Rhenium Tricarbonyl Complexes Research Articles

Organometallic rhenium tricarbonyl-enrofloxacin and -levofloxacin complexes: synthesis, albumin-binding, DNA-interaction and cell viability studies.

Organometallic rhenium complexes have recently been considered in the development of novel antitumor agents due to their suitable properties. A series of rhenium(I) tricarbonyl complexes was synthesized with the quinolone antimicrobial agents enrofloxacin (Herx) and levofloxacin (Hlfx) and solvent (e.g., methanol), imidazole (im) or pyridine (py) as co-ligands. The complexes were characterized by spectroscopic methods. The interaction of the rhenium complexes with bovine serum albumin was investigated by fluorescence emission spectroscopy and the corresponding binding constants were determined. The binding of the rhenium complexes to calf-thymus DNA was monitored by UV-Vis spectroscopy, viscosity measurements and competitive studies with ethidium bromide. These studies indicated that intercalation is the most possible mode of action and the corresponding DNA-binding constants of the complexes were calculated. The cytotoxicity of the Re-complexes against human K-562 erythroleukemia cells was found to be moderate to high. These preliminary results are promising and warrant the design of new Re-complexes with improved properties in future studies.

Tricarbonylrhenium(I) complexes with heterodentate ligands based on functionalized amides: Synthesis, structural features, and cytotoxic activity

The reactions of 2-diphenylphosphorylaniline with 2-methylsulfanylbenzoyl chloride or 2-diphenylphosphinobenzoic acid in the presence of a coupling agent afforded new potentially tridentate ligands with different donor sets. Upon interaction with Re(CO)5Br, the compounds obtained formed either bidentately bound molecular or pincer-type tricarbonylrhenium(I) complexes depending on the reaction conditions. The resulting complexes were fully characterized in solution and in the solid state by multinuclear NMR and IR spectroscopy and, in most cases, by single-crystal X-ray diffraction. The preliminary evaluation of cytotoxicity of the complexes obtained against human colon (HCT116), breast (MCF7), and prostate (PC3) cancer cell lines revealed the high activity of κ3-S,N,O-pincer-type complex with ancillary S-donor group. The latter demonstrated considerable effect also on transformed breast cell line HBL100 and its doxorubicin-resistant subline HBL100/Dox.

In Vivo Anticancer Activity of a Rhenium(I) Tricarbonyl Complex.

The rhenium(I) complex fac-[Re(CO)3(2,9-dimethyl-1,10-phenanthroline)(OH2)]+ (1) was previously shown to exhibit potent in vitro anticancer activity in a manner distinct from conventional platinum-based drugs (J. Am. Chem. Soc. 2017, 139, 14302-14314). In this study, we report further efforts to explore its aqueous speciation and antitumor activity. The cellular uptake of 1 was measured in A2780 and cisplatin-resistant A2780CP70 ovarian cancer cells by inductively coupled plasma mass spectrometry, revealing similar uptake efficiency in both cell lines. High accumulation in the mitochondria was observed, contradicting prior fluorescence microscopy studies. The luminescence of 1 is highly dependent on pH and coordination environment, making fluorescence microscopy somewhat unreliable for determining compound localization. The in vivo anticancer activity of 1 was evaluated in mice bearing patient-derived ovarian cancer tumor xenografts. These studies conclusively show that 1 is capable of inhibiting tumor growth, providing further credibility for the use of these compounds as anticancer agents.

Mitochondria-Accumulating Rhenium(I) Tricarbonyl Complexes Induce Cell Death via Irreversible Oxidative Stress and Glutathione Metabolism Disturbance.

Mitochondria play a critical role in tumorigenesis. Targeting mitochondria and disturbing related events have been emerging as a promising way for chemotherapy. In this work, two binuclear rhenium(I) tricarbonyl complexes of the general formula [Re2(CO)6(dip)2L](PF6)2 (dip = 4,7-diphenyl-1,10-phenanthroline; L = 4,4'-azopyridine (ReN) or 4,4'-dithiodipyridine (ReS)) were synthesized and characterized. ReN and ReS can react with glutathione (GSH). They exhibit good in vitro anticancer activity against cancer cell lines screened. Besides, they can target mitochondria, cause oxidative stress, and disturb GSH metabolism. Both ReN and ReS can induce necroptosis and caspase-dependent apoptosis simultaneously. We also demonstrate that ReN and ReS can inhibit tumor growth in nude mice bearing carcinoma xenografts. Our study shows the potential of Re(I) complexes as chemotherapeutic agents to kill cancer cells via a mitochondria-to-cellular redox strategy.

