Rhenium Tricarbonyl Complexes Research Articles

Synthesis and characterization of novel naphthalene-derivatized tridentate ligands and their net neutral rhenium tricarbonyl complexes and cytotoxic effects on non-small cell lung cancer cells of interest

Rhenium complexes have possible fluorescence imaging, radioimaging and therapeutic applications and can also serve as a model system for 99mTc. The quest for new pharmaceutical agents is thus an expanding area of research. In this study, we report two net neutral complexes, [Re(CO)3(N(SO2)(1-nap)dien)] and [Re(CO)3(N(SO2)(2-nap)dien)], synthesized by treating fac-[Re(CO)3(H2O)3]+ with two novel tridentate ligands, (N(SO2)(1-nap)dienH and N(SO2)(2-nap)dienH), derived from diethylenetriamine (dien) attached to a sulfonamide group. The compounds were characterized by UV–Visible, FTIR, 1H NMR and fluorescence spectroscopies, together with X-ray crystallography. It is evident from the 1H NMR spectroscopic data recorded in DMSO‑d6 as well as X-ray crystallography supported by FTIR data, that upon coordination to the metal centre, the sulfonamide nitrogen atom is deprotonated and the ligand binds with the metal in a tridentate fashion. Both the complexes have a distorted octahedral structure where the Re(I) metal is coordinated by three nitrogen atoms of the dien backbone and three CO ligands. Emission spectra were recorded in methanol and an enhanced fluorescence emission was observed in the 330–345 nm range for the ligands while the corresponding Re complexes showed no or quenched fluorescence intensities. The in vitro cytotoxic activity of the synthesized compounds was examined using NCI-H292 (non-small cell lung cancer cells) and MRC-5 (the human normal lung fibroblast cell line). The highest cytotoxic activity was observed for the [Re(CO)3(N(SO2)(1-nap)dien)] complex on NCI-H292 cells with an IC50 value of 9.91 μM at 48 h. However all four compounds show acute cytotoxicity for MRC-5 cells at 24 h. The promising cytotoxic activity of the novel ligands and metal complexes indicate that these compounds may be good candidates to be utilized as anticancer drug leads against lung cancer.

Exploring ovarian cancer cell resistance to rhenium anticancer complexes.

Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO)3(dmphen)(ptolICN)]+, where dmphen = 2,9-dimethyl-1,10-phenanthroline and ptolICN = para-tolyl isonitrile, called TRIP. This TRIP-resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild-type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP-resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184-fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP-binding cassette transporter P-glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report high-lights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes.

Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO)3 (dmphen)(ptolICN)]+ , where dmphen=2,9-dimethyl-1,10-phenanthroline and ptolICN=para-tolyl isonitrile, called TRIP. This TRIP-resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild-type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP-resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184-fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP-binding cassette transporter P-glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report highlights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.

Excited-State Switching Frustrates the Tuning of Properties in Triphenylamine-Donor-Ligand Rhenium(I) and Platinum(II) Complexes.

The photophysical properties of a series of rhenium(I) tricarbonyl and platinum(II) bis(acetylide) complexes containing a triphenylamine (TPA)-substituted 1,10-phenanthroline ligand have been examined. The complexes possess both metal-to-ligand charge-transfer (MLCT) and intraligand charge-transfer (ILCT) transitions that absorb in the visible region. The relative energies and ordering of the absorbing CT states have been successfully controlled by changing the metal center and modulating the donating ability of the TPA group through the addition of electron-donating methoxy and electron-withdrawing cyano groups. The ground-state properties behave in a predictable manner as a function of the TPA substituent and are characterized with a suite of techniques including electronic absorption spectroscopy, resonance Raman spectroscopy, electrochemistry, and time-dependent density functional theory calculations. However, systematic control over the ground-state properties of the complexes does not extend to their excited-state behavior. Unexpectedly, despite variation of both the MLCT and ILCT state energies, all of the luminescent complexes displayed near-isoenergetic emission at 298 K, yet the emissive lifetimes of the complexes vary from 290 ns to 3.9 μs. Excited-state techniques including transient absorption and transient resonance Raman, combined with a suite of quantum-chemical calculations, including scalar relativistic effects to elucidate competitive excited-state relaxation pathways, have been utilized to aid in assignment of the long-lived state in the complexes, which was shown to possess differing 3MLCT and 3ILCT contributions across the series.

