Aminocarbyne-Alkyne Coupling in Diruthenium Complexes: Exploring the Anticancer Potential of the Resulting Vinyliminium Complexes and Comparison with Diiron Homologues.

New diruthenium complexes based on the scaffold Ru2Cp2(CO)2 (Cp = η5-C5H5) and containing a bridging vinyliminium ligand, [2a-d]CF3SO3, were synthesized through regioselective coupling of alkynes with an aminocarbyne precursor (85-90% yields). The reaction involving phenylacetylene proceeded with the formation of a diruthenacyclobutene byproduct, [4]CF3SO3 (10% yield). Complexes [2a-d]+ undergo partial alkyne extrusion in contact with alumina or CDCl3. All products were characterized by elemental analysis, infrared and multinuclear NMR spectroscopy, and single crystal X-ray diffraction in two cases. Complexes [2a-d]+ revealed an outstanding stability in DMEM cell culture medium at 37 °C (<1% degradation over 72 h). These complexes exhibited cytotoxicity in human colon colorectal adenocarcinoma HT-29 cells in the low micromolar range, with lower IC50 values than those obtained with the homologous diiron complexes previously reported. Evaluation of ROS (reactive oxygen species) production and O2 consumption rate (OCR) highlighted the higher potential of Ru2 complexes, compared to the Fe2 counterparts, to impact mitochondrial activity, with the heterometallic Ru2-ferrocenyl complex [2d]+ showing the best performance.

Triiron Complex with N-Ferrocenyl Aminocarbyne Ligand Bridging a Diiron Core: DFT, Electrochemical, and Biological Insights.

The first N-ferrocenyl aminocarbyne complex, [Fe2Cp2(CO)2(µ-CO){µ-CN(Me)(Fc)}]CF3SO3 ([2]CF3SO3), was synthesized with an 88% yield from [Fe2Cp2(CO)4], isocyanoferrocene (CNFc), and methyl triflate. The synthesis proceeded through the intermediate formation of [Fe2Cp2(CO)3(CNFc)], 1. Multinuclear NMR experiments revealed the presence of cis and trans isomers for [2]CF3SO3 in organic solvents, in agreement with DFT outcomes. Electrochemical and spectroelectrochemical studies demonstrated one reduction process occurring prevalently at the diiron core and one oxidation involving the ferrocenyl substituent. The oxidation process is expected to favor the redox activation of [2]+ in a biological environment. Both [2]CF3SO3 and its phenyl analogue [Fe2Cp2(CO)2(µ-CO){µ-CN(Me)(Ph)}]CF3SO3 ([3]CF3SO3), prepared for comparison, exerted moderate antiproliferative activity against the human cancer cell lines A431, HCT-15, PSN-1, 2008, and U1285. However, [2]CF3SO3 exhibited a higher cytotoxicity than [3]CF3SO3, showed a substantial ability to induce intracellular ROS production, and outperformed cisplatin in a three-dimensional SCLC cell model.

Triazine Chalcogenones from Thiocyanate or Selenocyanate Addition to Tetrazine Ligands in Ruthenium Arene Complexes.

