Half-Sandwich Ru(p-cymene) Compounds with Diphosphanes: In Vitro and In Vivo Evaluation As Potential Anticancer Metallodrugs.

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.

Laccases: Versatile Biocatalysts for the Synthesis of Heterocyclic Cores.

Laccases are multicopper oxidases that have shown a great potential in various biotechnological and green chemistry processes mainly due to their high relative non-specific oxidation of phenols, arylamines and some inorganic metals, and their high redox potentials that can span from 500 to 800 mV vs. SHE. Other advantages of laccases include the use of readily available oxygen as a second substrate, the formation of water as a side-product and no requirement for cofactors. Importantly, addition of low-molecular-weight redox mediators that act as electron shuttles, promoting the oxidation of complex bulky substrates and/or of higher redox potential than the enzymes themselves, can further expand their substrate scope, in the so-called laccase-mediated systems (LMS). Laccase bioprocesses can be designed for efficiency at both acidic and basic conditions since it is known that fungal and bacterial laccases exhibit distinct optimal pH values for the similar phenolic and aromatic amines. This review covers studies on the synthesis of five- and six-membered ring heterocyclic cores, such as benzimidazoles, benzofurans, benzothiazoles, quinazoline and quinazolinone, phenazine, phenoxazine, phenoxazinone and phenothiazine derivatives. The enzymes used and the reaction protocols are briefly outlined, and the mechanistic pathways described.

Conventional vs. Microwave- or Mechanically-Assisted Synthesis of Dihomooxacalix[4]arene Phthalimides: NMR, X-ray and Photophysical Analysis.

Direct O-alkylation of p-tert-butyldihomooxacalix[4]arene (1) with N-(bromopropyl)- or N-(bromoethyl)phthalimides and K2CO3 in acetonitrile was conducted under conventional heating (reflux) and using microwave irradiation and ball milling methodologies. The reactions afforded mono- and mainly distal di-substituted derivatives in the cone conformation, in a total of eight compounds. They were isolated by column chromatography, and their conformations and the substitution patterns were established by NMR spectroscopy (1H, 13C, COSY and NOESY experiments). The X-ray structures of four dihomooxacalix[4]arene phthalimide derivatives (2a, 3a, 3b and 5a) are reported, as well as their photophysical properties. The microwave (MW)-assisted alkylations drastically reduced the reaction times (from days to less than 45 min) and produced higher yields of both 1,3-di-substituted phthalimides (3a and 6a) with higher selectivity. Ball milling did not reveal to be a good method for this kind of reaction.

RuII( p-cymene) Compounds as Effective and Selective Anticancer Candidates with No Toxicity in Vivo.

Ruthenium(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru( p-cymene)(L-N,N)Cl][CF3SO3] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis(pyridin-2-yl)quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru( p-cymene)(Cl)(µ-Cl)]2 and were characterized by elemental analysis, mass spectrometry, 1H NMR, UV-vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC50 values found for 2 are among the lowest previously reported for Ru( p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC50 concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru(phen)2(dppz)]2+. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log Kb) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity.

Methyl-cyclopentadienyl Ruthenium Compounds with 2,2'-Bipyridine Derivatives Display Strong Anticancer Activity and Multidrug Resistance Potential.

New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(η5-MeCp)(PPh3)(4,4'-R-2,2'-bpy)]+ (Ru1, R = H; Ru2, R = CH3; and Ru3, R = CH2OH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P21/ c, Ru2 in the triclinic P1̅, and Ru3 in the monoclinic P21/ n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents.

pH-Switchability and Second-Order Nonlinear Optical Properties of Monocyclopentadienylruthenium(II)/iron(II) Tetrazoles/Tetrazolates: Synthesis, Characterization, and Time-Dependent Density Functional Theory Calculations.

