelle specific imaging agents and to achieve organelle targeting anticancer drugs. Endoplasmic reticulum (ER), the largest organelle in human cells is largely responsible for the synthesis of protein, lipid and hormones. ER is also crucial for protein folding and detoxification of cells. Cellular stress within the ER generates an ER stress leading to cell death. Several naturally occurring anticancer agents have been reported to induce ER stress response as a main mechanism of cell death. In spite of these facts, ER targeting synthetic small molecules are rare in the literature and research on the development of ER targeting metal complexes is only a few years old. In this review, we have discussed about the recent development in the ER targeting metal complexes which are used as ER imaging and ER targeting anticancer agents with detailed mechanism of action. Moreover, we also discussed about the difficulties and their possible solution in order to translate these kinds of molecules to clinic. Ó 2020 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Endoplasmic reticulum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Methods for detecting ER localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Metal complexes for ER stress generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Metal complexes for ER targeting anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.1. 3rd row transition metal complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.2. 2nd row transition metal complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.3. 1st row transition metal complexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 6. Metal complexes for probing ER polarity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 7. Future direction and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1. Introduction With around 8.2 million deaths and 14 million new diagnoses in 2012, cancer is the main cause of death worldwide [1]. Death caused by cancer is predicted to increase up to 70% by 2030 [1]. But, the commonly used Pt based chemotherapeutics are now ⇑ Corresponding authors. E-mail addresses: [email protected] (H. Huang), [email protected]. cn (P. Zhang), [email protected] (S. Banerjee). https://doi.org/10.1016/j.ccr.2020.213178 0010-8545/Ó 2020 Elsevier B.V. All rights reserved.
not effective for various cancers [1,2]. These chemotherapeutics also suffer from several undesirable side effects and drug resistance [1,2]. For this reason, new cancer drugs with novel mechanisms are one of the high-priority needs to save life, reduce drugs’ side-effects and overcome acquired drug resistance. Metal complexes have a great potential as next generation anticancer agents and can increase the effectiveness of chemotherapeutic drugs [3]. The concepts of metal based anticancer drugs with new mechanism of actions are only a few years old and need to be explored with more details [1–14].
2
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 1. Structures of the gliberclamide and commercial organic ER-Tracker.
Fig. 2. Structure of the complex 1 (a) and its ability to generate perinuclear vacuole (b). The figures are reproduced from Ref. [53] with the permission.
For a successful drug design, understanding the target sites in cells and effects on biological pathways are of high importantance. Strategies for the discovery of next-generation metalloanticancer drugs with novel mechanisms of action include targeting cellular organelles. Over the last few years, designing molecules to target different cellular organelles such as nucleus, mitochondria and lysosomes have attracted significant attention to develop specific cellular organelle imaging agents and nextgeneration organelle targeting cancer therapy [15–24]. Metal complexes often exhibit significant larger Stokes shifts compared to organic organelle targeting dyes. The small Stokes shifts of organic dyes can lead to significant self-quenching (homo trans-
Fig. 3. (a) The ER stress inducing gold(III)–phosphine complex viz., [(C,N,C)2Au2(mdppp)](CF3SO3)2 (2) (b) Mechanism of anticancer action of 2 by inducing ER stress. The figures are adopted from Ref. [57] with the permission.
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
3
Fig. 4. Structure and mechanism of action of ER stress inducing organoruthenium complexes namely RAS-1H (3) and RAS-1 T (4). The figure is adopted from Ref. [58] with the permission.
Fig. 5. The ER stress inducing Ru(II)-arene based complexes (5–8) of Schiff-Base containing iminoquinoline chelate ligands and their mode of ER stress induction. The figure is adopted from Ref. [59] with the permission.
fer) when the dyes are at high concentration or when a biomolecule is multiply labeled with the dye [15]. The positive charge of metal complexes can enhance water solubility. Additionally,
metal complexes exhibit better photo- and chemo-stability during long-term light irradiation, allowing intracellular tracking the physiological dynamic of organelles [25].
4
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 6. Three FDA-approved drugs for various diseases are also known as ER stress inducer and are currently under reinvestigation as anticancer agents.
The endoplasmic reticulum (ER) is an absolutely necessary cellular organelle [26–34] and ER targeting anticancer metal complexes are of recent origin. Small molecules induced stress in the ER (termed as ER Stress) to effect cell death [36–39]. The interaction of small molecules with the ER and subsequent generation of ER stress can be studied by techniques such as: (i) transmission electron microscopy (TEM) which utilizes high energy electrons to provide morphological information of the stressed ER or cells; (ii) fluorescence microscopy, that uses ER staining dyes to study the morphological changes of the stained ER during ER stress generation; (iii) microarray analysis for genes expression study; (iv) reserve transcriptase-polymerase chain reaction to study RNA expression levels after ER stress induction and (v) western blot analysis, an antibody based technique, of different ER stress biomarkers such as CHOP, IRE1a, phopho-IRE1a, peif2a, PERK
and phospho-PERK to determine their levels after the generation of ER stress. In this review, we have discussed the advancements of the ER targeting and ER stress generating metal complexes for anticancer application in the light of recent literatures.
2. Endoplasmic reticulum Compared to the other subcellular targets, endoplasmic reticulum (ER) is not well explored as the target for anticancer agents, due to its complex role in human cells [26]. The largest organelle in human cells, endoplasmic reticulum has a crucial role in the synthesis of protein, lipid and hormones [26–31]. ER is also important for cellular sensing, signaling and detoxification, and is of high importance for protein folding and post-translational modifica-
Fig. 7. (a) The ER targeting luminescent platinum(II)-carbene complexes (9–17) (b) ER localization of complex 11 as was evident from the co-staining with ER tracker. The figures are reproduced from Ref. [61] with the permission.
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
5
Fig. 8. Pathway of cell death induced by the ER targeting complex 11. The figure is reproduced from Ref. [61] with the permission.