The chemistry of 1,2,4,5-tetrazines has attracted considerable interest both from a synthetic and applicative standpoint. Recently, regioselective reactions with alkynes and alkenes have been reported to be favored once the tetrazine ring is coordinated to Re(I), Ru(II), and Ir(III) centers. Aiming to further explore the effects of metal coordination, herein, we unveil the unexplored reactivity of tetrazines with chalcogenocyanate anions. Thus, ruthenium(II) tetrazine complexes, [RuCl{κ2N-3-(2-pyridyl)-6-R-1,2,4,5-tetrazine}(η6-arene)]+ (arene = p-cymene, R = H, [1a]+, R = Me, [1b]+, R = 2-pyridyl, [1c]+; arene = C6Me6, R = H, [1d]+, R = Me, [1e]+; PF6- salts), reacted quantitatively and in mild conditions with M(ECN) salts (M = Na, K, Bu4N; E = O, S, Se). The addition of thiocyanate or selenocyanate to the tetrazine ligand is regioselective and afforded, via N2 release, 1,2,4-triazine-5-chalcogenone heterocycles, the one with selenium being unprecedented. The novel ruthenium complexes [RuCl{κ2N-(2-pyridyl)}{triazine chalcogenone}(η6-arene)] 2a-e (sulfur), 3b, 3d, and 3e (selenium) were characterized by analytical (CHNS analyses, conductivity), spectroscopic (IR, multinuclear and two-dimensional (2D) NMR), and spectrometric (electrospray ionization mass spectrometry (ESI-MS)) techniques. According to density functional theory (DFT) calculations, the nucleophilic attack of SCN- on the tetrazine ring is kinetically driven. Compound 2b is selectively and reversibly mono-protonated on the triazine ring by HCl or other strong acids, affording a single tautomer. When reactions of chalcogenocyanates were performed on the 2,2'-bipyridine (bpy) complex [RuCl(bpy)(η6-p-cymene)]+, the chloride substitution products [Ru(ECN)(bpy)(η6-p-cymene)]+ (E = O, [4]+; E = S, [5]+; E = Se, [6]+) were obtained in 82-90% yields (PF6- salts). Combined spectroscopic data (IR, 1H/13C/77Se NMR) was revealed to be a useful tool to study the linkage isomerism of the chalcogenocyanate ligand in [4-6]+.

Switching on Cytotoxicity of Water-Soluble Diiron Organometallics by UV Irradiation.

The diiron compounds [Fe2Cp2(CO)2(µ-CO)(µ-CSEt)]CF3SO3, [1]CF3SO3, K[Fe2Cp2(CO)3(CNCH2CO2)], K[2], [Fe2Cp2(CO)2(µ-CO)(µ-CNMe2)]NO3, [3]NO3, [Fe2Cp2(CO)2(PTA){µ-CNMe(Xyl)}]CF3SO3, [4]CF3SO3, and [Fe2Cp2(CO)(µ-CO){µ-η:1η3-C(4-C6H4CO2H)CHCNMe2}]CF3SO3, [5]CF3SO3, containing a bridging carbyne, isocyanoacetate, or vinyliminium ligand, were investigated for their photoinduced cytotoxicity. Specifically, the novel water-soluble compounds K[2], [3]NO3, and [4]CF3SO3 were synthesized and characterized by elemental analysis and IR and multinuclear NMR spectroscopy. Stereochemical aspects concerning [4]CF3SO3 were elucidated by 1H NOESY NMR and single-crystal X-ray diffraction. Cell proliferation studies on human skin cancer (A431) and nontumoral embryonic kidney (HEK293) cells, with and without a 10-min exposure to low-power UV light (350 nm), highlighted the performance of the aminocarbyne [3]NO3, nicknamed NIRAC (Nitrate-Iron-Aminocarbyne), which is substantially nontoxic in the dark but shows a marked photoinduced cytotoxicity. Spectroscopic (IR, UV-vis, NMR) measurements and the myoglobin assay indicated that the release of one carbon monoxide ligand represents the first step of the photoactivation process of NIRAC, followed by an extensive disassembly of the organometallic scaffold.

New glycoconjugation strategies for Ruthenium(II) arene complexes via phosphane ligands and assessment of their antiproliferative activity.

Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, d-galactal and d-allal-derived vinyl epoxides (VEß and VEα) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1ß and 1α. Ligand exchange with [Ru(C2O4)(η6-p-cymene)(H2O)] gave the glycoconjugated complexes Ru1ß and Ru1α which were subsequently dihydroxylated with OsO4/N-methylmorpholine N-oxide to Ru2ß and Ru2α containing O-benzyl d-mannose and d-gulose units respectively. Besides, aminoethyl tetra-O-acetyl-ß-d-glucopyranoside was condensed with borane-protected (4-diphenylphosphanyl)benzoic acid by HATU/DIPEA under MW heating, to afford the amide 3∙BH3. Zemplén deacylation with MeONa/MeOH gave the deprotected d-glucopyranoside derivative 4∙BH3. The glycoconjugated phosphane complexes Ru3 and Ru4 were obtained by reaction of the phosphane-boranes 3∙BH3 and 4∙BH3 with [Ru(C2O4)(η6-p-cymene)(H2O)]. The employed synthetic strategies were devised to circumvent unwanted phosphine oxidation. The compounds were purified by silica chromatography, isolated in high yield and purity and characterized by analytical and spectroscopic (IR and multinuclear NMR) techniques. The behaviour of the six glycoconjugated Ru complexes in aqueous solutions was assessed by NMR and MS measurements. All compounds were screened for their in vitro cytotoxicity against A2780/A2780R human ovarian and MCF7 breast cancer cell lines, revealing a significant cytotoxicity for complexes containing the 2,3-unsaturated glycosyl unit (Ru1ß, Ru1α). Additional studies on five other human cancer cells, as well as time-dependent toxicity and cell-uptake analyses on ovarian cancer cells, confirmed the prominent activity of these two compounds - higher than cisplatin - and the better performance of the ß anomer. However, Ru1ß, Ru1α did not show preferential activity against cancer cells with respect to fetal lung fibroblast and human embryonic kidney cells as models of normal cells. The effects of the two ruthenium glycoconjugated compounds in A2780 ovarian cancer cells were further investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The latter is a relevant factor in the mechanism of action of the highly cytotoxic Ru1ß, inducing cell death by apoptosis.

Automated approach for the evaluation of glutathione-S-transferase P1-1 inhibition by organometallic anticancer compounds.

A novel automated method based on sequential injection analysis (SIA), a non-segmented flow injection technique, was developed to evaluate glutathione S-transferase P1-1 (GST P1-1) activity in the presence of organometallic complexes with putative anticancer activity. The assay is based on the reaction of L-glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB) in the presence of GST P1-1 to afford the GS-DNB conjugate and the reaction may be monitored by an increase in absorbance at 340 nm. A series of ruthenium, iron, osmium and iridium complexes were evaluated as GST P1-1 inhibitors by evaluating their half-maximal inhibitory concentration (IC50). An iridium compound displays the lowest IC50 value of 6.7 ± 0.7 µM and an iron compound displays the highest IC50 value of 275 ± 9 µM. The SIA method is simple to use, robust, reliable, and efficient and uses fewer reagents than batch methods and each analysis takes only 5 minutes.

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.

Hetero-Bis-Conjugation of Bioactive Molecules to Half-Sandwich Ruthenium(II) and Iridium(III) Complexes Provides Synergic Effects in Cancer Cell Cytotoxicity.

Four bipyridine-type ligands variably derivatized with two bioactive groups (taken from ethacrynic acid, flurbiprofen, biotin, and benzylpenicillin) were prepared via sequential esterification steps from commercial 2,2'-bipyridine-4,4'-dicarboxylic acid and subsequently coordinated to ruthenium(II) p-cymene and iridium(III) pentamethylcyclopentadienyl scaffolds. The resulting complexes were isolated as nitrate salts in high yields and fully characterized by analytical and spectroscopic methods. NMR and MS studies in aqueous solution and in cell culture medium highlighted a substantial stability of ligand coordination and a slow release of the bioactive fragments in the latter case. The complexes were assessed for their antiproliferative activity on four cancer cell lines, showing cytotoxicity to the low micromolar level (equipotent with cisplatin). Additional biological experiments revealed a multimodal mechanism of action of the investigated compounds, involving DNA metalation and enzyme inhibition. Synergic effects provided by specific combinations of metal and bioactive fragments were identified, pointing toward an optimal ethacrynic acid/flurbiprofen combination for both Ru(II) and Ir(III) complexes.

