Diiron Aminocarbyne Complexes with NCE- Ligands (E = O, S, Se).

Diiron µ-aminocarbyne complexes [Fe2Cp2(NCMe)(CO)(µ-CO){µ-CN(Me)(R)}]CF3SO3 (R = Xyl, [1aNCMe]CF3SO3; R = Me, [1bNCMe]CF3SO3; R = Cy, [1cNCMe]CF3SO3; R = CH2Ph, [1dNCMe]CF3SO3), freshly prepared from tricarbonyl precursors [1a-d]CF3SO3, reacted with NaOCN (in acetone) and NBu4SCN (in dichloromethane) to give [Fe2Cp2(kN-NCO)(CO)(µ-CO){µ-CN(Me)(R)}] (R = Xyl, 2a; Me, 2b; Cy, 2c) and [Fe2Cp2(kN-NCS)(CO)(µ-CO){µ-CN(Me)(CH2Ph)}], 3 in 67-81% yields via substitution of the acetonitrile ligand. The reaction of [1aNCMe-1cNCMe]CF3SO3 with KSeCN in THF at reflux temperature led to the cyanide complexes [Fe2Cp2(CN)(CO)(µ-CO){µ-CNMe(R)}], 6a-c (45-67%). When the reaction of [1aNCMe]CF3SO3 with KSeCN was performed in acetone at room temperature, subsequent careful chromatography allowed the separation of moderate amounts of [Fe2Cp2(kSe-SeCN)(CO)(µ-CO){µ-CN(Me)(Xyl)}], 4a, and [Fe2Cp2(kN-NCSe)(CO)(µ-CO){µ-CN(Me)(Xyl)}], 5a. All products were fully characterized by elemental analysis, IR, and multinuclear NMR spectroscopy; moreover, the molecular structure of trans-6b was ascertained by single crystal X-ray diffraction. DFT calculations were carried out to shed light on the coordination mode and stability of the {NCSe-} fragment.

Easily Available, Amphiphilic Diiron Cyclopentadienyl Complexes Exhibit in Vitro Anticancer Activity in 2D and 3D Human Cancer Cells through Redox Modulation Triggered by CO Release.

A straightforward two-step procedure via single CO removal allows the conversion of commercial [Fe2 Cp2 (CO)4 ] into a range of amphiphilic and robust ionic complexes based on a hybrid aminocarbyne/iminium ligand, [Fe2 Cp2 (CO)3 {CN(R)(R')}]X (R, R'=alkyl or aryl; X=CF3 SO3 or BF4 ), on up to multigram scales. Their physicochemical properties can be modulated by an appropriate choice of N-substituents and counteranion. Tested against a panel of human cancer cell lines, the complexes were shown to possess promising antiproliferative activity and to circumvent multidrug resistance. Interestingly, most derivatives also retained a significant cytotoxic activity against human cancer 3D cell cultures. Among them, the complex with R=4-C6 H4 OMe and R'=Me emerged as the best performer of the series, being on average about six times more active against cancer cells than a noncancerous cell line, and displayed IC50 values comparable to those of cisplatin in 3D cell cultures. Mechanistic studies revealed the ability of the complexes to release carbon monoxide and to act as oxidative stress inducers in cancer cells.

A Comprehensive Analysis of the Metal-Nitrile Bonding in an Organo-Diiron System.

Nitriles (N≡CR) are ubiquitous in coordination chemistry, yet literature studies on metal-nitrile bonding based on a multi-technique approach are rare. We selected an easily-available di-organoiron framework, containing both π-acceptor (CO, aminocarbyne) and donor (Cp = η5-C5H5) ligands, as a suitable system to provide a comprehensive description of the iron-nitrile bond. Thus, the new nitrile (2-12)CF3SO3 and the related imine/amine complexes (8-9)CF3SO3 were synthesized in 58-83% yields from the respective tris-carbonyl precursors (1a-d)CF3SO3, using the TMNO strategy (TMNO = trimethylamine-N-oxide). The products were fully characterized by elemental analysis, IR (solution and solid state) and multinuclear NMR spectroscopy. In addition, the structures of (2)CF3SO3, (3)CF3SO3, (5)CF3SO3 and (11)CF3SO3 were ascertained by single crystal X-ray diffraction. Salient spectroscopic data of the nitrile complexes are coherent with the scale of electron-donor power of the R substituents; otherwise, this scale does not match the degree of Fe → N π-back-donation and the Fe-N bond energies, which were elucidated in (2-7)CF3SO3 by DFT calculations.