Fig. 9. (a) The ER targeting anticancer red emissive Ir(III) complexes (18–20). (b) ER localization of complex 20 as was evident from the co-staining with ER tracker. The figures are reproduced from Ref. [62] with the permission.
tions of proteins, contributing about 30% of the total proteome [32–34]. Any perturbation of the ER’s protein-folding ability leads to the generation of ER stress and causes cell death [35–39]. For this hitherto less explored mechanism of cell death, selective disruption of ER function by ER-targeting molecules in cancer cells has opened up a gate of next-generation anticancer drug development [1,40–42]. In this direction, a very recent trend is the devel-
opment of synthetic ER targeting metal complexes for ER stress induction in cancer cells, leading to cell death. Metal complexes, with tuneable coordination geometry, are very attractive small molecules to achieve tumor targeting anticancer activity or selectivity towards the ER. The metal complexes have three main advantages over the organic small molecule viz., (i) attachment of pendent tumor targeting/recognizing moieties on the ligand
Fig. 10. The ORTEP diagram of complex 21 with 50% thermal ellipsoids and all atoms labeling. The figures are reproduced from Ref. [63] with the permission.
6
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 11. (a) The ER targeting bridged dinuclear Ir(III) complexes 22 and 23. (b) Live HeLa cells imaging showing the ER localization of complex 23. The figures are reproduced from Ref. [64] with the permission.
does not require very trivial and sophisticated synthetic route (ii) just by changing the ligand systems or attaching hydrophilic/hydrophobic group to the ligand, the liphophilicity can be easily tuned to direct the complex to a particular cellular organelle (iii) an emissive pendent moiety can be attached very easily to track the complex in cells by microscopy. Moreover, dual action metal complexes for imaging and therapy are easy to synthesize than organic small molecules with the same functions. Generation of ER stress is known to alter the ER polarity and irregular ER morphology [43,44]. To visualize such changes in live cells, design and synthesis of ER imaging agents is becoming a hot area of research for many active research groups across the globe [45–49]. In this minireview, we focus on the recent development of metal complexes as ER imaging agents as well as ER targeting anticancer agents with detailed mechanism of drug action.
include ER-TrackerTM Blue-White DPX (Fig. 1) with a broad emission between 430 and 640 nm. However, as shortcoming for other the organic dyes, the fluorescence signal sometimes significantly reduced after fixing the cells or under continuous irradiation, limiting their application for cellular imaging rather than the important long-term organelle dynamic tracking.
3. Methods for detecting ER localization With the development of laser scanning confocal microscopy, the cellular organelle in live cells can now be visualized via commercial organelle-targeting agents. Despite a large majority of fluorescent probes produced, there are limited reports for ER targeting, partly due to the challenge in controlling ER selectivity [50]. The commercial fluorescent dyes ER-Tracker TM Green and ERTrackerTM Red both contain the ‘‘glibenclamide” segment to target sulphonylurea receptors of ATP-sensitive K+ channels [51] that are prominent on ER (Fig. 1) [52]. Moreover, fluorescence dyes labelled calreticulin, which is abundant in non-muscular tissues and the principal calcium-binding proteins in the ER can also be used for ER immunofluorescence. However, it is important to point out that ‘‘glibenclamide” segment of the commercial fluorescent dyes for ER imaging may perturb other cellular activity during imaging upon long exposure. Few other ER staining organic dyes are also commercially available. DiOC6(3) (Fig. 1) is a cell permeable, green fluorescent, lipophilic dye traditionally used for the ER imaging. However, high concentration of working solution of DiOC6(3) results in toxicity to living cells. Other commercial organic dyes for ER imaging
Fig. 12. The ER Localized Ir(III) based photosensitizer (24–27) as efficient PDT agents. The figure is reproduced from Ref. [65] with the permission.
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
7
Fig. 13. (a) The ER targeting complex, 26, induced dimerization of biotin-phenol (BP) in presence of 100 mW cm2 light studied by MALDI-MS. (b) Cartoon representation showing the procedure of detection of 26 induced photo-oxidized proteins of by mass spectral analysis. The figures are reproduced from Ref. [65] with the permission.
The co-localization assay with ER imaging dyes, or dyes labeledproteins can be used to confirm the ER localization of the metal complexes. Transition metals such as iridium, gold are exogenous elements within the living cells. The amount of exogenous metals in the cells can be quantified by inductively coupled plasma mass spectrometry (ICP-MS). 4. Metal complexes for ER stress generation The first breakthrough came in 2013. Che and colleagues reported an anticancer active ytterbium(III) porphyrin complex viz., [Yb(Por)(m-OH)]2 [Por = octaethylporphyrinato (1)] with sub-micromolar half maximal inhibitory concentration (IC50) (Fig. 2a) [53]. The complex exists as a hydroxyl-bridged dimer, [Yb2(Por)2(m-OH)2] in solid state, but as monomer viz., [Yb(Por) (DMSO)(OH)(OH2)] in H2O/DMSO solution. This complex induced apoptotic death of cancer cells and interestingly before the apoptosis generated perinuclear vacuole (Fig. 2b). While most of anti-
cancer lanthanide complexes are known to target DNA for their anticancer effect [54–56], this complex showed anti-cancer effect which was highly associated with the ER stress pathway as was confirmed by microarray analysis, connectivity map analyses and western blotting analysis. In the same year, they also reported a stable gold(III)–phosphine complex viz., [(C,N,C)2Au2(m-dppp)](CF3SO3)2 [2, HC,N, CH = 2,6-diphenylpyridine; dppp = bis(diphenylphosphino)pro pane] with excellent in-vitro cytotoxicity against a range of cancers and significant inhibition of tumor growth in nude mice and beagle dogs (Fig. 3a) [57]. This complex is a potent inhibitor of thioredoxin reductase (TrxR) and simultaneously induced ER stress. They also identified TRAIL, a ligand for death receptor 5 (DR5), as a synergistic agent for the anti-cancer activity of 2. Taken together, the reasons behind the excellent anticancer activity of 2 were the TrxR inhibition, ER stress generation and a death-receptor-dependent apoptosis via the activation of the apoptotic cascade (Fig. 3b).