Cytotoxic Properties of Rhenium(I) Tricarbonyl Complexes Supported by S,N,S'-Pincer Ligands

Cytotoxic Properties of Rhenium(I) Tricarbonyl Complexes Supported by S,N,S'-Pincer Ligands

Towards better understanding of photophysical properties of rhenium(I) tricarbonyl complexes with terpy-like ligands.

Series of Re(I) carbonyls complexes were designed and synthesized to explore the impact of the triimine skeleton and number of methoxy groups attached to aryl substituents on their optoelectronic and thermal properties. The chemical structures of the prepared complexes were confirmed by 1H and 13C NMR spectroscopy, HR-MS, elemental anlsysis, and X-ray measurements. DSC measuremtns showed that they melted in the range of 198-325 °C. Some of them form stable molecular glasses with high glass transition temperatures (158-173 °C). Experimentally obtained optical properties were supported by DFT calculations. The UV-Vis spectra display a series of overlapping absorption bands in the range 200-350 nm, and much weaker broad band in the visible spectral region, due to intraligand and charge transfer transitions, respectively. All synthesized complexes were emissive in solution and in solid state as powder. Moreover, when applied in diodes, some of them exhibited ability for emission of light under external voltage with maximum of electroluminescence band located at 591-630 nm.

Cover Feature: Light‐Activated Rhenium Complexes with Dual Mode of Action against Bacteria (Chem. Eur. J. 13/2020)

The synthesis and characterization of a blue-light-activated rhenium tricarbonyl complex with antibacterial activity against methicillin resistant S. aureus and colistin resistant E. coli are described. Distinct activity profiles are observed in the presence and absence of light. Cellular uptake experiments in different E. coli mutants and synergy experiments with other antibiotics point to two distinct modes of action. More information can be found in the Full Paper by A. Frei, M. A. T. Blaskovich, et al. on page 2852.

Dinuclear phosphorescent rhenium(I) complexes as potential anticancer and photodynamic therapy agents.

Chemotherapeutic agents that affect lysosomal functions represent a promising strategy for selective tumor therapy and overcoming drug resistance. In this work, two dinuclear phosphorescent rhenium(i) tricarbonyl complexes (DRe1 and DRe2) containing carboline derivatives have been synthesized, characterized and explored as potential chemotherapeutic and photodynamic therapy agents. The two dinuclear rhenium(i) complexes have good intrinsic phosphorescence properties and can label the lysosomes in cancer cells. Both dinuclear rhenium(i) complexes show potent anticancer activities toward several tested cancer cells. Moreover, they also have marked inhibitory activities against cisplatin-resistant human lung carcinoma cells (A549R), with complex DRe2 displaying 16-fold higher activity than cisplatin. Mechanism studies reveal that complex DRe2 can induce cancer cells to overproduce reactive oxygen species (ROS), including superoxide anion radicals, which leads to lysosomal membrane permeabilization (LMP) and subsequent cell apoptosis. Additionally, both DRe1 and DRe2 display significant phototoxicity under light (425 nm) irradiation in A549 cells, with phototoxicity index values of 60.8 and 41.8, respectively. Therefore, these two dinuclear organometallic rhenium(i) tricarbonyl complexes are potential anticancer agents for combined chemo-photodynamic therapy.

Red-emitting neutral rhenium(i) complexes bearing a pyridyl pyridoannelated N-heterocyclic carbene.