Prototypical cis-ruthenium(II) complexes present differential fluorescent staining in walled-cell models (yeasts)

cis-Ru(deeb) 3 2+ (R1; where deeb is 4,4′-diethanoate-2,2′-bipyridine) and cis-Ru(phen) 3 2+ (R2; where phen is 1,10-phenanthroline) were synthesized. Although the presence of the cell wall (a structure that is present in yeasts and bacteria,) was previously described as a natural barrier that hampers the uptake of d6-based luminescent complexes, we previously demonstrated that rhenium(I) tricarbonyl complexes were useful to stain both yeasts and bacteria. Even though several studies of classical ruthenium(II) complexes can be found, none of those studies aimed to determine the potential of these compounds as biomarkers for walled cells, testing only cell lines that lack this permeability barrier. Walled cells exhibit a relatively rigid structure, mainly constituted by carbohydrates and proteins, and surround the plasma membrane. In this manuscript, we observed that both R1 and R2 exhibited very low cytotoxicity in different walled-cell models (including bacteria and yeasts). More importantly, we found that both R1 and R2 were able to fluorescently stain Candida albicans (yeast), with a simple and fast procedure, without the need of additional permeabilizer molecules and antibodies. Interestingly, R1 remained retained in a discrete central structure consistent with the cell nucleus, whereas R2 seemed to be accumulated in the cell wall. These results show that these two complexes can be used as biomarkers for walled cells as differential staining, supporting the fact that, as well as with rhenium(I) complexes, biomarkers properties can be modulated by changing the substituents in ruthenium(II)-derivative luminescent stains, even for walled cells.

Combinatorial Synthesis to Identify a Potent, Necrosis-Inducing Rhenium Anticancer Agent.

Combinatorial synthesis can be applied for developing a library of compounds that can be rapidly screened for biological activity. Here, we report the application of microwave-assisted combinatorial chemistry for the synthesis of 80 rhenium(I) tricarbonyl complexes bearing diimine ligands. This library was evaluated for anticancer activity in three different cancer cell lines, enabling the identification of three lead compounds with cancer cell growth-inhibitory activities of less than 10 μM. These three lead structures, Re-9B, Re-9C, and Re-9D, were synthesized independently and fully characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray crystallography. The most potent of these three complexes, Re-9D, was further explored to understand its mechanism of action. Complex Re-9D is equally effective in both wild-type and cisplatin-resistant A2780 ovarian cancer cells, indicating that it circumvents cisplatin resistance. This compound was also shown to possess promising activity against ovarian cancer tumor spheroids. Additionally, flow cytometry showed that Re-9D does not induce cell cycle arrest or flipping of phosphatidylserine to the outer cell membrane. Analysis of the morphological changes of cancer cells treated with Re-9D revealed that this compound gives rise to rapid plasma membrane rupture. Collectively, these data suggest that Re-9D induces necrosis in cancer cells. To assess the in vivo biodistribution and stability of this compound, a radioactive 99mTc analogue of Re-9D, 99mTc-9D(H2O), was synthesized and administered to naı̈ve BALB/c mice. Results of these studies indicate that 99mTc-9D(H2O) exhibits high metabolic stability and a distinct biodistribution profile. This research demonstrates that combinatorial synthesis is an effective approach for the development of new rhenium anticancer agents with advantageous biological properties.

Tricarbonyl rhenium(i) tetrazolato and N-heterocyclic carbene complexes: versatile visible-light-mediated photoredox catalysts.

