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The preparation of three families of phosphorescent iridium(III) emitters, including iridaoxazole derivatives, hydroxycarbene compounds, and N,C(sp³),C(sp²),O-tetradentate containing complexes, has been performed starting from dimers cis-[Ir(μ²-η²-C≡CR){κ²-C,N-(MeC₆H₃-py)}₂]₂ (R = ^tBu (1a), Ph (1b)). Reactions of 1a with benzamide, acetamide, phenylacetamide, and trifluoroacetamide lead to the iridaoxazole derivatives Ir{κ²-C,O-[C(CH₂^tBu)NC(R)O]}{κ²-C,N-(MeC₆H₃-py)}₂ (R = Ph (2), Me (3), CH₂Ph (4), CF₃ (5)) with a fac disposition of carbons and heteroatoms around the metal center. In 2-methyltetrahydrofuran and dichloromethane, water promotes the C-N rupture of the IrC-N bond of the iridaoxazole ring of 3-5 to form amidate-iridium(III)-hydroxycarbene derivatives Ir{κ¹-N-[NHC(R)O]}{κ²-C,N-(MeC₆H₃-py)}₂{═C(CH₂^tBu)OH} (R = Me (6), CH₂Ph (7), CF₃ (8)). In contrast to 1a, dimer 1b reacts with benzamide and acetamide to give Ir{κ⁴-N,C,C',O-[py-MeC₆H₃-C(CH₂-C₆H₄)NHC(R)O]}{κ²-C,N-(MeC₆H₃-py)}(R = Ph (9), Me (10)), which bear a N,C(sp³),C(sp²),O-tetradentate ligand resulting from a triple coupling (an alkynyl ligand, an amide, and a coordinated aryl group) and a C-H bond activation at the metal coordination sphere. Complexes 2-4 and 6-10 are emissive upon photoexcitation, in orange (2-4), green (6-8), and yellow (9 and 10) regions, with quantum yields between low and moderate (0.01-0.50) and short lifetimes (0.2-9.0 μs). Show less

Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances. Show less

In this work, three iridium(III) tetrazolato complexes have been designed and successfully synthesized. Beside photophysical properties, their performances in protein staining have been comprehensively investigated in this work for the first time. Notably, these iridium(III) tetrazolato complexes with high quantum efficiency exhibited much better protein staining properties than the commercial agent Coomassie Brilliant Blue (CBB) under the same experimental conditions, which may pave the way to explore new efficient iridium-based protein staining agents both for commercial markets and academic research in the future. Show less

In this work, we have synthesized a series of novel C,N-cyclometalated 2H-indazole-ruthenium(II) and -iridium(III) complexes with varying substituents (H, CH₃, isopropyl, and CF₃) in the R₄ position of the phenyl ring of the 2H-indazole chelating ligand. All of the complexes were characterized by ¹H, ¹³C, high-resolution mass spectrometry, and elemental analysis. The methyl-substituted 2H-indazole-Ir(III) complex was further characterized by single-crystal X-ray analysis. The cytotoxic activity of new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of triple negative breast cancer (TNBC) cell lines (MDA-MB-231 and MDA-MB-468) and colon cancer cell line HCT-116 to investigate their structure-activity relationships. Most of these new complexes have shown appreciable activity, comparable to or significantly better than that of cisplatin in TNBC cell lines. R₄ substitution of the phenyl ring of the 2H-indazole ligand with methyl and isopropyl substituents showed increased potency in ruthenium(II) and iridium(III) complexes compared to that of their parent compounds in all cell lines. These novel transition metal-based complexes exhibited high specificity toward cancer cells by inducing alterations in the metabolism and proliferation of cancer cells. In general, iridium complexes are more active than the corresponding ruthenium complexes. The new Ir(III)-2H-indazole complex with an isopropyl substituent induced mitochondrial damage by generating large amounts of reactive oxygen species (ROS), which triggered mitochondrion-mediated apoptosis in TNBC cell line MDA-MB-468. Moreover, this complex also induced G2/M phase cell cycle arrest and inhibited cellular migration of TNBC cells. Our findings reveal the key roles of the novel C-N-cyclometalated 2H-indazole-Ir(III) complex to specifically induce toxicity in cancer cell lines through contributing effects of ROS-induced mitochondrial disruption along with chromosomal and mitochondrial DNA target inhibition. Show less

