Divalent ansa-Octaphenyllanthanocenes: Synthesis, Structures, and EuII Luminescence.

Reductive dimerization of fulvenes using low-valent metal precursors is a straightforward one-step approach to access ethylene-bridged metallocenes. This process has so far mainly been employed with fulvenes carrying one or two substituents in the exocyclic position. In this work, a new synthesis of the unsubstituted exocyclic 1,2,3,4-tetraphenylfulvene (1), its full structural characterization by NMR spectroscopy and single-crystal X-ray diffraction, as well as some photophysical properties and its first use in reductive dimerization are described. This fulvene reacted with different lanthanoid metals in thf to provide the divalent ansa-octaphenylmetallocenes [Ln(C5Ph4CH2)2(thf)n] (Ln = Sm, n = 2 (2); Ln = Eu, n = 2 (3); and Ln = Yb, n = 1 (4)). These complexes were characterized by X-ray diffraction, laser desorption/ionization time of flight mass spectrometry, and, in the case of Sm and Yb, multinuclear NMR spectroscopy, showing the influence of the ansa-bridge on solution and solid-state structures compared to previously reported unbridged metallocenes. Furthermore, the luminescence properties of the Eu ansa complex 3 were studied in solution and the solid state, revealing significant differences with the known octa- and deca-phenyleuropocenes, [Eu(C5Ph4H)2(dme)] and [Eu(C5Ph5)2].

Generation of ϵ,ϵ-Difluorinated Metal-Pentadienyl Species through Lanthanide-Mediated C-F Activation.

Heavy metal on Lewis acid: The combination of lanthanide metals and AlCl3 has been employed for selective single C-F activation in benzofulvenes comprising an exocyclic CF3 substituent. Intermediate ϵ,ϵ-difluorinated metal-dienyl species react with a large variety of aldehydes in a highly regio- and diastereoselective fashion to afford 1,1-disubstituted indenes bearing a difluorovinyl group. These new building blocks have been further transformed through a hydrogenation-cyclization process into fluorinated heterocyclic spiro compounds.

Reduced net charge and heterogeneity of pI isoforms in familial amyotrophic lateral sclerosis mutants of copper/zinc superoxide dismutase.

Familial cases of amyotrophic lateral sclerosis (fALS) are related to mutations of copper/zinc superoxide dismutase 1 (SOD1). Aggregation of SOD1 plays a central role in the pathogenesis of fALS and altered metallation of SOD1 mutants could be involved in this process. Using IEF gel electrophoresis under non-denaturating conditions and particle induced X-ray emission (PIXE) analysis, we studied the pI distribution and metallation status of fALS SOD1 mutants (A4V, G93A, D125H) compared to human wild-type (hWT). SOD1 fALS mutants are characterized by a variable number of isoforms and higher pI compared to hWT, reflecting a reduced net charge that might explain their greater propensity to precipitation and aggregation. Cu/Zn ratios were slightly different for the predominant expressed isoforms of A4V, G93A, and D125H mutants compared to hWT. Differences in metallation were observed within each genotype, the more basic isoforms exhibiting lower Cu/Zn ratios. Moreover, we revealed the existence of a pool of fALS mutants SOD1 pI isoforms, slightly expressed (<10%), with a low Cu/Zn ratio and high pI values. Overall, IEF-PIXE results suggest that the toxicity of SOD1 mutants should be studied at the pI isoform level with a particular attention to the species with the lowest charges.

Two-photon Absorption Engineering of 5-(Fluorenyl)-1,10-phenanthroline-based Ru(II) Complexes.

This study deals with the fine tuning of the photophysical characteristics, and especially two-photon absorption (2PA) properties, of several homo- and heteroleptic ruthenium(II) complexes involving 5-substituted-1,10-phenanthroline ligands. The 2PA spectra of the complexes were determined in the 700-930 nm range by investigating their two-photon excited luminescence (2PEL). Structure - linear and nonlinear optical properties correlations are discussed, and potential applications (therapy and optical power limiting in the near infrared) can be anticipated.

Choosing between Ti(II) and Ti(III): selective reduction of titanocene dichloride by elemental lanthanides.