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.

Bis-conjugation of Bioactive Molecules to Cisplatin-like Complexes through (2,2'-Bipyridine)-4,4'-Dicarboxylic Acid with Optimal Cytotoxicity Profile Provided by the Combination Ethacrynic Acid/Flurbiprofen.

A facile route to PtII complexes doubly functionalized with bioactive molecules through a bipyridine-type ligand is described. Initially, ligands LEE (containing two ethacrynic acid units), LEF (ethacrynic acid+flurbiprofen) and LEB (ethacrynic acid+biotin) were obtained in moderate to good yields from 2,2'-bipyridine-4,4'-dicarboxylic acid. Subsequent reaction of the ligands with [PtCl2 (DMSO)2 ] afforded complexes [PtCl2 (LEE )] (2), [PtCl2 (LEF )] (3) and [PtCl2 (LEB )] (4) in high yields. All compounds were fully characterized by analytical and spectroscopic methods. Complexes 2-4 are highly stable in water/DMSO solution at 37 °C after 72 h, whereas progressive release of the bioactive fragments was detected in a cell culture medium. The compounds were assessed for their in vitro antiproliferative activity towards tumorigenic A2780, A2780cisR and Y79 cells and non-tumourigenic HEK293 cells. In particular, the combination of ethacrynic acid and flurbiprofen in 3 overcomes cisplatin-based resistance and provides strong cancer cell selectivity. Enzyme inhibition assays on human GST P1 and human COX-2 and cross-experiments with complex 1, analogous to 2-4 but lacking bio-groups, revealed a clear synergy between the PtII frame and the bioactive organic components.

Recent Advances in the Chemistry of Metal Carbamates.

Following a related review dating back to 2003, the present review discusses in detail the various synthetic, structural and reactivity aspects of metal species containing one or more carbamato ligands, representing a large family of compounds across all the periodic table. A preliminary overview is provided on the reactivity of carbon dioxide with amines, and emphasis is given to recent findings concerning applications in various fields.

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.

Anticancer Potential of Diiron Vinyliminium Complexes.

Invited for the cover of this issue is the group of Fabio Marchetti at the Università di Pisa and Paul J. Dyson at Ecole Polytechnique Fédérale de Lausanne (EPFL). Read the full text of the article at 10.1002/chem.201902885.

Anticancer Potential of Diiron Vinyliminium Complexes.

Although ferrocene derivatives have attracted considerable attention as possible anticancer agents, the medicinal potential of diiron complexes has remained largely unexplored. Herein, we describe the straightforward multigram-scale synthesis and the antiproliferative activity of a series of diiron cyclopentadienyl complexes containing bridging vinyliminium ligands. IC50 values in the low-to-mid micromolar range were determined against cisplatin sensitive and resistant human ovarian carcinoma (A2780 and A2780cisR) cell lines. Notable selectivity towards the cancerous cells lines compared to the non-tumoral human embryonic kidney (HEK-293) cell line was observed for selected compounds. The activity seems to be multimodal, involving reactive oxygen species (ROS) generation and, in some cases, a fragmentation process to afford monoiron derivatives. The large structural variability, amphiphilic character and good stability in aqueous media of the diiron vinyliminium complexes provide favorable properties compared to other widely studied classes of iron-based anticancer candidates.

α-Diimines as Versatile, Derivatizable Ligands in Ruthenium(II) p-Cymene Anticancer Complexes.