Two new coordination complexes of Cu(II) and Mn(II), viz., [Cu(bpy)(H2O)4]SO4·2H2O (1) and [Mn(4-CNpy)2(H2O)3SO4]·H2O (2) (bpy = 2,2′-bipyridine, 4-CNpy = 4-cyanopyridine), have been synthesized and characterized by using single crystal X-ray diffraction, elemental analysis, FT-IR spectroscopy, electronic spectroscopic techniques and TGA. The crystal structure of 1 uncovers the formation of sulfate–water assemblies involving lattice and coordinated water molecules, while complex 2 reveals the presence of unconventional weak T-shaped CN⋯CN contacts in the layered architecture. We have analysed the unconventional interesting interactions using DFT calculations, molecular electrostatic potential (MEP), the NCI plot and QTAIM computational tools. The interaction energies of the two H-bonded dimers in 1 are very large because of the coulombic attraction between the dicationic H-bonded donor and the dianionic acceptor. It is interesting to observe that despite the energy of the H-bonds being very small compared to the total dimerization energy, the final geometry of the assembly in 1 is due to the charge assisted directional H-bonds instead of the non-directional ion-pair interactions. The DFT study reveals that the T-shaped CN⋯CN interaction in 2 is very weak, in good agreement with the small MEP energy at the nitrile carbon atom. Anticancer studies of the compounds have been carried out using Dalton's lymphoma cell line using MTT and apoptosis assay. The results of compound 1 and 2 mediated cell cytotoxicity on the DL cancer cell line showed a significant concentration-dependent reduction in cell viability, while negligible cytotoxicity was observed in normal (PBMC) cells. The docking simulation results also confirm the interaction of the complexes with the active sites of amino acids of the target proteins. Furthermore, pharmacophore models (2D and 3D) for the compounds were mapped to the H-bond donor, positive ionisable area and hydrophobic features that are important for establishing biological activities. No hematotoxicity was recorded for the compounds after treatment in normal mice. Show less

A rise in atmospheric carbon dioxide levels, following years of burning fossil fuels, has brought about increase in global temperatures and climate change due to the green-house effect. As such, recent efforts aimed at addressing this problem have been directed to the use of carbon dioxide as an inexpensive and non-toxic single carbon source for making chemical products. Herein, we report the use of tetrazolyl complexes as catalysts precursors for hydrogenation of carbon dioxide. Specifically, tetrazolyl compounds bearing phosphorus-sulfur bonds have been synthesized with the view of using these as phosphorus-nitrogen bidentate tetrazolyl ligands that can coordinate to iridium(III) thereby forming heteroatomic five-member complexes. Interestingly, reacting the phosphorus-nitrogen bidentate tetrazolyl ligands with iridium dimer led to serendipitous isolation of chiral-at-metal iridium(III) half-sandwich complexes instead. The complexes were obtained via prior formation non-chiral iridium half-sandwich complexes. The complexes undergo initial phosphorus-sulfur bond heterolysis of the precursor ligands, which then ultimately results in new half-sandwich iridium complexes featuring monodentate phosphine co-ligands with proton responsive functionalities. Conditions necessary to significantly affect the rate of phosphorus-sulfur bond heterolysis in the precursor ligand and the subsequent coordination to iridium have been reported. The complexes served as catalyst precursors and exhibited activity in carbon dioxide and bicarbonate hydrogenation in excellent catalytic activity, at low catalyst loadings, producing concentrated formate solutions exclusively. Catalyst precursors with proton responsive phosphines were found to influence catalytic activity when present as racemates, while ease of dissociation of the ligand from the iridium centre was observed to influence activity in spite of the presence of electron-donating ligands. A test for homogeneity indicated that hydrogenation of carbon dioxide proceeded by homogenous means. Subsequently, the mechanism of the reaction by the iridium catalyst precursors was studied using proton NMR techniques. This revealed that a chiral-at-metal iridium hydride species generated in situ, served as the active catalyst. Show less

A new application for bis(cyclometalated) iridium(III) species containing ancillary acyclic diaminocarbene ligands, viz. for sensing of mercury(II) ions, is disclosed. A family of bis(cyclometalated) iridium(III) species supported by both parent isocyanide and acyclic diaminocarbene ligands was prepared, and their electrochemical and photophysical properties were evaluated, revealing efficient blue-green phosphorescence in solution with quantum yields of up to 55%. We uncovered that the photophysical properties of these complexes are dramatically altered by the presence of metal ions and that the complex [Ir(ppy)₂(CN){C(NH₂)(NHC₆H₄-4-X)}] with an ADC ligand reacts selectively with Hg²⁺ ions, enabling its use for sensing of mercury(II) ions in solution. The limit of detection was as low as 2.63 × 10^-7 M, and additional mechanistic studies indicated the formation of an unusual dinuclear iridium(III) cyclometalated intermediate, bridged by a mercury dicyano fragment as a driving force of mercury sensing. Show less

