Novel Silver Complexes Based on Phosphanes and Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands Targeting TrxR: New Promising Chemotherapeutic Tools Relevant to SCLC Management.

Bis(pyrazol-1-yl)acetic acid (HC(pz)2COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pzMe2)2COOH) were converted into the methyl ester derivatives 1 (LOMe) and 2 (L2OMe), respectively, and were used for the preparation of silver(I) complexes 3-5. The Ag(I) complexes were prepared by the reaction of AgNO3 and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine (PPh3) with LOMe and L2OMe in methanol solution. All Ag(I) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in the in-house human cancer cell line panel containing examples of different solid tumors. Compounds were particularly effective against the highly aggressive and intrinsically resistant human small-cell lung carcinoma (SCLC) cells, either in 2D and 3D cancer cell models. Mechanistic studies revealed their ability to accumulate into cancer cells and to selectively target Thioredoxin (TrxR), thus leading to redox homeostasis unbalance and ultimately inducing cancer cell death through apoptosis.

Cu(I) and Cu(II) Complexes Based on Lonidamine-Conjugated Ligands Designed to Promote Synergistic Antitumor Effects.

Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh3-containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death.

Exploring the Antitumor Potential of Copper Complexes Based on Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands.

Bis(pyrazol-1-yl)acetic acid (HC(pz)2COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pzMe2)2COOH) were converted into the methyl ester derivatives 1 (LOMe) and 2 (L2OMe), respectively, and were used for the preparation of Cu(I) and Cu(II) complexes 3-10. The copper(II) complexes were prepared by the reaction of CuCl2·2H2O or CuBr2 with ligands 1 and 2 in methanol solution. The copper(I) complexes were prepared by the reaction of Cu[(CH3CN)4]PF6 and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine with LOMe and L2OMe in acetonitrile solution. Synchrotron radiation-based complementary techniques (XPS, NEXAFS, and XAS) were used to investigate the electronic and molecular structures of the complexes and the local structure around copper ions in selected Cu(I) and Cu(II) coordination compounds. All Cu(I) and Cu(II) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human cancer cell lines, and were able to overcome cisplatin resistance. Noticeably, Cu complexes appeared much more effective than cisplatin in 3D spheroid cultures. Mechanistic studies revealed that the antitumor potential did not correlate with cellular accumulation but was consistent with intracellular targeting of PDI, ER stress, and paraptotic cell death induction.

Cyclo- and Polyphosphazenes for Biomedical Applications.

Cyclic and polyphosphazenes are extremely interesting and versatile substrates characterized by the presence of -P=N- repeating units. The chlorine atoms on the P atoms in the starting materials can be easily substituted with a variety of organic substituents, thus giving rise to a huge number of new materials for industrial applications. Their properties can be designed considering the number of repetitive units and the nature of the substituent groups, opening up to a number of peculiar properties, including the ability to give rise to supramolecular arrangements. We focused our attention on the extensive scientific literature concerning their biomedical applications: as antimicrobial agents in drug delivery, as immunoadjuvants in tissue engineering, in innovative anticancer therapies, and treatments for cardiovascular diseases. The promising perspectives for their biomedical use rise from the opportunity to combine the benefits of the inorganic backbone and the wide variety of organic side groups that can lead to the formation of nanoparticles, polymersomes, or scaffolds for cell proliferation. In this review, some aspects of the preparation of phosphazene-based systems and their characterization, together with some of the most relevant chemical strategies to obtain biomaterials, have been described.

Dinuclear gold(I) Complexes with Bidentate NHC Ligands as Precursors for Alkynyl Complexes via Mechanochemistry.

The use of alkynyl gold(I) complexes covers different research fields, such as bioinorganic chemistry, catalysis, and material science, considering the luminescent properties of the complexes. Regarding this last application, we report here the synthesis of three novel dinuclear gold(I) complexes of the general formula [(diNHC)(Au-C≡CPh)2]: two Au-C≡CPh units are connected by a bridging di(N-heterocyclic carbene) ligand, which should favor the establishment of semi-supported aurophilic interactions. The complexes can be easily synthesized through mechanochemistry upon reacting the pristine dibromido complexes [(diNHC)(AuBr)2] with phenylacetylene and KOH. Interestingly, we were also able to isolate the monosubstituted complex [(diNHC)(Au-C≡CPh)(AuBr)]. The gold(I) species were fully characterized by multinuclear NMR spectroscopy and mass spectrometry. The emission properties were also evaluated, and the salient data are comparable to those of analogous compounds reported in the literature.