Two novel rhenium(i) tricarbonyl complexes of general formula fac-[Re(N^C:)(CO)3X] are herein presented, where N^C: is the pyridoannelated N-heterocyclic carbene (NHC) arising from 2-(2-pyridinyl)imidazo[1,5-a]pyridinium hexafluorophosphate proligand, namely [pyipy]PF6, and X being Cl and Br. The synthetic pathway is a one-pot reaction that starts from the azolium salt as the NHC source and [Re(CO)5X] to yield the desired charge-neutral fac-[Re(pyipy)(CO)3X] complexes (1-2). Both complexes were thoroughly characterized by spectroscopic, electrochemical, theoretical investigation as well as X-ray diffraction analysis. They display a rather similar electronic absorption spectrum in dilute CH2Cl2 solution, which is characterized by a broad profile extending into the blue region. This lowest-lying absorption band is attributed to a transition with admixed metal-to-ligand charge transfer and intraligand charge transfer (1MLCT/1ILCT) character. Degassed samples of the complexes display moderate (Φ≈ 1.5%) and long-lived (τ = 12.8-13.4 μs) red photoluminescence with highly structured profile independent of the nature of the ancillary halogen ligand and little sensitivity to the solvent polarity, highlighting the markedly different nature of the emitting excited state in comparison with the lowest-lying absorption. Indeed, photoluminescence is ascribed to a long-lived excited state with metal-perturbed triplet ligand-centred (3LC) character as supported by both experimental and density functional theory (DFT) investigations.

Charge neutral rhenium tricarbonyl complexes of tridentate N-heterocyclic carbene ligands that bind to amyloid plaques of Alzheimer's disease.

Two tridentate ligand systems bearing N-heterocyclic carbene (NHC), amine and carboxylate donor groups coupled to benzothiazole- or stilbene-based amyloid binding moieties were synthesised. Reaction of the imidazolium salt containing pro-ligands with Re(CO)5Cl yielded the corresponding rhenium metal complexes which were characterised by NMR, and X-ray crystallography. These ligands are of interest for the potential preparation of technetium-99m imaging agents for Alzheimer's disease and the capacity of these rhenium complexes bind to amyloid fibrils composed of amyloid-β peptide and amyloid plaques in human frontal cortex brain tissue was evaluated using fluorescence microscopy. These studies show that the complexes bound efficiently to amyloid-β fibrils and some evidence of binding to amyloid-β plaques.

Rhenium(I) carbonyl complexes bearing the alkenylphosphinite ligand Ph2POCH2CH[dbnd]CH2

New bromo- and chloro- tricarbonylrhenium(I) complexes [ReX(CO)3)L2] [X = Cl (1); Br(2)] containing the bifunctional phosphinite/ alkene ligand Ph2POCH2CH = CH2(L), have been prepared by reaction of the complexes[ReX(CO)5] (X = Cl, Br) with L, in refluxing toluene. Both mer, trans (a) and fac, cis (b) isomers were obtained and the structures of derivatives 1a, 1b and 2a have been determined by single crystal X-ray diffraction analysis.

Thermal Properties and Crystal Structures of Rhenium(I) Carbonyl Complexes with Tridentate Ligands: Preparation of Rhenium-Containing Ionic Liquids.

Although the coordination chemistry of rhenium complexes is a rapidly expanding research field, little is known about their thermal properties. In this study, we synthesized several rhenium tricarbonyl complexes with tridentate ligands (L) having S or N as donor atoms, fac-[Re(CO)3L]X (X = Tf2N [= bis(trifluoromethanesulfonyl)amide)], PF6) and fac-[Re(CO)3LCl], and investigated their thermal properties and crystal structures. The Tf2N salts were room temperature ionic liquids. The S-coordinated complexes, having longer coordination bonds, were less thermally stable than the N-coordinated complexes. Even though fac-[Re(CO)3LCl] are bidentate coordination complexes, they were thermally more stable than the isomeric tridentate complexes fac-[Re(CO)3L]Cl.

Synthesis, characterization, and biological properties of rhenium(I) tricarbonyl complexes bearing nitrogen-donor ligands