We have investigated the capacity of a range of structurally-diverse, photoactive rhenium(i) tricarbonyl complexes featuring either tetrazolato or N-heterocyclic carbene (NHC) ligands to facilitate fundamental classes of visible-light-mediated photoredox-catalysed reactions. In this study, we demonstrate that these systems mediate representative atom-transfer radical addition, hydrodehalogenation, and α-amino C-H functionalisation reactions. These rhenium(i) complexes provide greater or at least comparable reactivity to the prototypical photoredox catalyst [Ru(bpy)3]2+ in many cases.

Effect of Rhenium(I) Complexation on Aza-Michael Additions to 5-Amino-1,10-Phenanthroline with [18F]Ethenesulfonyl Fluoride towards PET Optical Tracer Development

Conjugations with the recently developed [18F]ethenesulfonyl fluoride ([18F]ESF) were performed on 5-amino-1,10-phenanthroline, in its free form and coordinated to a rhenium(i) tricarbonyl complex, as a means of radiosynthesizing dual-modal optical and positron emission tomography (PET) tracers. The Michael-donating ability of the aromatic amine was noticeably perturbed on coordination with the rhenium(i) centre, resulting in decreased radiochemical yields from 34%, in the case of the free ligand, to 1%. We attribute the decreased nucleophilicity of the amine to metal deactivation from the electron-withdrawing feature of the rhenium(i) tricarbonyl centre, based on spectroscopic and computational evidence, thus highlighting this effect as a crucial parameter in designing late-stage metal coordination methods employing related aza-Michael additions. Photophysical analyses were also performed on the ESF-conjugated rhenium(i) complex, exhibiting a longer decay lifetime from the triplet metal-to-ligand charge transfer excited state when compared with the non-conjugated analogue.

Optimization of aggregation-induced phosphorescence enhancement in mononuclear tricarbonyl rhenium(i) complexes: the influence of steric hindrance and isomerism.

In order to improve the remarkable performance of a mononuclear tricarbonyl rhenium(i) complex (ReL1) that exhibits rare aggregation-induced phosphorescence enhancement (AIPE) behavior, two new complexes (ReL3 and ReL4) were prepared and investigated. They incorporate a 2-pyridyl-1,2,4-triazole (pyta) ligand connected to a 2-phenylbenzoxazole (PBO) moiety. Complex ReL3 differs from ReL1 by the presence of a bulky tert-butyl substituent, and ReL4 is an isomer where the PBO group is linked to the pyta ligand by its phenyl group. Theoretical calculations were in congruence with electrochemical and spectroscopic properties in solutions. Both new compounds exhibited strong AIPE and much better solid-state emission efficiency than ReL1, with photoluminescence quantum yields up to 55% for ReL4. Crystallographic data indicate that this increase in emission efficiency is due to optimum packing that prevents quenching. This work shows that minor structural changes may have major effects upon the solid-state spectroscopic properties and it provides a rational basis for accessing AIPE-active strongly emissive rhenium(i) complexes.

New rhenium-tricarbonyl complexes bearing halogen-substituted bidentate ligands: structural, computational and Hirshfeld surfaces studies

The intermolecular interactions in a series of new complexes Re(CO)3(N,N)X (N,N is a halogen substituted bidentate N–N donor and X is Cl or Br) have been studied crystallographically and computationally. Metal-bound halogens are more effective than carbon-bound halogens in forming significant intermolecular interactions.

Cyclic voltammetry, relativistic DFT calculations and biological test of cytotoxicity in walled-cell models of two classical rhenium (I) tricarbonyl complexes with 5-amine-1,10-phenanthroline

fac-[Re(CO)3(5-amine-1,10-phenanthroline)Cl or Br] (D1 and D2) were synthesized and characterized. D2 was obtained by al alternative method. The electrochemical reaction mechanisms of both D1 and D2 corresponded to EEC for reduction, and ECE for oxidation. Moreover, geometry, electronic, and luminescent properties were analyzed by relativistic DFT and TD-DFT calculations. We determined the lability of Cl and Br by a Morokuma–Ziegler analysis. We found that these compounds were less toxic than the ligand alone, and it depends on the cell model tested, where bacteria seem to be more susceptible than yeasts.