Activation of Vegetable Oils by Reaction with Maleic Anhydride as a Renewable Source in Chemical Processes: New Experimental and Computational NMR Evidence.

Vegetable oils are bio-based and sustainable starting materials that can be used to develop chemicals for industrial processes. In this study, the functionalization of three vegetable oils (grape, hemp, and linseed) with maleic anhydride was carried out either by conventional heating or microwave activation to obtain products that, after further reactions, can enhance the water dispersion of oils for industrial applications. To identify the most abundant derivatives formed, trans-3-octene, methyl oleate, and ethyl linoleate were reacted as reference systems. A detailed NMR study, supported by computational evidence, allowed for the identification of the species formed in the reaction of trans-3-octene with maleic anhydride. The signals in the 1H NMR spectra of the alkenyl succinic anhydride (ASA) moieties bound to the organic chains were clearly identified. The reactions achieved by conventional heating were carried out for 5 h at 200 °C, resulting in similar or lower amounts of ASA units/g of oil with respect to the reactions performed by microwave activation, which, however, induced a higher viscosity of the samples.

Synthesis and Biological Studies on Dinuclear Gold(I) Complexes with Di-(N-Heterocyclic Carbene) Ligands Functionalized with Carbohydrates.

The design of novel metal complexes with N-heterocyclic carbene (NHC) ligands that display biological activity is an active research field in organometallic chemistry. One of the possible approaches consists of the use of NHC ligands functionalized with a carbohydrate moiety. Two novel Au(I)-Au(I) dinuclear complexes were synthesized; they present a neutral structure with one bridging diNHC ligand, having one or both heterocyclic rings decorated with a carbohydrate functionality. With the symmetric diNHC ligand, the dicationic dinuclear complex bearing two bridging diNHC ligands was also synthesized. The study was completed by analyzing the antiproliferative properties of these complexes, which were compared to the activity displayed by similar mononuclear Au(I) complexes and by the analogous bimetallic Au(I)-Au(I) complex not functionalized with carbohydrates.

Synthesis, Characterization and Biological Activity of Novel Cu(II) Complexes of 6-Methyl-2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde-4n-Substituted Thiosemicarbazones.

Three new 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde-thiosemicarbazones-N-4-substituted pro-ligands and their Cu(II) complexes (1, -NH2; 2, -NHMe; 3, -NHEt) have been prepared and characterized. In both the X-ray structures of 1 and 3, two crystallographically independent complex molecules were found that differ either in the nature of weakly metal-binding species (water in 1a and nitrate in 1b) or in the co-ligand (water in 3a and methanol in 3b). Electron Paramagnetic Resonance (EPR) measurements carried out on complexes 1 and 3 confirmed the presence of such different species in the solution. The electrochemical behavior of the pro-ligands and of the complexes was investigated, as well as their biological activity. Complexes 2 and 3 exhibited a high cytotoxicity against human tumor cells and 3D spheroids derived from solid tumors, related to the high cellular uptake. Complexes 2 and 3 also showed a high selectivity towards cancerous cell lines with respect to non-cancerous cell lines and were able to circumvent cisplatin resistance. Via the Transmission Electron Microscopy (TEM) imaging technique, preliminary insights into the biological activity of copper complexes were obtained.

Possible Synthetic Approaches for Heterobimetallic Complexes by Using nNHC/tzNHC Heteroditopic Carbene Ligands.

The synthesis of heterobimetallic complexes remains a synthetic challenge in the field of organometallic chemistry. A possible approach in this regard might be the use of a bidentate heteroditopic bis(carbene) ligand that combines an imidazol-2-ylidene (nNHC) with a 1,2,3-triazol-5-ylidene (tzNHC) connected by an organic spacer. The optimized strategy to heterobimetallic complexes with this type of ligand involves a 3-step procedure: (i) Coordination of the nNHC, functionalized with a 1,2,3-triazole ring, to a metal center; (ii) formation of the triazolium ring by alkylation of the triazole N-3; (iii) deprotonation of the tzNHC precursor and coordination of the second metal center. Following this procedure, a novel Au(I)-Ag(I) dinuclear complex was isolated and its properties were compared to the analogous homobimetallic Ag(I)-Ag(I) and Au(I)-Au(I) complexes. The study was completed by the determination of the molecular structures of some synthetic intermediates.

