FETPY: a Diiron(I) Thio-Carbyne Complex with Prominent Anticancer Activity In Vitro and In Vivo.

FETPY, an organo-diiron(I) complex, showed strong cytotoxicity across a panel of human and mouse cancer cell lines, combined with an outstanding selectivity compared to nonmalignant cells. Enhanced iron uptake in aggressive, low-differentiated cell lines, caused membrane lipid peroxidation, which resulted in ferroptosis in human ovarian cancer cells. FETPY induced significant morphological changes in murine B16-F1 and B16-F10 melanoma cells, leading to senescence and/or trans-differentiation into Schwann-like cells, thus significantly reducing their tumorigenic potential. Additionally, FETPY substantially suppressed tumor growth in low- and high-grade syngeneic melanoma models when administered in a therapeutic regimen. FETPY is featured by satisfactory water solubility (millimolar range), an amphiphilic character (Log Pow = -0.17), and excellent stability in a biological medium (DMEM). These important requisites for drug development are rarely met in iron complexes investigated so far as possible anticancer agents. Overall, FETPY holds promise as a safe and potent targeted antitumor agent.

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.

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 beneficial effect of cyclohexyl substituent on the in vitro anticancer activity of diiron vinyliminium complexes.

Novel diiron vinyliminium complexes, [Fe2Cp2(CO)(µ-CO){µ-η1:η3-C(R3)CHCNMe(R2)}]CF3SO3 (2a-f; R2 = 4-C6H4OMe, Cy or Me; R3 = Cy, CH2Cy or 4-C6H4OMe; Cy = cyclohexyl, Cp = η5-C5H5), were synthesized by alkyne insertion reaction from the corresponding diiron aminocarbyne precursors, and isolated in 53-98% yields. The reactions of selected vinyliminium complexes with N2CHCO2Et and MeONa, followed by N-methylation, afforded the new hydrazone-vinyliminium [Fe2Cp2(CO)(µ-CO){µ-η1:η3-C(R3)C(NMeNCHCO2Et)CN(R1)(R2)}]X (4a-c; R1 = Me or CH2Ph; R2 = Cy, CH2Ph or Me; R3 = 4-C6H4OMe or Ph; X = NO3 or CF3SO3), in 53-67% yields. Compounds 2a-f and 4a-c were fully characterized by IR and multinuclear NMR spectroscopy, and the structures of 2a-c were ascertained by single crystal X-ray diffraction. Moreover, D2O solubility, Log Pow coefficients and the fraction of each complex preserved in aqueous media after 72 hours at 37 °C were determined by 1H NMR and UV-Vis methods. The antiproliferative activity of 2a-f and 4a-c was measured on the mouse colon CT26 and human glioblastoma U87 cancer cell lines, and on the retinal pigment epithelial RPE-1 non-cancerous cell line. Complexes 2a,d,e, which all bear R3 = Cy, stand out for their performance and their selectivity towards cancer cells. To give insight into the mechanism of action, the effect of 2a, 2d, 2e, 2f, 4b and 4c on the mitochondrial respiration was evaluated in CT26 cells (Seahorse Mito stress test), revealing a correlation between the effectiveness of the complexes and their influence on the mitochondrial metabolism.

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.

Hybrid nano-architectures loaded with metal complexes for the co-chemotherapy of head and neck carcinomas.

Head and neck squamous cell carcinomas (HNSCCs) are a complex group of malignancies that affect different body sites pertaining to the oral cavity, pharynx and larynx. Current chemotherapy relies on platinum complexes, the major exponent being cisplatin, which exert severe side effects that can negatively affect prognosis. For this reason, other metal complexes with less severe side effects are being investigated as alternatives or adjuvants to platinum complexes. In this context, exploiting (supra)additive effects by the concurrent administration of cisplatin and emerging metal complexes is a promising research strategy that may lead to effective cancer management with reduced adverse reactions. Here, the combined action of cisplatin and a ruthenium(II) η6-arene compound (RuCy), both as free molecules and loaded into hybrid nano-architectures (NAs), has been assessed on HPV-negative HNSCC models of increasing complexity: 2D cell cultures, 3D multicellular tumor spheroids, and chorioallantoic membranes (CAMs). Two new NAs have been established to explore all the delivery combinations and compare their ability to enhance the efficacy of cisplatin in the treatment of HNSCCs. A significant supra-additive effect has been observed in both 2D and 3D models by one combination of treatments, suggesting that cisplatin is particularly effective when loaded on NAs, whereas RuCy performs better when administered as a free compound. Overall, this work paves the way for the establishment of the next co-chemotherapeutic approaches for the management of HNSCCs.