Tetrazole/tetrazolate monocyclopentadienyliron(II) and ruthenium(II) compounds of general formulas [(η5-C5H5)M(dppe)(N4(H)CC6H4NO2)][PF6]/[(η5-C5H5)M(dppe)(N4CC6H4NO2)] were investigated for their pH-switching second-order nonlinear optical (SONLO) properties. Compounds [(η5-C5H5)M(dppe)(N4CC6H4NO2)] (M = Fe, Ru) and compound [(η5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)][PF6] were fully characterized by (1H-, 13C-, 31P-) NMR, cyclic voltammetry, and elemental analysis, and compounds [(η5-C5H5)Fe(dppe)(N4CC6H4NO2)] and [(η5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)][PF6] were further characterized by single-crystal X-ray diffraction; the synthesis of [(η5-C5H5)Fe(dppe)(N4(H)CC6H4NO2)][PF6] was unsuccessful. Time-dependent density functional theory calculations were performed using PBE0 and CAM-B3LYP functionals to evaluate the first hyperpolarizability (ßtot) of the tetrazole/tetrazolate complexes and for a detailed analysis of the experimental data. Both functionals predict (i) high first hyperpolarizabilities for the tetrazolate complexes [(η5-C5H5)M(dppe)(N4CC6H4NO2)], with ßtot[Ru] ≈ 1.2ßtot[Fe], and (ii) a 3-fold reduction in ßtot[Ru] upon protonation, in complex [(η5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)]+, forecasting [(η5-C5H5)Ru(dppe)(N4CC6H4NO2)]/[(η5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)]+ complexes as on/off, pH-switchable SONLO forms.

Unlocking Lignin's Potential: Engineered Bacterial Laccases to Produce Biologically Active Molecules.

Laccases are biocatalysts with immense potential in lignocellulose biorefineries to valorize emerging lignin monomers for sustainable chemicals. Despite reduced costs over the past two decades, enzymes remain a major expense in biorefining. Protein engineering can enhance enzyme properties and lower costs further. In this study, we used enzyme engineering tools to improve > 400-fold the catalytic efficiency (kcat/Km) of a hyperthermostable bacterial laccase for 2,6-dimethoxyphenol, a lignin-related phenolic compound. Furthermore, this evolved variant showed improved activity at neutral to alkaline pH for hydroxycinnamyl alcohols, hydrocinnamic acids, phenylpropanoid and vanillyl derivatives. We optimized conditions for the synthesis of syringaresinol, dehydrodiconiferyl alcohol, thomasidioic acid, biseugenol, dehydrodiisoeugenol, and diapocynin, detailing the pH, catalyst concentration, reaction time, temperature, and oxygenation of the reaction mixtures. Our biocatalytic system offers several advantages, including being free of organic solvents, achieving faster reaction times, using lower amounts of enzymes and delivering excellent yields (up to 100%) than reported methods. Additionally, we provide insights that advance the state-of-the-art in lignin combinatory chemistry. This progress marks a significant step forward in valorizing the lignin chemicals platform, enabling high yields of dimeric compounds with structural scaffolds that can be exploited in various biotechnological areas, such as medicinal chemistry and polymer synthesis.

A wide array of lignin-related phenolics are oxidized by an evolved bacterial dye-decolourising peroxidase.

Lignin is the second most abundant natural polymer next to cellulose and by far the largest renewable source of aromatic compounds on the planet. Dye-decolourising peroxidases (DyPs) are biocatalysts with immense potential in lignocellulose biorefineries to valorize emerging lignin building blocks for environmentally friendly chemicals and materials. This work investigates the catalytic potential of the engineered PpDyP variant 6E10 for the oxidation of 24 syringyl, guaiacyl and hydroxybenzene lignin-phenolic derivatives. Variant 6E10 exhibited up to 100-fold higher oxidation rates at pH 8 for all the tested phenolic substrates compared to the wild-type enzyme and other acidic DyPs described in the literature. The main products of reactions were dimeric isomers with molecular weights of (2 × MWsubstrate - 2 H). Their structure depends on the substitution pattern of the aromatic ring of substrates, i.e., of the coupling possibilities of the primarily formed radicals upon enzymatic oxidation. Among the dimers identified were syringaresinol, divanillin and diapocynin, important sources of structural scaffolds exploitable in medicinal chemistry, food additives and polymers.

Iron(II)-cyclopentadienyl compounds are cytotoxic against colon adenocarcinoma cell lines: Ethylenebis(diphenylphosphane) vs. triphenylphosphane.

Structure-activity studies aiming to understand the role of each coligand in the formulation of new metallodrugs is an important subject. In that frame, six new compounds with general formula [Fe(η5-C5H5)(dppe)(L)][CF3SO3] with L = benzonitriles (1-4) or carbon monoxide (5) and compound [Fe(η5-C5H5)(CO)(PPh3)2][CF3SO3] (6) were synthesized and compared with three other previously reported compounds [Fe(η5-C5H5)(CO)(L)(PPh3)][CF3SO3]. We were particularly interested in assessing the effect of dppe vs. (PPh3 + CO) for this set of compounds. For that, all compounds were tested against two human colon adenocarcinoma cell lines, Colo205 and the refractile Colo320 (expressing ABCB1, an efflux pump causing multidrug resistance), showing IC50 values in the micromolar range. The presence of dppe in the compound's coordination sphere over (PPh3 + CO) allows for more redox stable compounds showing higher cytotoxicity and selectivity, with improved cytotoxicity towards resistant cells that is not related to the inhibition of ABCB1. Further studies with GSH and H2O2 for selected compounds indicated that their antioxidant ability is not probably the main responsible for their cytotoxicity.