Microwave-assisted synthesis of isosorbide-derived diols for the preparation of thermally stable thermoplastic polyurethane.

In order to prepare thermally stable isosorbide-derived thermoplastic polyurethane, the synthesis of two new chiral exo-exo configured diols, prepared from isosorbide, and two types of diphenols (bisphenol A and thiodiphenol) was described. The synthesis conditions were optimized under conventional heating and microwave irradiations. To prove their suitability in polymerization, these monomers were successfully polymerized using 4,4'-diphenylmethane diisocyanate (MDI) and hexamethylene diisocyanate (HDI). Both monomers and polymers have been studied by NMR, FT-IR, TGA, DSC; intrinsic viscosity of polymers has also been determined. The results showed the effectiveness of the synthetic strategy proposed; moreover, a dramatic reduction of the reaction time and an important improvement of the monomers yield using microwave irradiation have been demonstrated. The monomers, as well as the polymers, showed excellent thermal stability both in air and nitrogen. It was also shown that the introduction of sulphur in the polyurethane backbone was effective in delaying the onset of degradation as well as the degradation rate.

Magnetic hyperthermia efficiency and (1)H-NMR relaxation properties of iron oxide/paclitaxel-loaded PLGA nanoparticles.

Magnetic iron oxide nanoparticles (Fe-NPs) can be exploited in biomedicine as agents for magnetic fluid hyperthermia (MFH) treatments and as contrast enhancers in magnetic resonance imaging. New, oleate-covered, iron oxide particles have been prepared either by co-precipitation or thermal decomposition methods and incorporated into poly(lactic-co-glycolic acid) nanoparticles (PLGA-Fe-NPs) to improve their biocompatibility and in vivo stability. Moreover, the PLGA-Fe-NPs have been loaded with paclitaxel to pursue an MFH-triggered drug release. Remarkably, it has been found that the nanoparticle formulations are characterized by peculiar (1)H nuclear magnetic relaxation dispersion (NMRD) profiles that directly correlate with their heating potential when exposed to an alternating magnetic field. By prolonging the magnetic field exposure to 30 min, a significant drug release was observed for PLGA-Fe-NPs in the case of the larger-sized magnetic nanoparticles. Furthermore, the immobilization of lipophilic Fe-NPs in PLGA-NPs also made it possible to maintain Néel relaxation as the dominant relaxation contribution in the presence of large iron oxide cores (diameters of 15-20 nm), with the advantage of preserving their efficiency when they are entrapped in the intracellular environment. The results reported herein show that NMRD profiles are a useful tool for anticipating the heating capabilities of Fe-NPs designed for MFH applications.

A case of chemical scalp burns after hair highlights: experimental evidence of oxidative injuries.

Hair highlights are quite common procedures carried out in hair salons by using a mixture of a lightening powder containing persulfates with a suspension containing hydrogen peroxide: a representative case of chemical scalp burns is described as a consequence of this treatment. The aim of the paper is to demonstrate the strict relationship between the scalp damage and the commercial products used in a case of hair highlighting. The results of some chemical analyses have been reported, showing, in particular, that the chemical reactivity of the mixture changes in the time, thus strongly suggesting that the procedure for the application of the mixture is critical for the occurrence of possible accidents. The presence in the powder of chemical compounds bearing aliphatic chains as surfactants explains the appearance of dramatic symptoms after days due to a slow dissolution of the oxidant compounds in the stratum corneum of skin with no effect in reducing injury of palliative treatments. Safety suggestions and recommendations for producers and workers are also included.

Discriminating halogen-bonding from other noncovalent interactions by a combined NOE NMR/DFT approach.