Synthesis and antitumour evaluation of mono- and multinuclear [2+1] tricarbonylrhenium(I) complexes

A series of mono- and multinuclear [2 + 1] Re(I) tricarbonyl complexes were synthesised and evaluated as antiproliferative agents against the epithelial carcinoma (A431), colon carcinoma (DLD-1) and ovarian cancer (A2780) tumour cell lines and a healthy fibroblast (BJ) cell line. The compounds have moderate to good activity against the tumour cell lines, with the trinuclear and tetranuclear complexes showing selective cytotoxicity towards the tumour cell lines. The Re(I) complexes were found to influence programmed cell death mechanisms in vitro. They were able to inhibit the soluble form of the Fas receptor in malignant cells, allowing the Fas domain to receive the apoptotic signal through an extrinsic pathway. The complexes augmented the pro-apoptotic Bax-α concentrations, with the tetranuclear complex more superior at modulating the Bax-α molecular target in all tested cell lines, which influenced its cell growth inhibitory activity. The tetranuclear complex has the best activity against all tumour cell lines.

Rhenium Complexes of Bis(benzothiazole)-Based Tetraarylethylenes as Selective Luminescent Probes for Amyloid Fibrils.

Probes for monitoring aggregation of amyloid beta (Aβ) peptides are crucial to advance understanding of the molecular pathogenesis of Alzheimer's Disease (AD). Here, we report luminescent tricarbonyl rhenium complexes of tetraarylethylene (TAE) ligands featuring bis(benzothiazole) chelating groups in combination with (oligo)thiophene units that have been designed for monitoring amyloid fibrillation. Variation in the number of thiophenes influenced the photophysical properties of these complexes, as well as their binding affinities toward Aβ42 fibrils. All complexes displayed submicromolar Kd's for binding Aβ42 aggregates accompanied by up to 34-fold enhanced luminescence and red-shifted emission wavelengths. The high binding affinities and desirable photophysical properties of these complexes render them potential alternatives to established fluorescent Aβ probes such as thioflavin T. Additionally, the general and modular design approach implemented in this study should facilitate development of second-generation TAE-based diagnostic tools for studying protein aggregation in AD and other neurological diseases.

Photoreversible Molecular Motion of stpyCN Coordinated to fac-[Re(CO)3(NN)]+ Complexes.

In this work, efficient trans ⇌ cis photoswitchings of 4-(4-cyano)styrylpyridine (stpyCN) coordinated to organometallic bipyridyl tricarbonyl rhenium(I) complexes, fac-[Re(CO)3(NN)( trans-stpyCN)]+, where NN = 2,2'-bipyridine (bpy) or 4,4'-dimethyl-2,2'-bipyridine (dmb), are described. For both complexes, the true trans-to- cis quantum yields determined by 1H NMR spectroscopy are similar at 313, 334, and 365 nm irradiations (Φ trans→ cistrue(313-365 nm) ∼ 0.45), with a small decrease at 404 nm (Φ trans→ cistrue(404 nm) ∼ 0.37). The investigated complexes also exhibit significant quantum yields for the reversible cis-to- trans photoreactions (Φ cis→ trans(255 nm) = 0.22). The luminescent properties of these complexes were also analyzed in different media to elucidate a key role of the 3ILstpyCN state in photophysical and photochemical processes, giving new insights on their intriguing photobehavior.

Reactions of pyridine-2-ethyl/methyl cyclopentadienes with metal carbonyls

Thermal treatment of pyridine-2-ethyl cyclopentadiene (1) with Fe(CO)5 and Ru3(CO)12 gave novel intramolecular C–H activated dinuclear products (3 and 5). In the case of Fe(CO)5, the reaction also afforded the normal bis(cyclopentadienyl) diiron complex (4). However, similar reaction of pyridine-2-methyl cyclopentadiene (2) with Fe(CO)5 and Ru3(CO)12 only afforded the normal bis(cyclopentadienyl) dinuclear metal complexes (7 and 8). For Ru3(CO)12, the reaction also yielded a pendant η1-pyridyl-coordinated product (9). In addition, the reactions of 1 and 2 with Re2(CO)10 formed the corresponding pyridylethyl/pyridylmethyl cyclopentadienyl rhenium tricarbonyl complexes 10 and 11, which further underwent pyridine to rhenium cyclization via photoirradiation to provide the rhenium dicarbonyl complexes 12 and 13. The molecular structures of 3, 5, 6, 7, 8, 9, and 12 were determined by X-ray diffraction.