Wasteful Azo Dyes as a Source of Biologically Active Building Blocks.

In this work, an environment-friendly enzymatic strategy was developed for the valorisation of dye-containing wastewaters. We set up biocatalytic processes for the conversion of azo dyes representative of the main classes used in the textile industry into valuable aromatic compounds: aromatic amines, phenoxazinones, phenazines, and naphthoquinones. First, purified preparations of PpAzoR azoreductase efficiently reduced mordant, acid, reactive, and direct azo dyes into aromatic amines, and CotA-laccase oxidised these compounds into phenazines, phenoxazinones, and naphthoquinones. Second, whole cells containing the overproduced enzymes were utilised in the two-step enzymatic conversion of the model mordant black 9 dye into sodium 2-amino-3-oxo-3H-phenoxazine-8-sulphonate, allowing to overcome the drawbacks associated with the use of expensive purified enzymes, co-factors, or exquisite reaction conditions. Third, cells immobilised in sodium alginate allowed recycling the biocatalysts and achieving very good to excellent final phenoxazine product yields (up to 80%) in water and with less impurities in the final reaction mixtures. Finally, one-pot systems using recycled immobilised cells co-producing both enzymes resulted in the highest phenoxazinone yields (90%) through the sequential use of static and stirring conditions, controlling the oxygenation of reaction mixtures and the successive activity of azoreductase (anaerobic) and laccase (aerobic).

Studies of the Antiproliferative Activity of Ruthenium (II) Cyclopentadienyl-Derived Complexes with Nitrogen Coordinated Ligands.

Four cationic ruthenium(II) complexes with the formula [Ru(eta(5)-C(5)H(5))(PPh(3))(2)](+), with L = 5-phenyl-1H-tetrazole (TzH) 1, imidazole (ImH) 2, benzo[1,2-b;4,3-b'] dithio-phen-2-carbonitrile (Bzt) 3, and [5-(2-thiophen-2-yl)-vinyl]-thiophene-2-carbonitrile] (Tvt) 4 were prepared and characterized in view to evaluate their potentialities as antitumor agents. Studies by Circular Dichroism indicated changes in the secondary structure of ct-DNA. Changes in the tertiary structure of pBR322 plasmid DNA were also observed in gel electrophoresis experiment and the images obtained by atomic force microscopy (AFM) suggest strong interaction with pBR322 plasmid DNA; the observed decreasing of the viscosity with time indicates that the complexes do not intercalate between DNA base pairs. Compounds 1, 2, and 3 showed much higher cytotoxicity than the cisplatin against human leukaemia cancer cells (HL-60 cells).

Ruthenium carboranyl complexes with 2,2'-bipyridine derivatives for potential bimodal therapy application.

Ruthenium complexes of carboranyl ligands offer the possibility of dual action (chemo + radiotherapy) that might result in significant clinical benefits. In that frame, we describe herein the development of ruthenium-carboranyl complexes bearing bipyridyl derivatives with the general formula [3-CO-3,3-{κ2-4,4'-R2-2,2'-bipy}-closo-3,1,2-RuC2B9H11] (R = CH3, RuCB1 or R = CH2OH, RuCB2). Both compounds crystallized in the monoclinic system, showing the expected three-legged piano stool structure. The ruthenacarboranes are stable in cell culture media and were tested against two cell lines that have shown favorable clinical responses with BNCT, namely melanoma (A375) and glioblastoma (U87). RuCB1 shows no cytotoxic activity up to 100 µM while RuCB2 showed moderate activity for both cell lines. Cell distribution assays showed that RuCB2 presents high boron internalization that is proportional to the concentration used indicating that RuCB2 presents features to be further studied as a potential anticancer bimodal agent (chemo + radiotherapy).

Novel "ruthenium cyclopentadienyl"-peptide conjugate complexes against human FGFR(+) breast cancer.