8
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
platin, and 5-fluorouracil. The p-acidity of the chelating ligand was found to alter the stability, ROS generation ability and ER stress induction efficiency of the complex. Moreover, this p-acidity played an important role in the switching between ROS-induced ER stress activation and ROS-independent ER stresses activation. These complexes have the potential as anticancer agents for the drug resistance cancers and suitable tuning of the ligand was expected to improve the drug efficacy. Moreover, auranofin, nelfinavir and sorafenib (Fig. 6), the FDAapproved drugs for various diseases are also known as ER stress inducer and are currently under reinvestigation as anticancer agents [60].
5. Metal complexes for ER targeting anticancer activity 5.1. 3rd row transition metal complexes
Fig. 14. Mechanistic pathway for the photoactivated anticancer activity of complexes (24–27). The figure is reproduced from Ref. [65] with the permission.
Multidrug resistance (MDR) is one of the major problems in cancer therapy to overcome [1–14]. MDR generally resist malignant cells to cellular apoptosis. Most of the current cancer drugs act via apoptosis and are suffering from the drug resistance issue. In order to combat this problem, compounds that can induce other forms of programmed cell death are of current interest to bypass MDR. In this line of research, W. H. Ang and C. Gaiddon and other coworkers in 2016 reported two organo-ruthenium complexes namely RAS-1H (3) and RAS-1T (4) (Fig. 4) which induced non-apoptotic programmed cell death by ER stress pathways [58]. Although the complexes shared similar chemical structure but their modes of drug action were completely different. RAS-1T (4) induced ROS-mediated ER stress and thereafter XBP-1s splicing while the mechanism of action for RAS-1H (3) was ROSindependent and via XBP-1s splicing. Both of them were more effective against apoptosis-resistant cells while comparing to oxaliplatin. For the first time they opened up the lock for metal complex induced ER stress modulation to bypass apoptosis related resistance. Another report from Prof. W. H. Ang laboratory presented a new class of ER stress-inducing and highly cytotoxic Ru(II)-arene based complexes (5–8) of Schiff-Base containing iminoquinoline chelate ligands (Fig. 5) [59]. The complexes showed high efficacies towards both the drug-sensitive (ovarian cancer; A2780, gastric cancer; AGS, colorectal cancers; HT29 and HCT116) and cisplatin resistant (ovarian cancer; A2780cisR and colorectal cancers; HCT116 p53/) cancer types with nano molar IC50 values. The complexes were also active against multidrug-resistant colorectal cancer TC7 with micromolar IC50 values. Interestingly, the complexes were multiple times more potent than the clinical drugs cisplatin, oxali-
A report from the C.M. Che group in 2013 demonstrated the ability of a series of luminescent platinum (II) complexes (9–17) (Fig. 7a) containing bidentate N-heterocyclic carbene ligands for ER targeting photo-toxicity [61]. The complex 11 selectively localized in the ER which was proved by co-staining with ER-TrackerTM (Fig. 7b). The complexes showed potent anticancer activity against a wide range of cancer cell lines including HeLa, breast cancer (MCF-7), nasopharyngeal carcinoma (HONE1, SUNE1), lung carcinoma (HCC827, H1975), hepatocellular carcinoma (HepG2). Complex 11 was the highly active in this series with the IC50 values ranging from 0.45 mM to 1.59 mM. Interestingly 11 was 5.3–60 times more potent than cisplatin against the above-mentioned cell lines and was significantly less toxic to non-tumorigenic liver cell line (MIHA). Complex 11 also generated ER stress after accumulating in the ER as was probed by the dramatic up-regulation of the expressions of phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK), phosphorylated eukaryotic initiation factor 2a (eIF2a) and C/EBP homologous protein (CHOP). Moreover, 11 induced mitochondrial dysfunction and ultimately produced apoptosis as the mode of cell death. The activity of the complexes 9–17 was further enhanced by 5.6- to 33.1-fold upon irradiation (2.8 mWcm2 visible light for 1 h) compared to that in the dark. The complex 11 generated 1O2 very efficiently in the ER on visible light irradiation. The generated 1O2 caused ER stress which leads to photo-cytotoxicity. Overall, the reported complexes specifically selectively targeted the ER and induced mitochondrial dysfunction and ER stress, which ultimately lead to the cell apoptosis (Fig. 8). A few months later, Cao et al. reported synthesis of a series of red emissive cationic iridium(III) complexes viz., [Ir(ppy)2(N,N)]+ (ppy: 1-phenyl-pyridine; N,N = 2,20 -bipyridine (18) or phenanthroline (19) or 4,7-diphenyl-1,10- phenanthroline (20)) (Fig. 9a) [62]. The highly hydrophobic complex 20 showed highest quantum yields, lipophilicity and intracellular uptake. All these complexes were effective as anticancer agents against HeLa, MCF-7 and A549 cells. Complex 20 was the most cytotoxic among these complexes and was also much efficient than that of cisplatin under identical experimental conditions (24 h drug incubation). Complex 20 was accumulated mostly to the ER (Fig. 9b) and caused ER stress in cancer cells. Notably, for the first time, the authors have tried to draw a co-relation between ER localization with the physiochemical properties of the complex and have mentioned the strong hydrophobic nature as the main factor that might drive the accumulation of 20 in the ER. Complex 20 induced stress in the ER and during the stress, fast cytosolic release of calcium from the stressed ER was found to disturb the mitochondrial morphology and function and ultimately initiate cellular apoptosis via the intrinsic pathway. In this context, a better understanding of the cell death mechanism would be helpful for structure-activity optimiza-
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
9
Fig. 15. (a) The cyclometallated Ir(III) complexes (28–30) for ER targeting photocytotoxicty. (b) Confocal images showing the intracellular Ca2+ level at differentconcentrations of complex 29. BF: Bright field; Scale bars: 20 lm. The figure is reproduced from Ref. [67] with the permission.