α-Diimines are among the most robust and versatile ligands available in synthetic coordination chemistry, possessing finely tunable steric and electronic properties. A series of novel cationic ruthenium(II) p-cymene complexes bearing simple α-diimine ligands, [(η6- p-cymene)RuCl{κ2 N-(HCNR)2}]NO3 (R = Cy, [1]NO3; R = 4-C6H10OH, [2]NO3; R = 4-C6H4OH, [3]NO3), were prepared in near-quantitative yields as their nitrate salts. [2]NO3 displays high water solubility. The potential of the α-diimine ligand in [3]NO3 as a carrier of bioactive molecules was investigated via esterification reactions with the hydroxyl groups. Thus, the double-functionalized derivatives [(η6- p-cymene)RuCl{κ2 N-(HCN(4-C6H4OCO-R))2}]NO3 (R = aspirinate, [5]NO3; valproate, [6]NO3) and also [4]Cl (R = Me) were obtained in good-to-high yields. UV-vis and multinuclear NMR spectroscopy and cyclic voltammetric studies in aqueous solution revealed only minor ruthenium chloride hydrolytic cleavage, biologically accessible reduction potentials, and pH-dependent behavior of [3]NO3. Density functional theory analysis was performed in order to compare the Ru-Cl bond strength in [1]+ with the analogous ethylenediamine complex, showing that the higher stability observed in the former is related to the electron-withdrawing properties of the α-diimine ligand. In vitro cytotoxicity studies were performed against tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK-293) cell lines, with the complexes bearing simple α-diimine ligands ranging from inactive to IC50 values in the low micromolar range. The complexes functionalized with bioactive components, i.e., [5]NO3 and [6]NO3, exhibited a marked increase in the cytotoxicity with respect to the precursor [3]NO3.

Modifying bis(triflimide) ionic liquids by dissolving early transition metal carbamates.

The authors report the first modification of ionic liquids with metal carbamates. A selection of homoleptic N,N-dialkylcarbamates of group 4 and 5 metals, M(O2CNR2)n, were dissolved in bis(trifluoromethylsulfonyl)imide-based ionic liquids, i.e. [bmim][Tf2N] and [P(oct)4][Tf2N], at 293 K. The resulting solutions were characterized by means of IR, UV and NMR spectroscopy, and the data were compared to those of the respective metal compounds. Notably, the dissolution process did not proceed with the release of any of the original carbamato ligands, thus preserving the intact coordination frame around the metal centre. The solvation process of Ti(O2CNiPr2)4, as a model species, in [bmim][Tf2N] was rationalized by DFT calculations. As a comparative study, solutions of NbF5 and MCl5 (M = Nb, Ta) in [bmim][Tf2N] were also investigated, revealing the possible occurrence of solvent anion coordination to the metal centres.

Arene Ruthenium(II) Complexes with Phosphorous Ligands as Possible Anticancer Agents.

Ruthenium(II) complexes of formula [Ru(η6-arene)Cl2 (PTA)] (RAPTA) are potential anticancer drugs with notable antimetastatic and antiangiogenic activity, which are now pointing to clinical trials. Following the great interest aroused by these compounds, a variety of RAPTA derivatives, obtained by chloride substitution and/or containing functionalized arene ligands, and complexes resembling the RAPTA structure but bearing different phosphorous ligands have been synthesized and evaluated for their anticancer activity. An overview of all of these biologically relevant complexes will be given, with particular reference to the anticancer behaviour exhibited by the compounds and the possible relationship with structural aspects.

Ovalbumin labeling with p-hydroxymercurybenzoate: The effect of different denaturing agents and the kinetics of reaction.

The aim of our study was to investigate how denaturing agents commonly used in protein analysis influence the labeling between a reactive molecule and proteins. For this reason, we investigated the labeling of ovalbumin (OVA) as a globular model protein with p-hydroxymercurybenzoate (pHMB) in its native state (phosphate buffer solution) and in different denaturing conditions (8 molL(-1) urea, 3 molL(-1) guanidinium thiocyanate, 6 molL(-1) guanidinium chloride, 0.2% sodium dodecyl sulfate, and 20% methanol). In addition to chemical denaturation, thermal denaturation was also tested. The protein was pre-column simultaneously denatured and derivatized, and the pHMB-labeled denatured OVA complexes were analyzed by size exclusion chromatography (SEC) coupled online with chemical vapor generation-atomic fluorescence spectrometry (CVG-AFS). The number of -SH groups titrated greatly depends on the protein structure in solution. Indeed, we found that, depending on the adopted denaturing conditions, OVA gave different aggregate species that influence the complexation process. The results were compared with those obtained by a common alternative procedure for the titration of -SH groups that employs monobromobimane (mBBr) as tagging molecule and molecular fluorescence spectroscopy as detection technique. We also investigated the labeling kinetics for denatured OVA and pHMB, finding that the 4 thiolic groups of OVA have a very different reactivity toward mercury labeling, in agreement with previous studies.