Mono-, Di- and Tetra-iron Complexes with Selenium or Sulphur Functionalized Vinyliminium Ligands: Synthesis, Structural Characterization and Antiproliferative Activity.

A series of diiron/tetrairon compounds containing a S- or a Se-function (2a-d, 4a-d, 5a-b, 6), and the monoiron [FeCp(CO){SeC1(NMe2)C2HC3(Me)}] (3) were prepared from the diiron µ-vinyliminium precursors [Fe2Cp2(CO)( µ-CO){ µ-η1: η3-C3(R')C2HC1N(Me)(R)}]CF3SO3 (R = R' = Me, 1a; R = 2,6-C6H3Me2 = Xyl, R' = Ph, 1b; R = Xyl, R' = CH2OH, 1c), via treatment with S8 or gray selenium. The new compounds were characterized by elemental analysis, IR and multinuclear NMR spectroscopy, and structural aspects were further elucidated by DFT calculations. The unprecedented metallacyclic structure of 3 was ascertained by single crystal X-ray diffraction. The air-stable compounds (3, 4a-d, 5a-b, 6) display fair to good stability in aqueous media, and thus were assessed for their cytotoxic activity towards A2780, A2780cisR, and HEK-293 cell lines. Cyclic voltammetry, ROS production and NADH oxidation studies were carried out on selected compounds to give insights into their mode of action.

Butadienyl Diiron Complexes: Nonplanar Metalla-Aromatics Involving σ-Type Orbital Overlap.

A new class of nonplanar metalla-aromatics, diiron complexes bridged by a 1,3-butadienyl dianionic ligand, were synthesized in high yields from dilithio reagents and two equivalents of FeBr2 . The complexes consist of two antiferromagnetically coupled high-spin FeII centers, as revealed by magnetometry, Mössbauer spectroscopy, and DFT calculations. Furthermore, experimental (X-ray structural analysis) and theoretical analyses (NICS, ICSS, AICD, MOs) suggest that the complexes are aromatic. Remarkably, this nonplanar metalla-aromaticity is achieved by an uncommon σ-type overlap between the ligand p and metal d orbitals, in sharp contrast to the intensively studied planar aromatic systems featuring delocalized π-type bonding. Specifically, the σ-type interaction between the two Fe 3dxz orbitals and the butadienyl π orbital results in the formation of a six-electron conjugated system and hence enables the aromatic character.

A Non-Heme Iron Photocatalyst for Light-Driven Aerobic Oxidation of Methanol.

Non-heme (L)FeIII and (L)FeIII -O-FeIII (L) complexes (L=1,1-di(pyridin-2-yl)-N,N-bis(pyridin-2-ylmethyl)ethan-1-amine) underwent reduction under irradiation to the FeII state with concomitant oxidation of methanol to methanal, without the need for a secondary photosensitizer. Spectroscopic and DFT studies support a mechanism in which irradiation results in charge-transfer excitation of a FeIII -µ-O-FeIII complex to generate [(L)FeIV =O]2+ (observed transiently during irradiation in acetonitrile), and an equivalent of (L)FeII . Under aerobic conditions, irradiation accelerates reoxidation from the FeII to the FeIII state with O2 , thus closing the cycle of methanol oxidation to methanal.

A two-in-one pincer ligand and its diiron(II) complex showing spin state switching in solution through reversible ligand exchange.