tion to develop next generation ER targeting Ir(III) based cancer therapeutics. In 2014, S. Mandal and co-workers reported a very similar ER targeting heteroleptic phosphorescent cyclometalated Ir(III) complex (21) with the same [(ppy)2Ir(pipt)] (pipt = 2-phenyl-(1H-imi dazo[4,5–f][1,10]-phenanthroline) co-ordination core site (Fig. 10) [63]. The complex exhibited high luminescence in the endoplasmic reticulum and on 405 nm light irradiation for 1 h gave membrane blebbing and cell death in MCF-7 cancer cells by generating ROS. Interesting authors proved that the indication of 20 -OH group in the phenyl ring of complex 21 with the imidazolyl N is very crucial for its ER localization and luminescence. T. F. Anjong and co-workers reported two Ir(III) based bridged (by conjugated aromatic ligand, tppz) dinuclear complexes viz., [(bhq)2Ir(tppz)Ir(bhq)2] (22) and [(ppy)2Ir(tppz)Ir(ppy)2] (23) where bhq is benzo(h)quinolone, ppy is phenyl-pyridine and tppz istetrapyrido-[3,2-a:20 ,30 -c:300 ,200 -h:2000 ,3000 -j]phenazine (Fig. 11a) [64]. The complexes effectively interacted with liposomes indicating their possible intracellular localization within lipid-rich organelles in live cells. Complex 23 interacted with the liposomes more strongly than complex 22. The complex was cytotoxic to the HeLa cervical cancer cells with the IC50 of 15.6 mM for 22 and 18.2 mM for 23 respectively upon 24 h incubation. The photostable complexes showed primarily ER localization in the HeLa cells indicating their possible applications as imaging agent and ER tracker in the live cells (Fig. 11b).
In 2018, Tae-Hyuk Kwon and co-workers designed and synthesized ER Localized Ir(III) based photosensitizer (24–27) as efficient PDT agents (Fig. 12) [65]. The complexes were designed via ligand tuning to achieve efficient ROS generation, accounted for appropriate energy levels and high emission quantum yields. The ER localized complexes even at a low concentration (2 lM) and very less light energy (1 Jcm2) triggered cancer cells death by spatiotemporal cell killing activity via efficient ROS generation. Complex 26 also showed potent anticancer activity by 860 nm two photon irradiation. The complexes damaged protein via both protein crosslink formation and protein oxidation. Photo-induced protein cross-links formation by metal complexes commonly occurred through coupling with the tyrosyl radicals, present over the protein surfaces. They employed a tyrosine residue containing biotinphenol (BP) to confirm the covalent dimerization by in vitro cross-linking upon photoactivation of the complexes. Matrixassisted laser desorption ionization mass spectrometry (MALDIMS) was used to study the BP cross-links formation, induced by the complexes (Fig. 13a). They mainly focused on the proteins modifications that contain oxidized methionine residues such as mono-oxidized methionine (O-Met) and used methionine sulfoxide antibody to identify such protein modification (Fig. 13b). Proteins damage in live cells was mainly in proteins near to the ER and mitochondria. Mitochondria and the ER are within a few nanometers distance at the ER- mitochondria-tethered junction [66]. As the complexes generate 1O2 on photo-irradiation in the
10
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 16. (a) The ER targeting cytotoxic binuclear Ru(II) complex 31. (b) Co-staining of MCF-7 cells with complex 31 and ER-localized calnexin protein (visualized by immunofluorescence; FITC-conjugated secondary antibody). The figures are reproduced from Ref. [68] with the permission.
Fig. 17. (a) The complex 32. (b) Localization of the complex 32 in the ER and Lysosomes. The figures are reproduced from Ref. [69] with the permission.
ER, a fraction of generated 1O2 can reach the mitochondrial space from the ER via the outer mitochondrial membrane and ultimately damage both proximal ER and mitochondrial proteins. Complex 23 induced aggregation of mitochondria, a signature of mitochondrial pathway of apoptosis. Overall, these ER targeting Ir(III) based com-
plexes efficiently acted as a photosensitizer for PDT application through effective protein disablement (Fig. 14). Recently in 2019, Chao et al., developed three cyclometallated Ir (III) complexes (28–30) for ER-targeted PDT with a gradually enhanced conjugation area in the ligand (Fig. 15a) [67]. The
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
11
A549R, L02, HeLa, HepG2). Interestingly, their singlet oxygen quantum yields and cytotoxicity increase with the enhancement of the conjugation in ligands. Very interestingly, the photo-induced ERstress leads to the efflux of Ca2+ from the ER in A549 cells (Fig. 15b). They have confirmed the release Ca2+ from the ER using Fluo-4 AM as the fluorogenic probe. Fluo-4 AM, after internalization in the cells converted to Fluo-4 via hydrolysis by the intracellular esterase. This Fluo-4 on binding to the released and free Ca2+ turns its green fluorescence on. As depicted in Fig. 15, the green fluorescence intensity of Fluo-4 increases with the gradual enhancement complex 29 concentrations, indicating a significant increase of intracellular Ca2+ level. No significant fluorescence was observed under the dark which indicated light activation was the triggering factor for the anticancer activity of this complex. As the ER is an indispensable organelle for synthesis and export of proteins and membrane lipids, any interference to the ER redox signaling leads to the apoptosis via ER-stress. Considering this, all these above reports indicate the promising potential of 5d complexes as the ER targeting next generation chemo/photochemotherapeutics for the effective treatment of cancer. 5.2. 2nd row transition metal complexes
Fig. 18. (a) Oxovanadium(IV) complex 33 which localized in the ER. (b) Photoinduced apoptotic cell death by ER targeting complex 33. Coordinate (1) represents percentage of live cells; Coordinate (2), percentage of early apoptotic cells; Coordinate (3), percentage of late apoptotic cells and Coordinate (4), percentage of necrotic cells. The figures are reproduced from Refs. [70,71] with the permission.