In this work we explored the possibility of improving the selectivity of a cytotoxic Ru complex [RuCp(PPh3)(2,2'-bipy)][CF3SO3] (where Cp = η5-cyclopentadienyl) TM34 towards FGFR(+) breast cancer cells. Molecular dynamics (MD) simulations of TM34 in a phosphatidylcholine membrane model pinpointed the cyclopentadienyl group as a favorable derivatization position for the peptide conjugation approach. Three new Ru(ii) complexes presenting a functionalized η5-cyclopentadienyl were synthesized, namely [Ru(η5-C5H4COOH)(2,2'-bipy)(PPh3)][CF3SO3] (TM281) and its precursors, [Ru(η5-C5H4COOCH2CH3)(η2-2,2'-bipy)(PPh3)][CF3SO3] (3) and [Ru(η5-C5H4COOCH2CH3)(PPh3)2Cl] (2). Complex TM281 was prepared by the hydrolysis of the ethyl ester group appended to the η5-cyclopentadienyl ligand of complex 3 with K2CO3 in water/acetonitrile, followed by mild protonation using an ion exchange resin. The newly synthesized complexes were fully characterized by NMR, FTIR and UV-vis spectroscopic techniques. Also, electrochemical studies were carried out by means of cyclic voltammetry in order to evaluate the stability of the compounds. Single crystal X-ray diffraction studies were carried out for compounds 3 and TM281 which crystallized in the monoclinic system, space group P21/n. The unprecedented synthesis and characterization of three half-sandwich ruthenium(ii)-cyclopentadienyl peptide conjugates and their preliminary biological evaluation against human FGFR(+) and FGFR(-) breast cancer cells are also reported.

Synthesis of Azobenzene Dyes Mediated by CotA Laccase.

An eco-friendly protocol for the synthesis of azobenzene dyes by oxidative coupling of primary aromatic amines is reported. As efficient biocatalytic systems, CotA laccase and CotA laccase/ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) enable the oxidation of various substituted anilines, in aqueous medium, ambient atmosphere and under mild reaction conditions of pH and temperature. A series of azobenzene dyes were prepared in good to excellent yields in an one-pot reaction. A mechanistic proposal for the formation of the azo derivatives is presented. Our strategy offers an alternative approach for the direct synthesis of azobenzene dyes, avoiding the harsh conditions generally required for most of the traditional synthetic methods.

Novel ruthenium methylcyclopentadienyl complex bearing a bipyridine perfluorinated ligand shows strong activity towards colorectal cancer cells.

Three new compounds have been synthesized and completely characterized by analytical and spectroscopic techniques. The new bipyridine-perfluorinated ligand L1 and the new organometallic complex [Ru(η5-MeCp)(PPh3)2Cl] (Ru1) crystalize in the centrosymmetric triclinic space group P1¯. Analysis of the phenotypic effects induced by both organometallic complexes Ru1 and [Ru(η5-MeCp)(PPh3)(L1)][CF3SO3] (Ru2), on human colorectal cancer cells (SW480 and RKO) survival, showed that Ru2 has a potent anti-proliferative activity, 4-6 times higher than cisplatin, and induce apoptosis in these cells. Data obtained in a noncancerous cell line derived from normal colon epithelial cells (NCM460) revealed an intrinsic selectivity of Ru2 for malignant cells at low concentrations, showing the high potential of this compound as a selective anticancer agent.

The key role of coligands in novel ruthenium(II)-cyclopentadienyl bipyridine derivatives: Ranging from non-cytotoxic to highly cytotoxic compounds.

A new family of eight ruthenium(II)-cyclopentadienyl bipyridine derivatives, bearing nitrogen, sulfur, phosphorous and carbonyl sigma bonded coligands, has been synthesized. Compounds bearing nitrogen bonded coligands were found to be unstable in aqueous solution, while the others presented appropriate stabilities for the biologic assays and pursued for determination of IC50 values in ovarian (A2780) and breast (MCF7 and MDAMB231) human cancer cell lines. These studies were also carried out for the [5: HSA] and [6: HSA] adducts (HSA=human serum albumin) and a better performance was found for the first case. Spectroscopic, electrochemical studies by cyclic voltammetry and density functional theory calculations allowed us to get some understanding on the electronic flow directions within the molecules and to find a possible clue concerning the structural features of coligands that can activate bipyridyl ligands toward an increased cytotoxic effect. X-ray structure analysis of compound [Ru(η(5)-C5H5)(bipy)(PPh3)][PF6] (7; bipy=bipyridine) showed crystallization on C2/c space group with two enantiomers of the [Ru(η(5)-C5H5)(bipy)(PPh3)](+) cation complex in the racemic crystal packing.

New water-soluble ruthenium(II) cytotoxic complex: biological activity and cellular distribution.