A novel pyrazolate-bridged ligand providing two {PNN} pincer-type compartments has been synthesized. Its diiron(II) complex LFe2(OTf)3(CH3CN) (1; Tf = triflate) features, in solid state, two bridging triflate ligands, with a terminal triflate and a MeCN ligand completing the octahedral coordination spheres of the two high-spin metal ions. In MeCN solution, 1 is shown to undergo a sequential, reversible, and complete spin transition to the low-spin state upon cooling. Detailed UV/Vis and (19)F NMR spectroscopic studies as well as magnetic measurements have unraveled that spin state switching correlates with a rapid multistep triflate/MeCN ligand exchange equilibrium. The spin transition temperature can be continuously tuned by varying the triflate concentration in solution.

A diiron(III,IV) imido species very active in nitrene-transfer reactions.

Metal-catalyzed nitrene transfer reactions arouse intense interest as clean and efficient procedures for amine synthesis. Efficient Rh- and Ru-based catalysts exist but Fe alternatives are actively pursued. However, reactive iron imido species can be very short-lived and getting evidence of their occurrence in efficient nitrene-transfer reactions is an important challenge. We recently reported that a diiron(III,II) complex is a very efficient nitrene-transfer catalyst to various substrates. We describe herein how, by combining desorption electrospray ionization mass spectrometry, quantitative chemical quench experiments, and DFT calculations, we obtained conclusive evidence for the occurrence of an {Fe(III) Fe(IV) NTosyl} intermediate that is very active in H-abstraction and nitrene-transfer reactions. DFT calculations revealed a strong radical character of the tosyl nitrogen atom in very low-lying electronic configurations of the Fe(IV) ion which are likely to confer its high reactivity.

Low-spin pseudotetrahedral iron(I) sites in Fe2(µ-S) complexes.

Fe(I) centers in iron-sulfide complexes have little precedent in synthetic chemistry despite a growing interest in the possible role of unusually low valent iron in metalloenzymes that feature iron-sulfur clusters. A series of three diiron [(L3Fe)2(µ-S)] complexes that were isolated and characterized in the low-valent oxidation states Fe(II)-S-Fe(II), Fe(II)-S-Fe(I), and Fe(I)-S-Fe(I) is described. This family of iron sulfides constitutes a unique redox series comprising three nearly isostructural but electronically distinct Fe2(µ-S) species. Combined structural, magnetic, and spectroscopic studies provided strong evidence that the pseudotetrahedral iron centers undergo a transition to low-spin S=1/2 states upon reduction from Fe(II) to Fe(I). The possibility of accessing low-spin, pseudotetrahedral Fe(I) sites compatible with S(2-) as a ligand was previously unknown.

Effect of monodentate heterocycle co-ligands on the µ-1,2-peroxo-diiron(III) mediated aldehyde deformylation reactions.

Peroxo-diiron(III) species are present in the active sites of many metalloenzymes that carry out challenging organic transformations. The reactivity of these species is influenced by various factors, such as the structure and topology of the supporting ligands, the identity of the axial and equatorial co-ligands, and the oxidation states of the metal ion(s). In this study, we aim to diversify the importance of equatorial ligands in controlling the reactivity of peroxo-diiron(III) species. As a model compound, we chose the previously published and fully characterized [(PBI)2(CH3CN)FeIII(µ-O2)FeIII(CH3CN)(PBI)2]4+ complex, where the steric effect of the four PBI ligands is minimal, so the labile CH3CN molecules easily can be replaced by different monodentate co-ligands (substituted pyridines and N-donor heterocyclic compounds). Thus, their effect on the electronic and spectral properties of peroxo-divas(III) intermediates could be easily investigated. The relationship between structure and reactivity was also investigated in the stoichiometric deformylation of PPA mediated by peroxo-diiron(III) complexes. It was found that the deformylation rates are influenced by the Lewis acidity and redox properties of the metal centers, and showed a linear correlation with the FeIII/FeII redox potentials (in the range of 197 to 415 mV).

N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity.