The reduction of titanocene dichloride Cp2TiCl2 with lanthanide metals has led to the discovery of a surprising lanthanide effect: while with most lanthanides, a divalent [Cp2Ti] equivalent was obtained, the use of samarium or ytterbium only led to the reduction to trivalent [Cp2TiCl]-type complexes, including the structurally characterized heterobimetallic complex [Cp2Ti(µ-Cl)2SmCl2(THF)3]. These results were corroborated by reactivity studies (alkyne coupling and radical reactions), EPR spectroscopy and electrospray mass spectrometry, providing new insights into the reduction chemistry of lanthanide metals.

Coupling of native IEF and extended X-ray absorption fine structure to characterize zinc-binding sites from pI isoforms of SOD1 and A4V pathogenic mutant.

Extended X-ray absorption fine structure (EXAFS) has already provided high-resolution structures of metal-binding sites in a wide variety of metalloproteins. Usually, EXAFS is performed on purified metalloproteins either in solution or crystallized form but purification steps are prone to modify the metallation state of the protein. We developed a protocol to couple EXAFS analysis to metalloprotein separation using native gel electrophoresis. This coupling opens a large field of applications as metalloproteins can be characterized in their native state avoiding purification steps. Using native isoelectric focusing, the method enables the EXAFS analysis of metalloprotein pI isoforms. We applied this methodology to SOD1, wild-type, and Ala4Val mutant (A4V), a mutation found in amyotrophic lateral sclerosis (ALS) because decreased Zn affinity to SOD1 mutants is suggested to be involved in the pathogenesis of this neurodegenerative disease. We observed similar coordination structures for Zn in wild-type and mutant proteins, in all measured pI isoforms, demonstrating the feasibility of EXAFS on electrophoresis gels and suggesting that the Zn-binding site is not structurally modified in A4V SOD1 mutant.

Molecular engineering for optical properties of 5-substituted-1,10-phenanthroline-based Ru(II) complexes.

A series of homo- and heteroleptic Ru(ii) complexes [Ru(phen)3-n(phen-X)n](PF6)2 (n = 0-3, X = CN, epoxy, H, NH2) were prepared and characterized. The influence of electron-withdrawing or electron-releasing substituents of the 1,10-phenanthroline ligands on the photo-physical properties was evaluated. It reveals fundamental interests in the fine tuning of redox potentials and photo-physical characteristics, depending both on the nature of the substitution of the ligand, and on the symmetry of the related homo- or heteroleptic complex. These complexes exhibit linear absorption and two-photon absorption (2PA) cross-sections over a broad range of wavelength (700-900 nm) due to absorption in the intra-ligand charge transfer (ILCT) and the metal-to-ligand charge transfer (MLCT) bands. These 2PA properties were more particularly investigated in the 700-1000 spectral range for a family of complexes bearing electro-donating ligands (phen-NH2).

Crystal structure of (4bS,8aR)-1-isopropyl-4b,8,8-trimethyl-7-oxo-4b,7,8,8a,9,10-hexa-hydro-phenanthren-2-yl acetate.

The title compound, C22H28O3, was prepared by a direct acetyl-ation reaction of naturally occurring totarolenone. The mol-ecule contains three fused rings, which exhibit different conformations. The central ring has a half-chair conformation, while the non-aromatic oxo-substituted ring has a screw-boat conformation. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds and C-H⋯π inter-actions, forming sheets parallel to the bc plane. The carbonyl O atoms and the C atom at the 6-position of the cyclo-hexene ring are each disordered over two sets of sites with major occupancy components of 0.63 (7) and 0.793 (14), respectively.

Application of Elemental Lanthanides in the Selective C-F Activation of Trifluoromethylated Benzofulvenes Providing Access to Various Difluoroalkenes.

The selective activation of one carbon-fluorine bond in polyfluorinated aromatic molecules or in trifluoromethyl-containing substrates offers the possibility of accessing unique fluorine-containing molecules, which are difficult to obtain by other synthetic pathways. Among various metals, which can undergo C-F activation, lanthanides (Ln) are good candidates as they form strong Ln-F bonds. Lanthanide metals are strong reducing agents with a redox potential Ln3+/Ln of approximately -2.3 V, which is comparable to the value of the Mg2+/Mg redox couple. In addition, lanthanide metals display a promising functional group tolerance and their reactivity can vary along the lanthanide series, making them suitable reagents for fine-tuning reaction conditions in organic and organometallic transformations. However, due to their oxophilicity, lanthanides react readily with oxygen and water and therefore require special conditions for storage, handling, preparation, and activation. These factors have limited a more widespread use in organic synthesis. We herein present how dysprosium metal - and by analogy all lanthanide metals - can be freshly prepared under anhydrous conditions using glovebox and Schlenk techniques. The freshly filed metal, in combination with aluminum chloride, initiates the selective C-F activation in trifluoromethylated benzofulvenes. The resulting reaction intermediates react with nitroalkenes to obtain a new family of difluoroalkenes.