complexes showed preferential uptake and localization in the ER and induced apoptosis on PDT treatment (405 nm, 6 Jcm2) via an ER stress mechanism in different cancer cell lines (A549,
Thomas et al., reported a highly lipophilic and ER-targeting dinuclear ruthenium(II) complex, [{Ru(DIP)2}2(tpphz)]4+ (31) where DIP is 4,7-diphenyl-1,10-phenanthroline and tpphz is tetrapyrido [3,2-a:20 ,30 -c:300 ,200 -h:2000 ,3000 -j]phenazine (Fig. 16a) [68]. They confirmed the ER localization by the immunofluorescent co-staining with the antibodies for ER specific proteins such as calnexin (Fig. 16b). In order to explain the affinity of this complex for ER, they have proposed that due to the strong lipophilic character, the complex interact very strongly with the lipid-dense organelle, the ER. This explanation is in the same direction with what Cao et al has proposed and indicates that hydrophobicity and lipophilicity of a molecule may have a direct relation with its ER affinity. This complex also demonstrated marked cytotoxicity towards both MCF-7 and HeLa cell lines. 5.3. 1st row transition metal complexes Arion and co-workers reported a green fluorescent dimeric zinc complex, [Zn2(MeOOCLCOO)(CH3COO)2] (32) (Fig. 17a) (MeOOCLCOO = Diethyl-2,20 -((3-(((5H-indolo[3,2–c]quinolin-6(11H)-ylidene)-hyd razono)methyl)-2-hydroxy-5 methylbenzyl)azanediyl)-diacetate) which was cytotoxic to the A549 (nonsmall cell lung carcinoma),
Fig. 19. (a) The ER targeting photocytotoxic Fe(III) complexes 34 and 35. The figures are reproduced from Ref. [72] with the permission.
12
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
Fig. 20. The ER targeting biotinylated zinc(II) phthalocyanine (36). The figure is reproduced from Ref. [73] with the permission.
Fig. 21. (a) Representation of pH dependent sulphonamide ligation in europium complex 37. (b) Changes in the Eu emission intensity ratio and excited state lifetimes (t) for 37 as a function of pH. The figures are reproduced from Ref. [76] with the permission.
CH1 (ovarian carcinoma), and SW480 (colon adenocarcinoma) in micromolar concentrations [69]. Very interestingly this complex was localized both in the ER and lysosomes (Fig. 17b). The oxovanadium(IV) vitamin-B6 Schiff base complex of formulation [VO(HL1)(acdppz)]Cl (33) (acdppz is 11-(9-acridinyl) dipyrido[3,2-a:20 ,30 -c]phenazine and H2L1∙HCl is 3-hydroxy-5-(hy droxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyri din-1-ium chloride) reported by Chakravarty and co-workers
showed tumor selective ER targeting photocytotoxicity (Fig. 18a) [70,71]. The complex was highly stable in cellular medium and was photo-stability under 400–700 nm visible light irradiation. Preferential uptake of this complex to MCF-7 and HeLa cancer cells over MCF-10A normal cells was due to the vitamin-B6 transporting membrane carrier (VTC) mediated entry of the complex. The complex with acdppz moiety acted as an excellent photosensitizer for photodynamic therapy (PDT) with nano-molar IC50 upon light irra-
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
diation (400–700 nm, 1 h) while was not toxic even treated with up to 40 mM of 33 in the dark and also to the normal MCF-10A cells both upon light irradiation and under the dark. Importantly, photocytotoxicity of the complex was 10 times higher compared to the FDA approved drug PDT drug PhotofrinÒ. Fluorescence microscopy revealed that the complex localized in the ER and thereafter generates reactive oxygen species (ROS) upon photo-irradiation. The ER localization of the complex and generation of ROS resulted in cell apoptosis possibility by triggering ER stress response (Fig. 18b). Another report from the same group indicated the ability of Iron (III) complexes of vitamin B6 with the general formulae [Fe(B)(L)] NO3 (34, 35) (B: (anthracen-9-yl)-N,N-bis((pyridin-2-yl)methyl)m ethanamine in 2; (pyren-1-yl)-N,N-bis((pyridin-2-yl)-methyl)met hanamine in 3 and H2L is 3-hydroxy-5-(hydroxymethyl)-4-(((2-h ydroxyphenyl)imino)methyl)-2-methylpyridine) as ER targeting visible light photocytotoxicity agents for PDT application (Fig. 19) [72]. Complexes were 10-fold more potent as anticancer agents when irradiated with visible light of 400–700 nm for 1 h than that of the dark. A report by L. Yu et al., in 2018 showed the potential of a glutathione (GSH)-responsive biotinylated zinc(II) phthalocyanine as a targeted photodynamic therapeutic agent [73]. The biotinylated zinc(II) phthalocyanine (36) (Fig. 20) localized in the ER and its fluorescence and singlet oxygen generation ability were silenced due to presence of 2,4-dinitrobenzenesulfonyl moiety. The complex shows ca. 3 times higher uptake in human hepatocarcinoma cells (HepG2 cells; known for higher biotin receptor expression) compared to the Chinese hamster ovary (CHO cells with lower biotin receptor expression), indicating the tumor selective nature of the complex. Under high GSH concentration, the complex restored its
13
photosensitizing ability in phosphate buffered saline and inside cancer cells. In HepG2 cells, it gave a nanomolar photocytotoxicity (IC50 = 0.1 mM; 2 h incubation, 20 min illumination, Light source: 300 W halogen lamp, Newport, cut-on 610 nm, total fluence: 21.6 Jcm2) by generating ER stress. All these 3d metals-based ER targeting anticancer complexes indicate the future potential of 3d metal complexes for the next generation ER targeting anticancer drug development. As most of the 3d metals are essential elements of human life, 3d metal complexes are expected to have less side effects or inherent metal toxicity compared to the heavy 4d/5d metals [74,75]. Moreover, considering the availability and cost of these 3d metals, it is expected that any 3d metal based anticancer drug will be much less expensive compared to the platinum based chemotherapeutics. 6. Metal complexes for probing ER polarity The pursuit of non-invasive, responsive optical probes which target specific organelles for the real time bioactive species tracking in live cells remain a challenging area of research. In particular, reliable probes that represent change of intracellular pH have potential to monitor several pathological and physiological processes. David Parker and et al., in 2013 reported a europium based probe (37) to monitor the change in pH within the endoplasmic reticulum of live cells (Fig. 21a) [76]. Earlier works by Kim et al., and J. Lopis et al., indicated that significant communication occurs with the homeostatic mechanism that controls cytosolic pH due to the large proton permeability of the ER membrane [77,78]. Based
Fig. 22. (a) Structure of the complex 39 for probing polarity in the ER. (b) Confocal microscopy images of the live A549 cells incubated with 39 alone (10 lM) at different time points. (c) Confocal microscopy images of the live A549 cells incubated with both the complex 32 and ER stress stimulus tunicamycin (Tm, 50 lg mL1) at different time points. The figures are reproduced from Ref. [79] with the permission. In this minireview, the recent development in the endoplasmic reticulum (ER) imaging and ER targeting anticancer 1st–3rd row metal complexes are detailed discussed.