Ten manganese(I) tricarbonyl diimine complexes bound to variably functionalised 5‐aryl‐tetrazolato ligands were prepared, and their photochemical properties were investigated. Upon exposure to light at 365 nm, each complex decomposed to its free diimine and tetrazolato ligands, simultaneously dissociating three CO ligands, as evidenced by changes in the IR spectra of the irradiated complexes over time. The anti‐bacterial properties of one of these complexes were tested against Escherichia coli. While the complex displayed no effect on the bacterial growth in the dark, pre‐irradiated solutions inhibited bacterial growth. Comparative studies revealed that the antibacterial properties originate from the presence of free 1,10‐phenanthroline. Show less

Bis-ADC complexes cis-[Pd{C(NHC6H4NH2)N(H)R}2]Cl2 (R = Xyl 4a, Cy 4b, C6H4-4-F 4c) and cis-[Pt{C(NHC6H4NH2)N(H)R}2]Cl2 (R = Xyl 5a, Cy 5b, C6H4-4-F 5c) were synthesized via the metal-mediated coupling of two isocyanide ligands in cis-[MCl2(CNR)2] (M = Pd, Pt; R = Xyl, Cy, C6H4-4-F) and 1,2-diaminobenzene. New compounds 4c and 5a–c were characterized by HR ESI+-MS, IR, and 1H, 13C{1H} and 195Pt{1H} NMR spectroscopy; the structures of 4a and 5a were elucidated by single-crystal X-ray diffraction. The stability of the ADC complexes in aqueous media (5 mM NaCl) was monitored by UV absorption spectroscopy, HR ESI+ mass spectrometry, and 195Pt{1H} NMR spectroscopy (for 5a). Molar conductivity measurements in MeOH (ΛM = 167–173 Ω−1 mol−1 cm2) indicate that, in this solvent, the ADC complexes exist as dicationic species of [A][Q]2 type. The ADC complexes binding to CT DNA was investigated by means of spectroscopic and hydrodynamic techniques including UV absorption and circular dichroism spectroscopy, fluorescence spectroscopy, low-gradient viscometry, flow birefringence, and AFM imaging. As a result, complexes 4a and 5a were shown to bind double-stranded DNA predominantly via the formation of monofunctional adducts in the major groove of the macromolecule. Binding of the ADC complexes also provokes the formation of a large number of intermolecular DNA–DNA contacts in solution. The antiproliferative activity of all prepared ADC complexes 4a–c and 5a–c was evaluated in vitro against three human carcinoma cell lines (HT-29, MDA-MB-231, and MCF-7) and two non-tumorigenic cell lines (L929 and RC-124) and compared to that of cisplatin. Among the compounds studied, complexes 4a and 5a appeared to be the most active species with IC50 values in MCF-7 cells of about 10 μM. Show less

The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor-specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin-like growth factor-I receptor (IGF-IR), while PF-562,271 is a dual inhibitor of FAK and proline-rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF-562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF-562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF-IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future. Show less

RuII compounds have been universally investigated due to their unique physical and chemical properties. In this paper, a new RuII compound based on 2,2′‐bipy and Hpmtz [2,2′‐bipy = 2,2′‐bipyridine, Hpmtz = 5‐(2‐pyrimidyl)‐1H‐tetrazole], namely [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O was prepared and characterized by elemental analysis, IR and single‐crystal X‐ray diffraction. [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O shows a mononuclear structure and forms a three‐dimensional network by non‐classic hydrogen bonds. The ability of generation of ROS (reactive oxygen species) makes it has a low phototoxicity IC50 (half‐maximal inhibitory concentration) after Xenon lamp irradiation on Hela cells in vitro. The results demonstrate that [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O with high light toxicity and low dark toxicity may be a potential candidate for photodynamic therapy. Show less

The coupling of bis(xylylisocyanide) complex of Pd(II) with 1,2,4-thiadiazole-5-amines leads to the formation of an equilibrium mixture of the binuclear complexes. In each of the studied cases, one of the formed complexes is the kinetic product, and the other one is the thermodynamic product. The complexes which are thermodynamic products have been isolated in the pure form and characterized by means of high-resolution mass spectrometry, IR and NMR spectroscopy, and X-ray diffraction analysis. NMR study of the regioisomerization in a solution has revealed that the relative stability of the thermodynamic products in comparison with the kinetic ones is higher than for the corresponding regioisomers containing 1,3-thiazole or 1,3,4- thiadiazole fragment. Show less