Ruthenium(II) Polypyridyl Complexes as Photosensitizers for Antibacterial Photodynamic Therapy: A Structure-Activity Study on Clinical Bacterial Strains.

As a growing public health concern, the worldwide spread of antimicrobial resistance urges the development of new therapies. Antibacterial photodynamic therapy (a-PDT) may be an alternative to conventional antibiotic therapy. Herein we report the synthesis and characterization of seven original reactive oxygen species (ROS)-producing ruthenium(II) polypyridyl complexes. These are part of a collection of 17 derivatives varying in terms of the nature of the substituent(s), molecular symmetry, electrical charge, and counterions. They were characterized by considering 1) their physical properties (absorption coefficient at irradiation wavelength, 1 O2 generation quantum yield, luminescence) and 2) their antibacterial activity in a series of photodynamic assays using Gram-positive and Gram-negative bacteria of clinical relevance. The results unveiled some structure-activity relationships: one derivative that combines multiple beneficial features for a-PDT was effective against all the bacteria considered, regardless of their Gram status, species, or antibiotic resistance profile. This systematic study could guide the design of next-generation ruthenium-based complexes for enhanced antibacterial photodynamic strategies.

Silica-Based Nanoparticles as Bifunctional and Bimodal Imaging Contrast Agents.

New bifunctional and bimodal nanoparticles (NPs) have been elaborated and characterised. They are based on silica NPs that incorporate a silylated ruthenium tris-bipyridine complex. The resulting suspension of amine-modified NPs with diameters of 20 nm was post-functionalised with a stable gadolinium ion complex. Interest in these NPs lies mainly in the confinement of optical and magnetic imaging agents (Ru and Gd complexes, respectively) within the NP volume. Their potential use as a bimodal probe (luminescence/magnetic resonance imaging) and theranostic agent (photodynamic therapy/imaging) is described. The biological potential of these NPs has been studied on HCT-116 cells and microscopy and cytotoxicity results are given.

Crystal structure of methyl (Z)-2-[(Z)-3-methyl-2-({(E)-1-[(R*)-4-methyl-cyclo-hex-3-en-1-yl]ethyl-idene}hydrazinyl-idene)-4-oxo-thia-zolidin-5-yl-idene]acetate.

The new title 4-thia-zolidinone derivative, C16H21N3O3S, was obtained from the cyclization reaction of 4-methyl-3-thio-semicarbazone and dimethyl acetyl-enedi-carboxyl-ate (DMAD). The cyclo-hexyl-idene ring has an envelope conformation with the stereogenic centre C atom as the flap. Its mean plane makes a dihedral angle of 56.23 (9)° with the thia-zolidine ring mean plane. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds forming chains propagating in the [001] direction. Within the chains there are offset π-π inter-actions between the thia-zolidine rings of inversion-related mol-ecules [centroid-centroid distance = 3.703 (1) Å]. The chains are linked by further C-H⋯O hydrogen bonds, forming slabs parallel to the ac plane.

Magnetic Dextran Nanoparticles That Bear Hydrophilic Porphyrin Derivatives: Bimodal Agents for Potential Application in Photodynamic Therapy.

Invited for this month's cover is the group of Prof. Vincent Sol from the University of Limoges, France. This study is a collaboration between the Universities of Limoges, Reims, Pierre et Marie Curie (UPMC, Paris), and Paris Sud (Orsay). The cover picture shows a magnetic dextran nanoparticle bearing hydrophilic porphyrin derivatives; the illustration shows bimodal nanoplatforms that could be used as contrast agents in magnetic resonance imaging as well as photosensitizers in photodynamic therapy. Read the full text of the article at 10.1002/cplu.201500087.

Magnetic Dextran Nanoparticles That Bear Hydrophilic Porphyrin Derivatives: Bimodal Agents for Potential Application in Photodynamic Therapy.