14
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178
on the unique fluorescent property of europium complex, timegated spectral imaging microscope was applied to measure the pH via intensity ratio of emission bands or the variation of excited state lifetime. Notably, each method was independent of complex concentration. Such imaging technology effectively enhanced signal-to-noise ratio by filtrating the short-lived background autofluorescence and light scattering from the surrounding biological environment. The value of ER pH was measured to be 7.15, like that found within the cytoplasm (7.1, Fig. 21b). In addition to pH, the polarity of ER is the feedback of a series of complicated mechanisms that establish and maintain functionality of particular domains. Many cellular processes involved in the spatial arrangement and protein composition such as differentiation, localized membrane growth, activation of the immune response, directional cell migration, and vectorial transport of molecules across cell layers may lead to change and development of ER polarity. Zhang and colleagues reported sensitively tracked the changes in the ER micro-environmental polarity using an iridium(III) complex 38 (Fig. 22) as fluorescent probe [79]. This probe exclusively targeted the ER and successfully tracked the polarity variations during ER stress in live cells in situ. Importantly, this complex 38 can also be used to monitor the blood polarity of diabetes. In the presence of blood from diabetic mice 38 exhibited distinguished phosphorescence compared with that from normal mice.
7. Future direction and conclusion As over the past decades, researchers are highly interested to develop metal based anticancer drugs with reduced side effects and drug resistance as the potential alternative of FDA proved and widely used platinum-based chemotherapeutics [5–20], ER targeting anticancer drug development is now a very hot area of research. The ER, so far, compared to the other cellular organelles is not well documented as a cancer drug target, but selective disruption of ER function by ER-targeting molecules in cancer cells has the potential to unlock a new gate of next-generation cancer drug development and cancer treatment [26,40–42]. To this direction all the above reported literatures are very much valuable to extend and broaden this research to reach the ultimate goal- ‘‘ER targeting anticancer drugs for clinical use”. Moreover, few of the above complexes (9–39) indicate that suitable metal-based ER tracker is indeed possible to develop for biological research. Complexes 37 and 39 indicate the potential of metal-based probes for monitoring change in the ER polarity during ER stress in live cells. The complexes discussed in this review did not show distinct structure-activity relationship to target the ER mainly due to a very limited no of ER-targeting metal complexes for comparison, thus the observations of ER localization of the above complexes were serendipitous in nature. When we tried to develop a statures activity relationship based on the literature reports, we see ER-targeting complexes have some common features like: (i) positively charged (ii) liphophilic (iii) molecular weight >500 g/mol. Overall, this new and hot area of research is highly exciting considering the facts that this might introduce triple action (imaging, polarity probe and therapy) metal complexes in cancer therapy. But ‘‘miles to go” for this newly born research for it’s translation from laboratory to clinic. A few very important issues need to be addressed such as (i) How to design selectively ER targeting metal complexes? Few studies indicated that the strong hydrophobicity of a molecule is one of its main driving forces for its selective accumulation in the ER, but it’s not a very straight forward guidance for developing ER targeting molecules. (ii) How to develop tumor recognizing and simultaneously ER targeting metal complexes? To achieve this goal ER targeting metal complexes probably have to attach with tumor recognizing moieties such as biotin, peptides,