Rhenium(I) tricarbonyl complexes have properties that make them valuable for various biomedical applications, such as imaging, cancer treatment, and bactericidal uses. The ability to modify the ligand coordination sphere of these complexes enables researchers to fine-tune and optimize their properties for biological use. In this study, we explored the role of axial nitrogen-donor ligands. Specifically, the compounds fac-[Re(CO)3(phen)(L)]+, where phen = 1,10-phenanthroline and L = pyridine (Re-py), piperidine (Re-pip), morpholine (Re-morph), and thiomorpholine (Re-thio), were synthesized and characterized. X-ray crystal structures of these complexes show that they obtain an expected pseudo-octahedral geometry with the three CO ligands arranged in a facial manner. Additionally, the X-ray crystal structure of a byproduct from these reactions, the hydroxo-bridged dinuclear Re compound [(CO)3(phen)Re(μ-OH)Re(phen)(CO)3]+, is described. The photophysical properties of these complexes were investigated in detail, revealing that they are photoluminescent in air-equilibrated pH 7.4 phosphate-buffered saline with quantum yields ranging from 1.7 to 3.1%. Both the quantum yields and emission energies were found to correlate with the basicity of the axial nitrogen donor, whereby more basic ligands give rise to smaller quantum yields and lower-energy emissions. These four compounds were further evaluated for their potential as fluorescence microscopy imaging agents. Of the four compounds, only Re-py showed detectable intracellular luminescence in HeLa cells. Lastly, the cytotoxicities of these compounds in HeLa cells were determined. None of the four compounds is significantly cytotoxic as reflected by their 50% growth inhibitory concentrations that exceed 30 μM.

Aggregation-induced emission generation via simultaneous N-alkylation and rhenium(I) tricarbonyl complexation for 2-(2-thienyl)imidazo[4,5-f][1,10]-phenanthroline

In this paper, imidazole N-alkylation (allyl and n-butyl) and the following rhenium(I) complexation strategy have been used for 2-(2-thienyl)imidazo[4,5-f][1,10]-phenanthroline (TIP) to generate two aggregation-induced emission (AIE) active rhenium(I) tricarbonyl complexes Re2 and Re3. The destroy of planarity and conjugation of TIP by introducing alkyl chains and the increase of steric hindrance via implanting octahedral Re(I) coordination sphere lead to the restrictions of intramolecular rotation and formation of intermolecular π-π stacking, which could be the main reasons for the AIE activation. X-ray single-crystal structures of Re1 and Re2 verify the increase of dihedral angle in the TIP skeleton from 10.8(5)o to 22.7(1)o as well as the different crystal packing fashions (AAAA vs ABAB) after introducing the spatial crowding allyl group. Further studies reveal that the above-mentioned simultaneous modifications are vital for the AIE generation because control experiments show that either single imidazole N-alkylation (L2 and L3) or single rhenium(I) tricarbonyl complexation (Re1) gives rise to the typical aggregation-caused fluorescence quenching. To the best of our knowledge, this is the first report on Re(I)-TIP complexes and corresponding dual functionality for the AIE activation.

An amine linker group modulates luminescent properties in a Rhenium(I) tricarbonyl complex. How can it be applied for ratiometric oxygen sensing?

The UV–Vis absorption spectrum of the rhenium(I) tricarbonyl complex [(NH2-phen)Re(CO)3Br] (ReNN-NH2Br, a deep-orange solid) in solution shows three bands located at 300, 370 and 445 nm. TD-DFT calculations and spectroscopic data indicate that the higher energy band corresponds to a ligand centered transition (LC), while the two lower energy bands have been ascribed to have major ILCT and MLCT character. Excitation at 370 nm leads to two emission bands centered at around 490 nm and 590 nm, which have different nature, 1ILCT and 3MLCT, respectively. Both show a low luminescent quantum yield, especially the lowest energy band. The emission quantum yields in argon-saturated solutions are largely increased, specially for the band at 590 nm. Our results demonstrate that adding the amino group has a non-innocent effect over the luminescent properties of the complex when is compared with those of [(phen)Re(CO)3Br] (ReNNBr). The capacity of these complexes to act as singlet oxygen sensitizers and their application as oxygen sensors were explored. Both complexes, ReNNBr and ReNN-NH2Br, were incorporated in silsesquioxane matrices and tested as ratiometric oxygen sensors using the intrinsic emission of the matrix as an emission internal reference signal. The SSO1-ReNN-NH2Br films was the most sensitive material for this application.

Heterogeneous Aqueous CO2 Reduction Using a Pyrene-Modified Rhenium(I) Diimine Complex.