The solution state of palladium cationic–anionic complexes (AmH n ) k [PdCl4] prepared for the first time, where Am is morpholine, methylmorpholine, aminoethylmorpholine, 5-aminovaleric acid, L-1-phenyl-2-methylaminopropanol, and m-xylilenediamine, has been studied by electronic absorption spectroscopy, NMR, and pH measurements. The agreement of obtained results for the state of the complexes in water and NaCl solutions with IR and X-ray diffraction data for these complexes has allowed us to substantiate the principle for designing patent formulation (C5H12NO)2[PdCl4], a new type of palladium complexes, palladium(II) cationic–anionic complexes showing high antitumor and antimetastatic activity. Crystallographic data for six obtained complexes have been presented. Show less

AbstractWhile NMR and IR spectroscopic signatures and structural characteristics of low‐barrier hydrogen bond (LBHB) formation are well documented in the literature, direct measurement of the LBHB energy is difficult. Here, we show that solid‐state 17O NMR spectroscopy can provide unique information about the energy required to break a LBHB. Our solid‐state 17O NMR data show that the HB enthalpy of the O⋅⋅⋅H⋅⋅⋅N LBHB formed in crystalline nicotinic acid is only 7.7±0.5 kcal mol−1, suggesting that not all LBHBs are particularly strong. Show less

The role of copper in the proliferation of cancer cells is under investigation and has been explored in the context of cancer chemotherapy. The evidence that proliferation of cancer cells requires a higher abundance of Cu(II) than their normal counterparts has prompted the development of new copper chelators that can avidly bind copper ions, forming redox active metal complexes that ultimately lead to harmful reactive oxygen species (ROS) in neoplasms. In this context, the mandatory properties of the chelators for medical applications are safety (neglectable cytotoxicity), high binding affinity and selectivity towards Cu(II). We report the synthesis, structure (calculations and single crystal X-ray diffraction), spectroscopic (IR; UV-Vis) and magnetic properties of two novel copper(II) complexes based on 5-(3-aminosaccharyl)-tetrazoles (TS and 2MTS), as well as their in vitro cytotoxicity against the human hepatic carcinoma cell line HepG2. Quite interestingly, we found that the saccharinate-tetrazoles tested exhibit strong binding selectivity to Cu(II), over Fe(II) and Ca(II). Additionally, the corresponding copper complexes have shown a huge increase in the in vitro cytotoxicity against tumoral cells, compared to the corresponding nontoxic ligands. Thus, the new ligands may be viewed as potential precursors of selective cytotoxic agents, acting as non-cytotoxic pro-drugs that can be activated inside neoplastic cells, known to be richer in Cu(II) than the corresponding normal cells. Show less

A nucleosome is made up of DNA and histones, and acetylation of histones perturbs the interaction of DNA and histones and thus affects the chromatin conformation and function. However, whether or how acetylation induces DNA conformation changes is still elusive. In this work, we applied FT-IR spectroscopy to monitor the DNA signals in cells as the histone acetylation was regulated by trichostatin A (TSA), a reversible inhibitor to histone deacetylases (HDACs). Our results unambiguously demonstrate the significant transformation of B-DNA to Z-DNA upon histone acetylation in the TSA treated HeLa cells. This is the first report providing the explicit experimental evidence for such a B-Z transformation of DNA in the epigenetic states of cells. Show less

AbstractComplexation studies of the dinucleating ligand H3L (H3L=2‐{[bis(pyridin‐2‐ylmethyl)amino]methyl}‐6‐{[bis(6‐pivaloylamidopyridin‐2‐ylmethyl)amino]methyl}‐4‐methylphenol), with metal‐binding sites A and B, which both provide four donors to a metal ion; a tertiary amine; two pyridines (substituted with amide hydrogen‐bond donors in site B), and a bridging phenolate, with ZnII, CuII, and GaIII are reported. The titration of H3L with the three metal ions in solution was monitored by NMR spectroscopy or EPR and UV/Vis/near‐IR spectroscopy, as well as by ESI‐MS to analyze the selectivity of the two metal‐ion sites A and B of this model ligand for metallophosphatases; the spectroscopic assignments are supported by X‐ray crystallography results. The first ZnII ion coordinates to site A with unsubstituted pyridine donors and, upon addition of a second equivalent of ZnII, this coordinates to the sterically less accessible site B. From a similar titration with GaIII, it emerges that only a mononuclear complex is obtained, with the GaIII center coordinated to site A. When one equivalent of GaIII is reacted with the mononuclear ZnII complex, ZnII is forced by GaIII to exchange the site; this results in a dinuclear complex with GaIII in site A and ZnII in site B. With CuII, two isomers are observed: one with and the other without a bridging phenolate; these differ significantly in their spectroscopic and magnetic properties. Show less