Mixed valence triiron complexes from the conjugation of [FeIFeI] and [FeII] complexes via intermolecular carbyne/alkyne coupling.

We present a new synthetic strategy for obtaining mixed-valence triiron complexes where the metal centers are bridged by a novel, highly functionalized hydrocarbyl ligand. The alkynyl-vinyliminium complexes [Fe2Cp2(CO)(µ-CO){µ-η1:η3-C(X-CCH)CHCNMe2}]CF3SO3 (X = 4-C6H4, [2a1]CF3SO3; X = (CH2)3, [2a2]CF3SO3) were synthesized in almost quantitative yields from the aminocarbyne precursor [Fe2Cp2(CO)2(µ-CO){µ-CNMe2}]CF3SO3, [1a]CF3SO3, and the di-alkynes HCC-X-CCH. Then, the ferracycle [Fe(Cp)(CO){C(NMe2)CHC(4-C6H4CCH)C(O)}], 4a1, was produced in 47% yield from the cleavage of [2a1]CF3SO3 promoted by pyrrolidine. Subsequent reactions of the acetonitrile adducts [Fe2Cp2(CO)(µ-CO)(NCMe){µ-CNMe(R)}]CF3SO3 (R = Me, [1aACN]CF3SO3; R = Xyl, [1bACN]CF3SO3) ([FeIFeI]) with 4a1 ([FeII]) at room temperature resulted in the formation of [FeIFeIFeII] complexes [Fe2Cp2(CO)(µ-CO){µ-η1:η3-C(X-CCHC(NMe2)FeCp(CO)CO)CHCNMe(R)}]CF3SO3 (R = Me, [5a1]CF3SO3; R = Xyl, [5b1]CF3SO3) in yields ranging from 56% to 64%. The new products were characterized by IR and multinuclear NMR spectroscopy, and the structures of [2a2]CF3SO3 and 4a1 were confirmed by single crystal X-ray diffraction. Cyclic voltammetry and spectroelectrochemical studies on [5a1]+ have revealed that reduction and oxidation events occur almost independently at the [FeIFeI] and [FeII] units, respectively. This observation underscores a minimal electronic interaction between the two fragments within the triiron complex. Accordingly, DFT studies pointed out that the HOMO and LUMO orbitals are predominantly localized in the two distinct compartments of [5a1]+.

1,3,5-Triaza-7-phosphaadamantane and Cyclohexyl Groups Impart to Di-Iron(I) Complex Aqueous Solubility and Stability, and Prominent Anticancer Activity in Cellular and Animal Models.

Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One compound from the series (FEACYP) emerged for its strong cytotoxicity in vitro against four human cancer cell lines, surpassing the activity of cisplatin by 3-6 times in three cell lines, with an average selectivity index of 6.2 compared to noncancerous HEK293 cells. FEACYP demonstrated outstanding water solubility (15 g/L) and stability in physiological-like solutions. It confirmed its superior antiproliferative activity when tested in 3D spheroids of human pancreatic cancer cells and showed a capacity to inhibit thioredoxin reductase (TrxR) similar to auranofin. In vivo treatment of murine LLC carcinoma with FEACYP (8 mg kg-1 dose) led to excellent tumor growth suppression (88%) on day 15, with no signs of systemic toxicity and only limited body weight loss.