Tricarbonylrhenium(I) complexes with the N,6-dimethylpyridine-2-carbothioamide ligand: combined experimental and calculation studies

A new series of tricarbonyl complexes of rhenium(I) in the “2 + 1” system with the bidentate ligand N,6-dimethylpyridine-2-carbothioamide ((CH3)NC5H4-CS-NH-CH3, MeLH(Me)NS) and a monodentate ligand (halides Cl, Br, or I, and the pseudohalide NCS anion) was synthesized. The use of mixed ligands led to the formation of neutral tricarbonylrhenium(I) complexes [Re(CO)3(MeLH(Me)NS)X] (X = Cl, Br, I, NCS) (1–4). Single-crystal X-ray diffraction was used to determine the crystal structures of all four compounds and those results were compared with molecular structures obtained from DFT calculations using the PBE0/def2-TZVPD approach. The complexes were also characterized by spectroscopic (FT-IR, NMR, and UV–vis) and analytical (HPLC, TGA, EA, ESI-MS) techniques. IR and UV–vis spectra were also calculated by DFT and TD-DFT methods. The cytotoxicity of these complexes was estimated using human ovarian cancer cell lines (A2780 and A2780cis), cervical cancer cells (HeLa), and non-cancerous human embryonic kidney cells (Hek-293). The toxicity of most complexes was moderate or low toward cancer cell lines (IC50 = 46–231 μM) and similar against non-cancerous cells (IC50 = 41-121 μM). Only the complex with chlorido ligand remarkably inhibited growth of ovarian cancer cells (IC50 = 3 and 12 μM for A2780 and A2780cis, respectively). The cytotoxicity of 1 was higher than that of cisplatin.

Tricarbonylrhenium(I) complexes with the N-methylpyridine-2-carbothioamide ligand – Synthesis, characterization and cytotoxicity studies

A new series of tricarbonyl complexes of rhenium(I) in the ‘2 + 1’ system with the bidentate ligand N-methylpyridine-2-carbothioamide (NC5H4-CS-NH-CH3, LH(Me)NS) and a monodentate ligand, being either an anion (Cl, Br, I or SCN) or a neutral molecule (3,5-dimethylpyrazole (Hdmpz) or imidazole (Him)), was synthesized. The use of mixed ligands leads to the formation of neutral or cationic (in the form of PF6− salts) tricarbonylrhenium(I) complexes: [Re(CO)3(LH(Me)NS)X] (X = Cl, Br, I, NCS) (complexes 1–4) and [Re(CO)3(LH(Me)NS)Y]+ (Y = Hdmpz, Him) (5 and 6), respectively. In case of the [Re(CO)3(LH(Me)NS)NCS] complex two polymorphic forms (4a and 4b) have been distinguished. Crystal structure of all complexes was determined by single-crystal X-ray diffraction method and the results were compared with the molecular structures obtained from DFT calculations. The compounds were characterized by FT-IR, NMR, UV-Vis and HPLC techniques. IR and UV-Vis spectra were also simulated by DFT and TD-DFT methods. Cytotoxicity of the complexes was estimated using human ovarian cancer cell line (A2780), its cisplatin resistant cell line (A2780cis) and non-cancerous human embryonic kidney cells (Hek-293). The toxicity of newly synthesized complexes was comparable to cisplatin when tested against both cancerous cell lines (IC50 = 2–49 μM), but lower than cisplatin towards non-cancerous cells (IC50 = 6–63 μM). Among them, the complexes with chloride and iodide anions exhibit remarkable cytotoxicities.