Anticancer ruthenium(II) tris(pyrazolyl)methane complexes with bioactive co-ligands.

In comparison with RuII-arene compounds, the medicinal potential of homologous RuII-tpm compounds [tpm = tris(pyrazolyl)methane] is underexplored. Pyridine, 4-pyridinemethanol and four functionalized pyridines, synthesized from the esterification of 4-pyridinemethanol with bioactive carboxylic acids (i.e., ethacrynic acid, ibuprofen, flurbiprofen and naproxen), react with the precursor [RuCl(κ3-tpm)(PPh3)2]Cl (1) to afford [RuCl(κ3-tpm)(PPh3)(L)]Cl (2-7, L = pyridine ligand), in 78-91% yields. All products were fully characterized by HR-ESI mass spectrometry, IR and multinuclear NMR spectroscopy and the solid-state structures of two of the complexes, i.e. where L = pyridine and 4-pyridinemethanol, were ascertained by single crystal X-ray diffraction. The {Ru-tpm-PPh3} assembly is stable in D2O and in biological medium (DMEM) at 37 °C, with a tendency to slowly dissociate the pyridine ligand. The antiproliferative activity of the complexes was assessed on the cancerous A2780 and A2780cisR cell lines, and the nontumoral HEK 293T cell line; moreover inhibition assays were carried out on the complexes towards COX-2 and GSTP1 enzymes.

Ruthenium(II)-Tris-pyrazolylmethane Complexes Inhibit Cancer Cell Growth by Disrupting Mitochondrial Calcium Homeostasis.

While ruthenium arene complexes have been widely investigated for their medicinal potential, studies on homologous compounds containing a tridentate tris(1-pyrazolyl)methane ligand are almost absent in the literature. Ruthenium(II) complex 1 was obtained by a modified reported procedure; then, the reactions with a series of organic molecules (L) in boiling alcohol afforded novel complexes 2-9 in 77-99% yields. Products 2-9 were fully structurally characterized. They are appreciably soluble in water, where they undergo partial chloride/water exchange. The antiproliferative activity was determined using a panel of human cancer cell lines and a noncancerous one, evidencing promising potency of 1, 7, and 8 and significant selectivity toward cancer cells. The tested compounds effectively accumulate in cancer cells, and mitochondria represent a significant target of biological action. Most notably, data provide convincing evidence that the mechanism of biological action is mediated by the inhibiting of mitochondrial calcium intake.

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.

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.

Role of the (pseudo)halido ligand in ruthenium(II) p-cymene α-amino acid complexes in speciation, protein reactivity and cytotoxicity.