folic acid etc. (iii) How to improve therapeutic efficacy of such ER targeting complexes? Probably the ER targeting metal complexes which can target specifically cancer cells over normal cells and generate ER stress will have the potential to address this issue. In this context, biocompatible metal such as iron, copper, zinc complexes will be interesting candidates as by using such metal, the inherent metal toxicity can be minimized. Moreover ER targeting photoactive complexes can provide both the temporal and spatial control over the anticancer drug action as such photoactive complexes will only be anticancer active at the target tumor site upon light irradiation. Using such design the issues of drug side effect and drug resistance can be overcome. Design of water soluble ER targeting metal complexes potentially can increase the in-vivo bioavailability of the drug. Moreover, ER targeting, cancer cells specific, photoactive and catalytic metal complexes which can alter the intracellular redox balance via catalytic mode of action only after photo-irradiation will have the potential as clinical ER targeting anticancer drugs. Acknowledgements We appreciate the financial support of the Sun Yat-sen University Startup fund 75110-18841213 and the Sun Yat-sen University Undergraduate Teaching ‘‘Quality Engineering” project 7511018842502 and the Fundamental Research Funds for the Central Universities project 75110-31610005 for H.H.; the National Natural Science Foundation of China (NSFC, 21701113); the Natural Science Foundation of SZU (2018036) and Peacock Talent Fund (827-000389) for P.Z. Declaration of Competing Interest The author declares no competing financial interests. References [1] K.D. Mjos, C. Orvig, Chem. Rev. 114 (2014) 4540–4563. [2] T.C. Johnstone, K. Suntharalingam, S.J. Lippard, Chem. Rev. 116 (2016) 3436– 3486. [3] A. Terenzi, C. Pirker, B.K. Keppler, W. Berge, J. Inorg. Biochem. 165 (2016) 71– 79. [4] M. Wenzel, A. Casini, Coord. Chem. Rev. 352 (2017) 432–460. [5] K. Laws, G. Bineva-Todd, A. Eskandari, C. Lu, N. O’Reilly, K. Suntharalingam, Angew. Chem. Int. Ed. 57 (2018) 287–291. [6] Z. Liu, P.J. Sadler, Acc. Chem. Res. 47 (2014) 1174–1185. [7] M. Patra, G. Gasser, Nat. Rev. Chem. 1 (2017) 0066. [8] B. Albada, N. Metzler-Nolte, Chem. Rev. 116 (2016) 11797–11839. [9] J.P.C. Coverdale, I. Romero-Canelón, C. Sanchez-Cano, G.J. Clarkson, A. Habtemariam, M. Wills, P.J. Sadler, Nat. Chem. 10 (2018) 347–354. [10] A.K. Renfrew, N.S. Bryce, T. Hambley, Chem. Eur. J. 21 (2015) 15224–15234. [11] S. Banerjee, J.J. Soldevila-Barreda, J.A. Wolny, C.A. Wootton, A. Habtemariam, I. Romero-Canelón, F. Chen, G.J. Clarkson, I. Prokers, L. Song, P.B. O’Connor, V. Schünemann, P.J. Sadler, Chem. Sci. 9 (2018) 3177–3185. [12] H. Huang, S. Banerjee, P.J. Sadler, ChemBioChem. 19 (2018) 1574–1589. [13] S.H.C. Askes, S. Bonnet, Nat. Rev. Chem. 2 (2018) 437–452. [14] S. Bonnet, Dalton Trans. 47 (2018) 10330–10343. [15] K. Qiu, Y. Chen, T.W. Rees, L. Ji, H. Chao, Coord. Chem. Rev. 378 (2019) 66–86. [16] S. Banerjee, A.R. Chakravarty, Acc. Chem. Res. 48 (2015) 2075–2083. [17] P. Zhang, H. Huang, Dalton Trans. 47 (2018) 14841–14854. [18] K.K.W. Lo, Acc. Chem. Res. 48 (2015) 2985–2995. [19] C. Imberti, P. Zhang, H. Huang, P.J. Sadler, Angew. Chem. Int. Ed. 132 (2020) 61–73. [20] P. Zhang, H. Huang, S. Banerjee, G.J. Clarkson, C. Ge, C. Imberti, P.J. Sadler, Angew. Chem. Int. Ed. 131 (2019) 2372–2376. [21] T. Sarkar, S. Banerjee, S. Mukherjee, A. Hussain, Dalton Trans. 45 (2016) 6424– 6438. [22] T. Sarkar, S. Banerjee, A. Hussain, RSC Adv. 5 (2015) 16641–16653. [23] L. He, C.P. Tan, R.R. Ye, Y.Z. Zhao, Y.H. Liu, Q. Zhao, L.N. Ji, Z.W. Mao, Angew. Chem. Int. Ed. 53 (2014) 12137–12141. [24] W. Zhou, X. Wang, M. Hu, C. Zhu, Z. Guo, Chem. Sci. 5 (2014) 2761–2770. [25] H. Huang, L. Yang, P. Zhang, K. Qiu, J. Huang, Y. Chen, J. Diao, J. Liu, L. Ji, J. Long, H. Chao, Biomaterials 83 (2016) 321–331. [26] J.R. Cubillos-Ruiz, S.E. Bettigole, L.H. Glimcher, Cell 168 (2017) 692–706. [27] J. Mandl, T. Mészáros, G. Bánhegyi, L. Hunyady, M. Csala, Trends. Endocrin. Met. 20 (2009) 194–201.
