Efficient Spin-Selective Electron Transport at Low Voltages of Thia-Bridged Triarylamine Hetero[4]helicenes Chemisorbed Monolayer.

The Chirality Induced Spin Selectivity (CISS) effect describes the capability of chiral molecules to act as spin filters discriminating flowing electrons according to their spin state. Within molecular spintronics, efforts are focused on developing chiral-molecule-based technologies to control the injection and coherence of spin-polarized currents. Herein, for this purpose, we study spin selectivity properties of a monolayer of a thioalkyl derivative of a thia-bridged triarylamine hetero[4]helicene chemisorbed on a gold surface. A stacked device assembled by embedding a monolayer of these molecules between ferromagnetic and diamagnetic electrodes exhibits asymmetric magnetoresistance with inversion of the signal according to the handedness of molecules, in line with the presence of the CISS effect. In addition, magnetically conductive atomic force microscopy reveals efficient electron spin filtering even at unusually low potentials. Our results demonstrate that thia[4]heterohelicenes represent key candidates for the development of chiral spintronic devices.

Combining Solid-State NMR with Structural and Biophysical Techniques to Design Challenging Protein-Drug Conjugates.

Several protein-drug conjugates are currently being used in cancer therapy. These conjugates rely on cytotoxic organic compounds that are covalently attached to the carrier proteins or that interact with them via non-covalent interactions. Human transthyretin (TTR), a physiological protein, has already been identified as a possible carrier protein for the delivery of cytotoxic drugs. Here we show the structure-guided development of a new stable cytotoxic molecule based on a known strong binder of TTR and a well-established anticancer drug. This example is used to demonstrate the importance of the integration of multiple biophysical and structural techniques, encompassing microscale thermophoresis, X-ray crystallography and NMR. In particular, we show that solid-state NMR has the ability to reveal effects caused by ligand binding which are more easily relatable to structural and dynamical alterations that impact the stability of macromolecular complexes.

VdW Mediated Strong Magnetic Exchange Interactions in Chains of Hydrogen-Free Sublimable Molecular Qubits.

Sulfur-rich molecular complexes of dithiolene-like ligands are appealing candidates as molecular spin qubits because spin coherence properties are enhanced in hydrogen-free environments. Herein, we employ the hydrogen-free mononegative 1,3,2-dithiazole-4-thione-5-thiolate (dttt-) ligand as an alternative to common dinegative dithiolate ligands. We report the first synthesis and structural characterization of its Cu2+, Ni2+, and Pt2+ neutral complexes. The XPS analysis of thermal deposition of [Cu(dttt)2] in UHV conditions indicates that films of intact molecules can be deposited on surfaces by sublimation. Thanks to a combined approach employing DC magnetometry and DFT calculations, we highlighted AF exchange interactions of 108 cm-1 and 36 cm-1 attributed to the two different polymorph phases. These couplings are exclusively mediated by S···S VdW interactions, which are facilitated by the absence of counterions and made particularly efficient by the diffuse electron density on S atoms. Furthermore, the spin dynamics of solid-state magnetically diluted samples was investigated. The longest observed T m is 2.3 µs at 30 K, which significantly diverges from the predicted T m > 100 µs. These results point to the diluting matrix severely affecting the coherence lifetime of Cu2+ species via different factors, such as the contributions of neighboring 14N nuclei and the formation of radical impurities in a non-completely controllable way. However, the ease of processing [Cu(dttt)2] via thermal sublimation can allow dispersion in matrices better suited for coherent spin manipulation of isolated molecules and the realization of AF-coupled VdW structures on surfaces.

Resolution of a Configurationally Stable Hetero[4]helicene.

We have developed an efficient chemical resolution of racemic hydroxy substituted dithia-aza[4]helicenes (DTA[4]H) 1(OH) using enantiopure acids as resolving agents. The better diastereomeric separation was achieved on esters prepared with (1S)-(-)-camphanic acid. Subsequent simple manipulations produced highly optically pure (≥ 99% enantiomeric excess) (P) and (M)-1(OH) in good yields. The role of the position where the chiral auxiliary is inserted (cape- vs. bay-zone) and the structure of the enantiopure acid used on successful resolution are discussed.