Herein a combined NOE NMR/DFT methodology to discriminate between adducts held together by halogen bonding (XB) and other noncovalent interactions (non-XB, such as lone pair/π), based on the determination of the XB donors' and acceptors' relative orientation, is proposed. In particular, (19) F,(1) H HOESY NMR spectroscopy experiments and DFT calculations on different XB donors, such as perfluorohexyl iodide (I1), iodopentafluorobenzene (I2) and bromopentafluorobenzene (Br), combined with different Lewis bases, such as 1,4-diazabicyclo[2.2.2]octane (DABCO) and 2,4,6-trimethylpyridine (Me3 Py), were performed. The results clearly show that in the case DABCO/I1 the XB adduct is practically the only one present in solution, whereas for the other pairs a certain amount of non-XB adduct is present. Combining DFT and HOESY results, the amount of non-XB adducts can be roughly quantified under our experimental conditions as 4 % for DABCO/I2, between 10 and 20 % for Me3 Py/I1 and Me3 Py/I2, and 44 % for DABCO/Br.

Adsorption of Heavy Metal Ions on Alginate-Based Magnetic Nanocomposite Adsorbent Beads.

Graphene oxide and its magnetic nanoparticle-based composites are a well-known tool to remove heavy metals from wastewater. Unfortunately, one of the major issues in handling such small particles consists of their difficult removal from treated wastewater (even when their magnetic properties are exploited), due to their very small diameter. One possible way to overcome this problem is to embed them in a macroscopic biopolymer matrix, such as alginate or chitosan beads. In this way, the adsorbent becomes easier to handle and can be used to build, for example, a packed column, as in a traditional industrial adsorber. In this work, the removal performances of two different embedded magnetic nanocomposite adsorbents (MNAs) are discussed. The first type of MNA is based on ferrite magnetic nanoparticles (MNPs) generated by coprecipitation using iron(II/III) salts and ammonium hydroxide, while the second is based on a 2D material composed of MNP-decorated graphene oxide. Both MNAs were embedded in cross-linked alginate beads and used to treat artificial water contaminated with chromium(III), nickel(II), and copper(II) in different concentrations. The yield of removal and differences between MNAs and non-embedded magnetic nanomaterials are also discussed. From the results, it was found that the time to reach the adsorption equilibrium is higher when compared to that of the nanomaterials only, due to the lower surface/volume ratio of the beads, but the adsorption capacity is higher, due to the additional interaction with alginate.

Novel imino thioether complexes of platinum(II): synthesis, structural investigation, and biological activity.

The reactions of the nitrile complexes cis- and trans-[PtCl2(NCR)2] (R = Me, Et, CH2Ph, Ph) with an excess of ethanethiol, EtSH, in the presence of a catalytic amount of n-BuLi in tetrahydrofuran (THF), afforded in good yield the bis-imino thioether derivatives cis-[PtCl2{E-N(H)═C(SEt)R}2] (R = Me (1), Et (2), CH2Ph (3), Ph (4)) and trans-[PtCl2{E-N(H)═C(SEt)R}2] (R = Me (5), Et (6), CH2Ph (7), Ph (8)). The imino thioether ligands assumed the E configuration corresponding to a cis addition of the thiol to the nitrile triple bond. The spectroscopic properties of these complexes have been reported along with the molecular structures of 1, 2, and 7 as established by X-ray crystallography which indicated that these compounds exhibit square-planar coordination geometry around the platinum center. Four N-H···Cl intermolecular contacts (N-H···Cl ca. 2.5-2.7 Å) between each chlorine atom and the N-H proton of the imino thioether ligand gave rise to "dimers" Pt2Cl4L4 (L = imino thioether) formed by two PtCl2L2 units. The cytotoxic properties of these new platinum(II) complexes were evaluated against various human cancer cell lines. Among all derivatives, trans-[PtCl2{E-N(H)═C(SEt)CH2Ph}2] showed the greatest in vitro cytotoxic activity being able to decrease cancer cell viability roughly 3-fold more effectively than cisplatin.

A Porous Gelatin Methacrylate-Based Material for 3D Cell-Laden Constructs.

3D constructs are fundamental in tissue engineering and cancer modeling, generating a demand for tailored materials creating a suitable cell culture microenvironment and amenable to be bioprinted. Gelatin methacrylate (GelMA) is a well-known functionalized natural polymer with good printability and binding motifs allowing cell adhesion; however, its tight micropores induce encapsulated cells to retain a non-physiological spherical shape. To overcome this problem, blended GelMa is here blended with Pluronic F-127 (PLU) to modify the hydrogel internal porosity by inducing the formation of larger mesoscale pores. The change in porosity also leads to increased swelling and a slight decrease in Young's modulus. All blends form stable hydrogels both when cast in annular molds and bioprinted in complex structures. Embedded cells maintain high viability, and while Neuroblastoma cancer cells typically aggregate inside the mesoscale pores, Mesenchymal Stem Cells stretch in all three dimensions, forming cell-cell and cell-ECM interactions. The results of this work prove that the combination of tailored porous materials with bioprinting techniques enables to control both the micro and macro architecture of cell-laden constructs, a fundamental aspect for the development of clinically relevant in vitro constructs.