A novel water soluble organometallic compound, [RuCp(mTPPMSNa)(2,2'-bipy)][CF3SO3] (TM85, where Cp=η(5)-cyclopentadienyl, mTPPMS=diphenylphosphane-benzene-3-sulfonate and 2,2'-bipy=2,2'-bipyridine) is presented herein. Studies of interactions with relevant proteins were performed to understand the behavior and mode of action of this complex in the biological environment. Electrochemical and fluorescence studies showed that TM85 strongly binds to albumin. Studies carried out to study the formation of TM85 which adducts with ubiquitin and cytochrome c were performed by electrospray ionization mass spectrometry (ESI-MS). Antitumor activity was evaluated against a variety of human cancer cell lines, namely A2780, A2780cisR, MCF7, MDAMB231, HT29, PC3 and V79 non-tumorigenic cells and compared with the reference drug cisplatin. TM85 cytotoxic effect was reduced in the presence of endocytosis modulators at low temperatures, suggesting an energy-dependent mechanism consistent with endocytosis. Ultrastructural analysis by transmission electron microscopy (TEM) revealed that TM85 targets the endomembranar system disrupting the Golgi and also affects the mitochondria. Disruption of plasma membrane observed by flow cytometry could lead to cellular damage and cell death. On the whole, the biological activity evaluated herein combined with the water solubility property suggests that complex TM85 could be a promising anticancer agent.

Biological activity and cellular uptake of [Ru(η5-C5H5)(PPh3)(Me2bpy)][CF3SO3] complex.

Anticancer activity of the new [Ru(η(5)-C5H5)(PPh3)(Me2bpy)][CF3SO3] (Me2bpy = 4,4'-dimethyl-2,2'-bipyridine) complex was evaluated in vitro against several human cancer cell lines, namely A2780, A2780CisR, HT29, MCF7, MDAMB231 and PC3. Remarkably, the IC50 values, placed in the nanomolar and sub-micromolar range, largely exceeded the activity of cisplatin. Binding to human serum albumin, either HSA (human serum albumin) or HSA(faf) (fatty acid-free human serum albumin) does not affect the complex activity. Fluorescence studies revealed that the present ruthenium complex strongly quench the intrinsic fluorescence of albumin. Cell death by the [Ru(η(5)-C5H5)(PPh3)(Me2bpy)][CF3SO3] complex was reduced in the presence of endocytosis modulators and at low temperature, suggesting an energy-dependent mechanism consistent with endocytosis. On the whole, the biological activity evaluated herein suggests that the complex could be a promising anticancer agent.

Important cytotoxicity of novel iron(II) cyclopentadienyl complexes with imidazole based ligands.

Four new compounds of general formula [FeCp(dppe)L][CF3SO3] with L=imidazole substituted ligands, and dppe=ethylenebis(diphenylphosphane) have been synthesized and characterized with the aim to evaluate their anticancer properties. The new compounds were fully characterized by spectroscopic and electrochemical methods and the structure of [Fe(η(5)-C5H5)(dppe)(1-BuIm)] [CF3SO3] (1), [Fe(η(5)-C5H5)(dppe) (ImH)][CF3SO3] (3) and [Fe(η(5)-C5H5)(dppe)(1HmIm)][CF3SO3] (4) (where 1-BuIm=1-butylimidazole, and 1HmIm=N-hydroxymethylimidazole) was determined by X-ray diffraction studies. Apparently, these compounds are the first reported 'Fe(η(5)-C5H5)' half sandwich derivatives presenting high cytotoxic activity against a set a human tumor cell lines predicting their potential value as antitumor drugs.

Methyl syringate: an efficient phenolic mediator for bacterial and fungal laccases.

The aim of the present work is to provide insight into the mechanism of laccase reactions using syringyl-type mediators. We studied the pH dependence and the kinetics of oxidation of syringyl-type phenolics using the low CotA and the high redox potential TvL laccases. Additionally, the efficiency of these compounds as redox mediators for the oxidation of non-phenolic lignin units was tested at different pH values and increasing mediator/non-phenolic ratios. Finally, the intermediates and products of reactions were identified by LC-MS and (1)H NMR. These approaches allow concluding on the (1) mechanism involved in the oxidation of phenolics by bacterial laccases, (2) importance of the chemical nature and properties of phenolic mediators, (3) apparent independence of the enzyme's properties on the yields of non-phenolics conversion, (4) competitive routes involved in the catalytic cycle of the laccase-mediator system with several new C-O coupling type structures being proposed.