The indole scaffold has been established as a key organic moiety for developing new drugs; on the other hand, a range of diiron bis-cyclopentadienyl complexes have recently emerged for their promising anticancer potential. Here, we report the synthesis of novel diiron complexes with an indole-functionalized vinyliminium ligand (2-5) and an indole-lacking analogue for comparative purposes (6), which were characterized by analytical and spectroscopic techniques. Complexes 2-6 are substantially stable in DMSO­d6 and DMEM-d solutions at 37 °C (8% average degradation after 48 h) and display a balanced hydrophilic/lipophilic behaviour (LogPow values in the range -0.32 to 0.47), associated with appreciable water solubility. The complexes display selective antiproliferative potency towards several cancer cells in monolayer cultures, mainly in the low micromolar range, with reduced toxicity towards noncancerous epithelial cells. Thus, the cytotoxicity of the complexes is comparable to or better than clinically used metallopharmaceutical cisplatin. Comparing the antiproliferative activity obtained for complexes containing different ligands, we confirmed the importance of the indolyl group in the mechanism of antiproliferative activity of these complexes. Cell-based mechanistic studies suggest that the investigated diiron vinyliminium complexes (DVCs) show cytostatic rather than cytotoxic effects and subsequently induce a population of cells to undergo apoptosis. Furthermore, the molecular mechanism of action involves interactions with mitochondrial DNA and proteins, the reactive oxygen species (ROS)-scavenging properties and antioxidant activity of these complexes in cancer cells. This study highlights the importance of DVCs to their cancer cell activity and reinforces their prospective therapeutic potential as anticancer agents.

The choice of µ-vinyliminium ligand substituents is key to optimize the antiproliferative activity of related diiron complexes.

Diiron vinyliminium complexes constitute a large family of organometallics displaying a promising anticancer potential. The complexes [Fe2Cp2(CO)(µ-CO){µ-η1:η3-C(R3)C(R4)CN(R1)(R2)}]CF3SO3 (2a-c, 4a-d) were synthesized, assessed for their behavior in aqueous solutions (D2O solubility, Log Pow, stability in D2O/Me2SO-d6 mixture at 37°C over 48 h) and investigated for their antiproliferative activity against A2780 and A2780cisR ovarian cancer cell lines and the nontumoral one Balb/3T3 clone A31. Cytotoxicity data collected for 50 vinyliminium complexes were correlated with the structural properties (i.e. the different R1-R4 substituents) using the partial least squares methodology. A clear positive correlation emerged between the octanol-water partition coefficient and the relative antiproliferative activity on ovarian cancer cell lines, both of which appear as uncorrelated to the cancer cell selectivity. However, the different effects played by the R1-R4 substituents allow tracing guidelines for the development of novel, more effective compounds. Based on these results, three additional complexes (4p-r) were designed, synthesized and biologically investigated, revealing their ability to hamper thioredoxin reductase enzyme and to induce cancer cell production of reactive oxygen species.

Anticancer Diiron Vinyliminium Complexes: A Structure-Activity Relationship Study.

A series of 16 novel diiron complexes of general formula [Fe2Cp2(CO)(µ-CO){µ-η1:η3-C(R')C(R″)CN(R)(Y)}]CF3SO3 (2-7), bearing different substituents on the bridging vinyliminium ligand, was synthesized in 69-95% yields from the reactions of diiron µ-aminocarbyne precursors with various alkynes. The products were characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy; moreover the X-ray structures of 2c (R = Y = CH2Ph, R' = R″ = Me) and 3a (R = CH2CH=CH2, Y = R' = Me, R″ = H) were ascertained by single-crystal X-ray diffraction studies. NMR and UV-Vis methods were used to assess the D2O solubility, the stability in aqueous solution at 37 °C and the octanol-water partition coefficients of the complexes. A screening study evidenced a potent cytotoxicity of 2-7 against the A2780 cancer cell line, with a remarkable selectivity compared to the nontumoral Balb/3T3 cell line; complex 4c (R = Cy, Y = R' = R″ = Me) revealed as the most performant of the series. The antiproliferative activity of a selection of complexes was also assessed on the cisplatin-resistant A2780cisR cancer cell line, and these complexes were capable of inducing a significant ROS production. Moreover, ESI-MS experiments indicated the absence of interaction of selected complexes with cytochrome c and the potentiality to inhibit the thioredoxin reductase enzyme (TrxR).