Chemical and Mechanical Characterization of Unprecedented Transparent Epoxy-Nanomica Composites-New Model Insights for Mechanical Properties.

Two nanomicas of similar composition, containing muscovite and quartz, but with different particle size distributions, have been used to prepare transparent epoxy nanocomposites. Their homogeneous dispersion, due to the nano-size, was achieved even without being organically modified, and no aggregation of the nanoparticles was observed, thus maximizing the specific interface between matrix and nanofiller. No exfoliation or intercalation has been observed by XRD, despite the significant dispersion of the filler in the matrix which produced nanocomposites with a loss in transparency in the visible domain of less than 10% in the presence of 1% wt and 3% wt of mica fillers. The presence of micas does not affect the thermal behavior of the nanocomposites, which remains similar to that of the neat epoxy resin. The mechanical characterization of the epoxy resin composites revealed an increased Young's modulus, whereas tensile strength was reduced. A peridynamics-based representative volume element approach has been implemented to estimate the effective Young's modulus of the nanomodified materials. The results obtained through this homogenization procedure have been used as input for the analysis of the nanocomposite fracture toughness, which has been carried out by a classical continuum mechanics-peridynamics coupling approach. Comparison with the experimental data confirms the capability of the peridynamics-based strategies to properly model the effective Young's modulus and fracture toughness of epoxy-resin nanocomposites. Finally, the new mica-based composites exhibit high values of volume resistivity, thus being excellent candidates as insulating materials.

Ruthenium Complexes Bearing α-Diimine Ligands and Their Catalytic Applications in N-Alkylation of Amines, α-Alkylation of Ketones, and ß-Alkylation of Secondary Alcohols.

New Ru(II) complexes encompassing α-diimine ligands were synthesized by reacting ruthenium precursors with α-diimine hydrazones. The new ligands and Ru(II) complexes were analyzed by analytical and various spectroscopic methods. The molecular structures of L1 and complexes 1, 3, and 4 were determined by single-crystal XRD studies. The results reveal a distorted octahedral geometry around the Ru(II) ion for all complexes. Moreover, the new ruthenium complexes show efficient catalytic activity toward the C-N and C-C coupling reaction involving alcohols. Particularly, complex 3 demonstrates effective conversion in N-alkylation of aromatic amines, α-alkylation of ketones, and ß-alkylation of alcohols.

Supramolecular control on chemo- and regioselectivity via encapsulation of (NHC)-Au catalyst within a hexameric self-assembled host.

The encapsulation of a Au(I) catalyst within a self-assembled, hydrogen bonded, hexameric capsule dramatically changes its catalytic activity, leading to unusual products due to the steric requirements of the host's cavity.

Novel Magnetic Inorganic Composites: Synthesis and Characterization.

The addition of magnetic particles to inorganic matrices can produce new composites exhibiting intriguing properties for practical applications. It has been previously reported that the addition of magnetite to concrete improves its mechanical properties and durability in terms of water and chloride ions absorption. Here we describe the preparation of novel magnetic geopolymers based on two different matrices (G1 without inert aggregates and G2 with inert quartz aggregates) containing commercial SrFe12O19 particles with two weight concentrations, 6% and 11%. The composites' characterization, including chemical, structural, morphological, and mechanical determinations together with magnetic and electrical measurements, was carried out. The magnetic study revealed that, on average, the SrFe12O19 magnetic particles can be relatively well dispersed in the inorganic matrix. A substantial increase in the composite samples' remanent magnetization was obtained by embedding in the geopolymer SrFe12O19 anisotropic particles at a high concentration under the action of an external magnetic field during the solidification process. The new composites exhibit good mechanical properties (as compressive strength), higher than those reported for high weight concretes bearing a similar content of magnetite. The impedance measurements indicate that the electrical resistance is mainly controlled by the matrix's chemical composition and can be used to evaluate the geopolymerization degree.