AbstractNew iridium tetrazolate complexes containing o‐, m‐, or p‐carboranyl substitution in different positions of a phenylpyridine ligand have been prepared. The carborane isomers and the effect of their substitution position in the tuning of optical properties have been examined. The neutral complexes with the carboranyl substituent on the phenyl ring in meta position relative to the metal exhibit redshifted emission bands in contrast to blueshifts for those with carboranyl in para position. All cationic complexes display evidently blueshifted dual‐peak emission compared with the carborane‐free complex (c‐TZ) with a broad single‐peak emission. Introduction of carborane leads to a blueshift over 70 nm relative to c‐TZ. Carboranes also significantly improve phosphorescence efficiency (ΦP) and lifetime (τ), that is, ΦP=0.64 versus 0.21 (c‐TZ) and τ=880 ns versus 241 ns (c‐TZ). The unique hydrophilic nido‐carborane‐based IrIII complex nido‐o‐1 shows the largest phosphorescence efficiency (abs ΦP=0.57) among known water‐soluble iridium complexes, long emission lifetime (τ=4.38 μs), as well as varying emission efficiency and lifetime with O2 content in aqueous solution. Therefore, nido‐o‐1 has been used as an excellent oxygen‐sensitive phosphor for intracellular O2 sensing and hypoxia imaging. Show less

Readily synthesised and functionalised di-1,2,3-triazole “click” ligands are shown to self-assemble into coordinatively saturated, quadruply stranded helical [Pd2L4](BF4)4 cages with Pd(II) ions. The cages have been fully characterised by elemental analysis, HR-ESMS, IR, 1H, 13C and DOSY NMR, DFT calculations, and in one case by X-ray crystallography. By exploiting the CuAAC “click” reaction we were able to rapidly generate a small family of di-1,2,3-triazole ligands with different core spacer units and peripheral substituents and examine how these structural modifications affected the formation of the [Pd2L4](BF4)4 cages. The use of both flexible (1,3-propyl) and rigid (1,3-phenyl) core spacer units led to the formation of discrete [Pd2L4](BF4)4 cage complexes. However, when the spacer unit of the di-1,2,3-triazole ligand was a 1,4-substituted-phenyl group steric interactions led to the formation of an oligomeric/polymeric species. By keeping the 1,3-phenyl core spacer constant the effect of altering the “click” ligands’ peripheral substituents was also examined. It was shown that ligands with alkyl, phenyl, electron-rich and electron-poor benzyl substituents all quantitatively formed [Pd2L4](BF4)4 cage complexes. The results suggest that a wide range of functionalised palladium(II) “click” cages could be rapidly generated. These novel molecules may potentially find uses in catalysis, molecular recognition and drug delivery. Show less

Cardiolipin is a key lipid component in many biological membranes. Proton conduction and proton-lipid interactions on the membrane surface are thought to be central to mitochondrial energy production. However, details on the cardiolipin headgroup structure are lacking and the protonation state of this lipid at physiological pH is not fully established. Here we present ab initio DFT calculations of the cardiolipin (CL) headgroup and its 2'-deoxy derivative (dCL), with the aim of establishing a connection between structure and acid-base equilibrium in CL. Furthermore, we investigate the effects of solvation on the molecular conformations. In our model, both CL and dCL showed a significant gap between the two pK(a) values, with pK(a2) above the physiological range, and intramolecular hydrogen bonds were found to play a central role in the conformations of both molecules. This behavior was also observed experimentally in CL. Structures derived from the DFT calculations were compared with those obtained experimentally, collected for CL in the Protein Data Bank, and conformations from previous as well as new molecular dynamics simulations of cardiolipin bilayers. Transition states for proton transfer in CL were investigated, and we estimate that protons can exchange between phosphate groups with an approximate 4-5 kcal/mol barrier. Computed NMR and IR spectral properties were found to be in reasonable agreement with experimental results available in the literature. Show less