Tricarbonylrhenium(I) Complexes of Dinucleating Redox-Active Pincer Ligands

Two homobimetallic tricarbonylrhenium(I) complexes of new redox-active dinucleating pincer ligands have been prepared to assess the impact of spacer size on the first oxidation potentials with respect to mononucleating analogues and on intramolecular electronic communication. The new pincer ligands feature two tridentate NNN- sites each composed of two pyrazolyl flanking donors and a diarylamido anchor that are either directly linked (to form a central benzidene core, H2(L1)) or linked via a para-phenylene group (to form a para-terphenyldiamine core, H2(L2)). The bimetallic complexes of the deprotonated ligands, [fac-Re(CO)3]2(μ-L1), 1, and [fac-Re(CO)3]2(μ-L2), 2, were fully characterized in solution and the solid state including by single-crystal X-ray diffraction for 1. The electrochemical properties of each depended strongly on solvent and electrolyte. Complex 1 exhibits two one-electron oxidations in all electrolyte-containing solutions but with separations between first and second oxidation potentia...

Novel coumarin rhenium(I) and -(V) complexes: Formation, DFT and DNA binding studies

Herein, we report the formation and characterisation of novel rhenium(I) and -(V) compounds with coumarin bidentate chelates: trans-[ReOBr2(PPh3)(hbc)] (1) (Hhbc = 7-(2-hydroxybenzylideneamino)-4-(trifluoromethyl)-2H-chromen-2-one), fac-[Re(CO)3Cl(aomc)] (2) (aomc = 7-(((2-amino-4-oxo-4H-chromen-3-yl)methylene)amino)-4-(trifluoromethyl)-2H-chromen-2-one) and fac-[Re(CO)3Cl(moac)] (3) (moac = 7-(((2-methoxy-4-oxochroman-3-yl)methylene)amino)-4-(trifluoromethyl)-2H-chromen-2-one). The coumarin free-ligands and the metal complexes 1–3 were characterized by NMR, UV–Vis and FTIR spectroscopy, melting point and molar conductivity measurements as well as time-of-flight mass spectrometry. Their structural elucidations were supported by the respective solid state structures of 1, Hhbc and moac. DNA binding studies conducted using the facial tricarbonylrhenium(I) complexes 2 and 3, revealed that they are DNA groove binders with intrinsic binding constants in the order of 105 and 104 M bp, respectively. This study was also complemented using density functional theory (DFT) and time-dependent DFT methods to attain a deeper understanding into the structural parameters, infrared and electronic spectra of these coumarin free-ligands and their metal complexes 1–3.

Photoactivated in Vitro Anticancer Activity of Rhenium(I) Tricarbonyl Complexes Bearing Water-Soluble Phosphines.

Fifteen water-soluble rhenium compounds of the general formula [Re(CO)3(NN)(PR3)]+, where NN is a diimine ligand and PR3 is 1,3,5-triaza-7-phosphaadamantane (PTA), tris(hydroxymethyl)phosphine (THP), or 1,4-diacetyl-1,3,7-triaza-5-phosphabicylco[3.3.1]nonane (DAPTA), were synthesized and characterized by multinuclear NMR spectroscopy, IR spectroscopy, and X-ray crystallography. The complexes bearing the THP and DAPTA ligands exhibit triplet-based luminescence in air-equilibrated aqueous solutions with quantum yields ranging from 3.4 to 11.5%. Furthermore, the THP and DAPTA complexes undergo photosubstitution of a CO ligand upon irradiation with 365 nm light with quantum yields ranging from 1.1 to 5.5% and sensitize the formation of 1O2 with quantum yields as high as 70%. In contrast, all of the complexes bearing the PTA ligand are nonemissive and do not undergo photosubstitution upon irradiation with 365 nm light. These compounds were evaluated as photoactivated anticancer agents in human cervical (HeLa), ovarian (A2780), and cisplatin-resistant ovarian (A2780CP70) cancer cell lines. All of the complexes bearing THP and DAPTA exhibited a cytotoxic response upon irradiation with minimal toxicity in the absence of light. Notably, the complex with DAPTA and 1,10-phenanthroline gave rise to an IC50 value of 6 μM in HeLa cells upon irradiation, rendering it the most phototoxic compound in this library. The nature of the photoinduced cytotoxicity of this compound was explored in further detail. These data indicate that the phototoxic response may result from the release of both CO and the rhenium-containing photoproduct, as well as the production of 1O2.