The reactions of the dimeric complexes [RuX2(η6-p-cymene)]2 (X = Br, I, SCN) with L-proline (ProH) and trans-4-hydroxy-L-proline (HypH), in methanol in the presence of NaOH, afforded [RuX(κ2N,O-Pro)(η6-p-cymene)] (X = Br, 1b; I, 1c; SCN, 1d) and [RuX(κ2N,O-Hyp)(η6-p-cymene)] (X = Br, 2b; I, 2c; SCN, 2d), respectively. Alternatively, the one-pot, sequential addition of the appropriate α-amino carboxylate and X- salt to [RuCl2(η6-p-cymene)]2 led to [RuX(κ2N,O-Pro)(η6-p-cymene)] (X = N3, 1e; NO2, 1f; CN 1g) and [Ru(N3)(κ2N,O-Hyp)(η6-p-cymene)] (2e). Complexes [Ru(κ3N,O,O'-O2CCH(NH2)(R)O)(η6-p-cymene)] (R = CH2, 3h; R = CHMe, 4h; R = CH2CH2, 5h) were prepared from the reaction of [RuCl2(η6-p-cymene)]2 with the appropriate α-amino acid and NaOH in refluxing isopropanol. Treatment of the L-serine (SerH2) derivative [RuCl(κ2N,O-SerH)(η6-p-cymene)] (3a) with 1,3,5-triaza-7-phosphaadamantane (PTA) in water at reflux produced [Ru(κ2N,O-Ser)(κP-PTA)(η6-p-cymene)]Cl ([3i]Cl). The products were isolated in good to excellent yields, and were characterized by elemental analysis, IR and multinuclear NMR spectroscopy. The structures of 1f and 2b-e were ascertained by X-ray diffraction studies. The behaviour of the complexes in water and cell culture medium was investigated by multinuclear NMR and UV-Vis spectroscopy, revealing a considerable influence of the monodentate ligand on the aqueous chemistry. Complexes 1d-e, 2d-e, 3h, 4h and [3i]Cl, showing substantial inertness in aqueous media, were assessed for their cytotoxicity towards A2780 and A2780cisR cancer cell lines and the noncancerous HEK 293T cell line. A selection of compounds was also investigated for Ru uptake in A2780 cells and interactions with cytochrome c as a model protein. Combined, these studies provide insights into the previously debated role of the 'leaving' ligand on the biological activity of Ru(II) arene α-amino acid complexes.

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).

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.

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.

Anticancer and antibacterial potential of robust Ruthenium(II) arene complexes regulated by choice of α-diimine and halide ligands.

Several complexes of general formula [Ru(halide)(η6-p-cymene)(α-diimine)]+, in the form of nitrate, triflate and hexafluorophosphate salts, including a newly synthesized iodide compound, were investigated as potential anticancer drugs and bactericides. NMR and UV-Vis studies evidenced remarkable stability of the complexes in water and cell culture medium. In general, the complexes displayed strong cytotoxicity against A2780 and A549 cancer cell lines with IC50 values in the low micromolar range, and one complex (RUCYN) emerged as the most promising one, with a significant selectivity compared to the non-cancerous HEK293 cell line. A variable affinity of the complexes for BSA and DNA binding was ascertained by spectrophotometry/fluorimetry, circular dichroism, electrophoresis and viscometry. The performance of RUCYN appears associated to enhanced cell internalization, favored by two cyclohexyl substituents, rather than to specific interaction with the evaluated biomolecules. The chloride/iodide replacement, in one case, led to increased cellular uptake and cytotoxicity at the expense of selectivity, and tuned DNA binding towards intercalation. Complexes with iodide or a valproate bioactive fragment exhibited the best antimicrobial profiles.

Ruthenium arene complexes in the treatment of 3D models of head and neck squamous cell carcinomas.

Current chemotherapy for head and neck squamous cell carcinomas (HNSCCs) are based on cisplatin, which is usually associated to severe side effects. In general, the exploration for metal-based alternatives to cisplatin has resulted in the development of a series of ruthenium complexes that are able to produce a safe therapeutic action against some neoplasms, among which are lung and ovarian cancers. Here, we evaluate the efficacy of well defined, easily available and robust ruthenium(II) η6-arene compounds on 3D models of HNSCCs with or without human papillomavirus (HPV) infection and compare their effects to the state-of-the-art RAPTA-C, a promising ruthenium compound with known anti-cancer activity. One of the compounds induces a significant therapeutic action especially on HPV negative carcinoma. Besides viability and repopulation evaluations, we performed quantitative analysis of the internalized Ru compounds to further validate our findings and elucidate the possible mechanisms of action. These results show that Ru arene compounds represent a promising alternative for the treatment of HNSCCs and pave the way for the composition of innovative (co)therapies.

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.

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.