C. Huang et al. / Coordination Chemistry Reviews 408 (2020) 213178 [28] D.W. Reid, C.V. Nicchitta, Nat. Rev. Mol. Cell. Bio. 16 (2015) 221–231. [29] L.M. Westrate, J.E. Lee, W.A. Prinz, G.K. Voeltz, Annu. Rev. Biochem. 84 (2015) 791–811. [30] T.A. Rapoport, Nature 450 (2007) 663–669. [31] D.N. Hebert, S.C. Garman, M. Molinari, Trends. Cell. Biol. 15 (2005) 364–370. [32] C.H. Jan, C.C. Williams, J.S. Weissman, Science 346 (2014) 1257521. [33] D.S. Schwarz, M.D. Blower, Cell. Mol. Life. Sci. 73 (2016) 79–94. [34] M. Wang, R.J. Kaufman, Nature 529 (2016) 326–335. [35] E. Bahar, J.Y. Kim, H. Yoon, Cancers 11 (2019) 338. [36] R.K. Yadav, S.W. Chae, H.R. Kim, H.J. Chae, J. Cancer. Prev. 19 (2014) 75–88. [37] R. Sano, J.C. Reed, BBA-Mol. Cell. Res. 1833 (2013) 3460–3470. [38] S.J. Marciniak, FEBS. J. 286 (2019) 228–231. [39] K. Nowotny, J.P. Castro, M. Hugo, S. Braune, D. Weber, M. Pignitter, V. Somoza, J. Bornhorst, T. Grune, Free. Radical. Bio. Med. 120 (2018) 102–113. [40] J.C. Simard, I. Durocher, D. Girard, Apoptosis 21 (2016) 1279–1290. [41] M. Wang, R.J. Kaufman, Nat. Rev. Cancer 14 (2014) 581–597. [42] S. Banerjee, W. Zhang, ChemBioChem 19 (2018) 2341–2343. [43] J.D. Malhotra, R.J. Kaufman, Antioxid. Redox, Sign. 9 (2007) 2277–2294. [44] B. Bhandary, A. Marahatta, H.R. Kim, H.J. Chae, Int. J. Mol. Sci. 14 (2012) 434– 456. [45] Q. Rao, M. Yang, G. Liu, H. Zhang, H. Xu, J. Wang, Y. Tian, J. Yu, A. Wang, H. Zhou, Dyes. Pigments. 169 (2019) 60–65. [46] H. Xiao, R. Zhang, C. Wu, P. Li, W. Zhang, B. Tang, Sensor. Actuat. B-Chem. 273 (2018) 1754–1761. [47] H. Xiao, X. Liu, C. Wu, Y. Wu, P. Li, X. Guo, B. Tang, Biosen. Bioelectron. 91 (2017) 449–455. [48] P. Shen, S. Ohta, S. Inasawa, Y. Yamaguchi, Chem. Commun. 47 (2011) 8409– 8411. [49] C. Ghosh, A. Nandi, S. Basu, Nanoscale 11 (2019) 3326–3335. [50] L. McDonald, B. Liu, A. Taraboletti, K. Whiddon, L.P. Shriver, M. Konopka, Q. Liu, Y. Pang, J. Mater. Chem. B 4 (2016) 7902–7908. [51] A. Hambrock, C. Löffler-Walz, U. Quast, Br. J. Pharmacol. 136 (2002) 995–1004. [52] A.J. Smith, T.K. Taneja, J. Mankouri, A. Sivaprasadarao, Expert Rev. Mol. Med. 9 (2007) 1–17. [53] W.L. Kwong, R.W.Y. Sun, C.N. Lok, F.M. Siu, S.Y. Wong, K.H. Low, C.M. Che, Chem. Sci. 4 (2013) 747–754. [54] A. Hussain, K. Somyajit, B. Banik, S. Banerjee, G. Nagaraju, A.R. Chakravarty, Dalton Trans 42 (2013) 182–195. [55] A. Hussain, A.R. Chakravarty, J. Chem. Sci. 124 (2012) 1327–1342. [56] R. Jastrza˛b, M. Nowak, M. Skroban´ska, A. Tolin´ska, M. Zabiszak, M. Gabryel, Ł. Marciniak, M.T. Kaczmarek, Coordin, Chem. Rev. 382 (2019) 145–159.
15
[57] R.W.Y. Sun, C.N. Lok, T.T.H. Fong, C.K.L. Li, Z.F. Yang, T. Zou, A.F.M. Siu, C.M. Che, Chem. Sci. 4 (2013) 1979–1988. [58] M.J. Chow, C. Licona, G. Pastorin, G. Mellitzer, W.H. Ang, C. Gaiddon, Chem. Sci. 7 (2016) 4117–4124. [59] M.J. Chow, M.V. Babak, K.W. Tan, M.C. Cheong, G. Pastorin, C. Gaiddon, W.H. Ang, Mol. Pharmaceut. 15 (2018) 3020–3031. [60] P. Zou, M. Chen, J. Ji, W. Chen, X. Chen, S. Ying, J. Zhang, Z. Zhang, Z. Liu, S. Yang, G. Liang, Oncotarget 6 (2015) 36505–36521. [61] T. Zou, C.N. Lok, Y.M.E. Fung, C.M. Che, Chem. Commun. 49 (2013) 5423–5425. [62] R. Cao, J. Jia, X. Ma, M. Zhou, H. Fei, J. Med. Chem. 56 (2013) 3636–3644. [63] S. Mandal, D.K. Poria, R. Ghosh, P.S. Ray, P. Gupta, Dalton Trans. 43 (2014) 17463–17474. [64] T.F. Anjong, G. Kim, H.Y. Jang, J. Yoon, J. Kim, New J. Chem. 41 (2017) 377–386. [65] J.S. Nam, M.G. Kang, J. Kang, S.Y. Park, S.J.C. Lee, H.T. Kim, J.K. Seo, O.H. Kwon, M.H. Lim, H.W. Rhee, T.H. Kwon, J. Am. Chem. Soc. 138 (2016) 10968–10977. [66] A.A. Rowland, G.K. Voeltz, Nat. Rev. Mol. Cell. Biol. 13 (2012) 607–625. [67] B. Yuan, J. Liu, R. Guan, C. Jin, L. Ji, H. Chao, Dalton Trans. 48 (2019) 6408–6415. [68] M.R. Gill, D. Cecchin, M.G. Walker, R.S. Mulla, G. Battaglia, C. Smythe, J.A. Thomas, Chem. Sci. 4 (2013) 4512–4519. [69] M.F. Primik, S. Göschl, S.M. Meier, N. Eberherr, M.A. Jakupec, E.A. Enyedy, G. Novitchi, V.B. Arion, Inorg. Chem. 52 (52) (2013) 10137–10146. [70] S. Banerjee, A. Dixit, R.N. Shridharan, A.A. Karande, A.R. Chakravarty, Chem. Commun. 50 (2014) 5590–5592. [71] S. Banerjee, A. Dixit, A.A. Karande, A.R. Chakravarty, Dalton Trans. 45 (2016) 783–796. [72] U. Basu, I. Pant, A. Hussain, P. Kondaiah, A.R. Chakravarty, Inorg. Chem. 54 (2019) 3748–3758. [73] L. Yu, Q. Wang, K.W. Yeung, W.P. Fong, P.C. Lo, Chem-Asian. J. 13 (2018) 3509– 3517. [74] A. Jan, M. Azam, K. Siddiqui, A. Ali, I. Choi, Q. Haq, Int. J. Mol. Sci. 16 (2015) 29592–29630. [75] S.M. Page, S.R. Boss, P.D. Barker, Future Med. Chem. 1 (2009) 541–559. [76] B.K. McMahon, R. Pal, D. Parker, Chem. Commun. 49 (2013) 5363–5365. [77] J.H. Kim, L. Johannes, B. Goud, C. Antony, C.A. Lingwood, R. Daneman, S. Grinstein, Proc. Natl. Acad. Sci. USA 95 (1998) 2997–3002. [78] J. Llopis, J.M. McCaffery, A. Miyawaki, M.G. Farquhar, R.Y. Tsien, Proc. Natl. Acad. Sci. USA 95 (1998) 6803–6808. [79] Q. Tang, X. Zhang, H. Cao, G. Chen, H. Huang, P. Zhang, Q. Zhang, Dalton Trans. 48 (2019) 7728–7734.