The development of molecular catalysts and materials that can convert carbon dioxide (CO2) into a value-added product is a great chemical challenge. Molecular catalysts set benchmarks in catalyst investigation and design, but their incorporationinto solid-state materials, and optimization of the electrochemical operating conditions, is still needed. For example, rhenium(I) diimine catalysts show almost quantitative selectivity for the conversion of CO2 to carbon monoxide (CO) in acetonitrile (MeCN), but the modification of diimine backbones can be challenging if the goal is to incorporate such molecules into materials. Presented here is a rhenium(I) complex with a 2-(2'-quinolyl)benzimidazole (QuBIm-H) ligand, where N-alkylation with a pyrene derivative allows access to a catalyst that can be adsorbed onto electrodes for aqueous CO2 reduction chemistry. The rhenium(I) catalysts are inactive for homogeneous CO2 reduction in MeCN. However, when adsorbed on edge-plane graphite, the same complexes show good activity for heterogeneous aqueous CO2 reduction, with 90% selectivity for CO. Comparative electrochemical studies between covalent and noncovalent modification of the graphite surfaces were also carried out for related rhenium(I) tricarbonyl complexes.

Geminate Recombination versus Cage Escape in the Reductive Quenching of a Re(I) Carbonyl Complex on Mesoporous ZrO2

In the wider context of artificial photosynthesis, this work aims to explore the functionality and characteristics of rhenium tricarbonyl complexes as photosensitizers in heterogeneous water reduct...

PC#9 - New tricarbonylrhenium(I) complexes: from structural study to a potential therapeutic radiopharmaceutical to target hepatocellular carcinoma metastases

PC#9 - New tricarbonylrhenium(I) complexes: from structural study to a potential therapeutic radiopharmaceutical to target hepatocellular carcinoma metastases

CONFOCAL MICROSCOPY STUDIES OF LIVING FUNGAL HYPHAE AND CONIDIA USING RHENIUM (I) TRICARBONYL COMPLEXES AS FLUORESCENT DYES.

Botrytis cinerea is a ubiquitous necrotrophic filamentous fungal pathogen, causing the “grey mold” disease in a wide range of plants, including species of importance in the food industry. Recently, we reported the use of fac-[Re(I)(CO)3(2,2’-bpy)L]PF6 (C3) and fac-[Re(I)(CO)3(4,4′-dimethyl-2,2′-bpy)L]PF6 (C4) complexes as biomarkers for yeasts and bacteria. Nevertheless, the use of these complexes to stain filamentous fungi, such as Botrytis cinerea, has not been explored so far. Since Botrytis cinerea exhibits a dynamic multilayer cell wall that changes the composition during normal growth, in both their hyphae and conidia, is not possible to directly extrapolate the use of both C3 and C4 as biomarkers for Botrytis cinerea without an experimental approach. In this work, we explored new features of the luminescent compounds C3 and C4 as biomarkers for the higher filamentous fungi Botrytis cinerea, including conidia and juvenile hyphae. We found that, with the new protocol proposed, both C3 and C4 were suitable to stain conidia with a simple procedure since no cell permeabilization is required. Additionally, these results suggest that C3 and C4 can selectively stain living conidia, allowing the differentiation from non-germinating conidia. This point opens a new focus of development for rhenium (I) tricarbonyl complexes as new fluorescent biomarkers for Botrytis cinerea with potential properties as vital staining.

Electrical and optical properties of organic light-emitting diodes with rhenium(I) complexes using DC and AC methods

Four rhenium(I) tricarbonyl complexes with 1,10-phenanthroline and derivative bearing electron-donating CH3 and OCH3 substituents were doped into host material poly (9-vinylcarbazole) (PVK) with a mass ratio of 8% as the emissive layer in organic light-emitting diodes (OLEDs). All complexes showed photoluminescence in the solution and embedded into a PVK matrix (λmax∼520–550 nm). The comparison with the bare PVK emission and the compound/PVK film shows that the emission of the polymer was quenched through an energy transfer process from PVK to the dopant. The electrical properties of the devices with FTO/PEDOT:PSS/Complex:PVK/Al architecture were investigated using the DC method by curves of current density-voltage and the AC method as admittance spectroscopy, which showed that the behavior of the devices is controlled by charge carrier injection rather than bulk transport.