This study reports the chemical synthesis of a class of dextran superparamagnetic nanoparticles that bear hydrophilic porphyrin units covalently grafted by a click chemistry reaction in aqueous solution. Magnetic nanoparticles are used in magnetic resonance imaging (MRI) and hyperthermia, and the grafting of hydrophilic photosensitizers (PS) leads to elaborate new multifunctional platforms for potential diagnostic and targeted photodynamic therapy (PDT). The therapeutic potential for PDT of these nanoparticles is evaluated in vitro against the HaCaT cell line. The results show that these new multicharged nanomagnets-in particular, those that bear cationic porphyrins-show a significant uptake and an interesting photocytotoxic activity toward HaCaT cells. The whole series of these synthesized PS are massively incorporated inside HaCat cells and associated with mitochondria.

A modified cyclen azaxanthone ligand as a new fluorescent probe for Zn2+.

A new cyclen derivative L, bearing a methyl-chromeno-pyridinylidene hydrazone moiety, was synthesized and studied in MeOH, as potential fluorescent "OFF-on-ON" sensors for Zn(ii). Photophysical properties of this ligand being PET regulated, L was only weakly emissive in the absence of metal ions (OFF). L fluorescence was increased modestly upon addition of one equivalent of Zn(II), and further increased upon addition of a second equivalent. Therefore, Zn : L behaved as a highly sensitive ON sensor for zinc. This efficiency was correlated to Zn(II) coordination via the hydrazone moiety of the fluorophore, producing an efficient CHelation-Enhanced Fluorescence (CHEF) effect. A complementary theoretical study carried out with DFT calculations further elucidated the optical properties.

Bifunctional polypyridyl-Ru(II) complex grafted onto gadolinium-based nanoparticles for MR-imaging and photodynamic therapy.

The synthesis, optical properties and efficiency of new multifunctional nanoparticles as theranostic (fluorescence/MRI/PDT) agents are described. They are based on a polysiloxane network and surrounded by gadolinium(III) chelates and ruthenium(II) complexes. The size of the nanoparticles is maintained under 5 nm in order to permit their efficient elimination from the body. Their potential use as a theranostic agent (PDT/MRI) is described. The magnetic properties of the nanoparticles are studied by relaxometry (r1 = 9.21 mM(-1) s(-1) at 40 MHz; r2/r1 = 1.14) and the signal enhancement is validated by the acquisition of phantoms on a 3 T MRI imager. The therapeutic potential for photodynamic therapy of the nanoparticles has been studied in vitro on HEK293 cells and an effective quantum yield of 0.33 for (1)O2 production has been determined in deuterated water.

Multimodal analysis of metals in copper-zinc superoxide dismutase isoforms separated on electrophoresis gels.

It has been suggested that copper-zinc superoxide dismutase (CuZnSOD) isoforms of distinct isoelectric point (pI) could result from differences in their metallation state. Our aim was then to develop and validate analytical methods for the determination and understanding of metallation states in human CuZnSOD isoforms. To avoid metal losses during sample preparation steps, CuZnSOD isoforms were separated according to their pI using non-denaturing isoelectric focusing (IEF) gel electrophoresis. Metal quantification was directly performed in-gel. Cu/Zn ratios of CuZnSOD isoforms were quantified by Particle-Induced X-ray Emission (PIXE) and Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP-MS). Cu/Zn ratios were measured close to the value of 1 as expected from the known stoichiometry of CuZnSOD with slight, but statistically significant, differences between acidic and basic isoforms. Overall, this study demonstrates that metal quantification can be performed directly on metalloproteins separated on electrophoresis gels.

Monodispersed glucose-responsive microgels operating at physiological salinity.

Monodispersed poly(N-isopropylacrylamide) submicrometric microgels modified with a phenylboronic acid (PBA) derivative have been synthesized by precipitation polymerization. Particles with a well-controlled size and adjustable composition were obtained. These particles were found to be glucose responsive at a pH close to the pKa of the PBA derivative, with a swelling degree proportional to the concentration of glucose. In addition, the response to glucose was found to strongly depend on the initial state of the microgel, which depended itself on the initial temperature and the functionalization degree of the particle. This result explained the fundamental difference in the behavior of PBA-poor particles and rich ones in the presence of electrolyte. Interestingly, the latter exhibited a high swelling ratio in the presence of glucose at physiological electrolyte concentration. These particles may serve as building blocks for the design of colorimetric sensors based on the light diffraction of colloidal crystals.