SET and HAT/PCET acid-mediated oxidation processes in helical shaped fused bis-phenothiazines.

Helical shaped fused bis-phenothiazines 1-9 have been prepared and their red-ox behaviour quantitatively studied. Helicene radical cations (Hel.+ ) can be obtained either by UV-irradiation in the presence of PhCl or by chemical oxidation. The latter process is extremely sensitive to the presence of acids in the medium with molecular oxygen becoming a good single electron transfer (SET) oxidant. The reaction of hydroxy substituted helicenes 5-9 with peroxyl radicals (ROO. ) occurs with a 'classical' HAT process giving HelO. radicals with kinetics depending upon the substitution pattern of the aromatic rings. In the presence of acetic acid, a fast medium-promoted proton-coupled electron transfer (PCET) process takes place with formation of HelO. radicals possibly also via a helicene radical cation intermediate. Remarkably, also helicenes 1-4, lacking phenoxyl groups, in the presence of acetic acid react with peroxyl radicals through a medium-promoted PCET mechanism with formation of the radical cations Hel.+ . Along with the synthesis, EPR studies of radicals and radical cations, BDE of Hel-OH group (BDEOH ), and kinetic constants (kinh ) of the reactions with ROO. species of helicenes 1-9 have been measured and calculated to afford a complete rationalization of the redox behaviour of these appealing chiral compounds.

Stabilization of an Enantiopure Sub-monolayer of Helicene Radical Cations on a Au(111) Surface through Noncovalent Interactions.

In the past few years, the chirality and magnetism of molecules have received notable interest for the development of novel molecular devices. Chiral helicenes combine both these properties, and thus their nanostructuration is the first step toward developing new multifunctional devices. Here, we present a novel strategy to deposit a sub-monolayer of enantiopure thia[4]helicene radical cations on a pre-functionalized Au(111) substrate. This approach results in both the paramagnetic character and the chemical structure of these molecules being maintained at the nanoscale, as demonstrated by in-house characterizations. Furthermore, synchrotron-based X-ray natural circular dichroism confirmed that the handedness of the thia[4]helicene is preserved on the surface.

Protective Role of Natural and Semi-Synthetic Tocopherols on TNFα-Induced ROS Production and ICAM-1 and Cl-2 Expression in HT29 Intestinal Epithelial Cells.

Vitamin E, a fat-soluble compound, possesses both antioxidant and non-antioxidant properties. In this study we evaluated, in intestinal HT29 cells, the role of natural tocopherols, α-Toc and δ-Toc, and two semi-synthetic derivatives, namely bis-δ-Toc sulfide (δ-Toc)2S and bis-δ-Toc disulfide (δ-Toc)2S2, on TNFα-induced oxidative stress, and intercellular adhesion molecule-1 (ICAM-1) and claudin-2 (Cl-2) expression. The role of tocopherols was compared to that of N-acetylcysteine (NAC), an antioxidant precursor of glutathione synthesis. The results show that all tocopherol containing derivatives used, prevented TNFα-induced oxidative stress and the increase of ICAM-1 and Cl-2 expression, and that (δ-Toc)2S and (δ-Toc)2S2 are more effective than δ-Toc and α-Toc. The beneficial effects demonstrated were due to tocopherol antioxidant properties, but suppression of TNFα-induced Cl-2 expression seems not only to be related with antioxidant ability. Indeed, while ICAM-1 expression is strongly related to the intracellular redox state, Cl-2 expression is TNFα-up-regulated by both redox and non-redox dependent mechanisms. Since ICAM-1 and Cl-2 increase intestinal bowel diseases, and cause excessive recruitment of immune cells and alteration of the intestinal barrier, natural and, above all, semi-synthetic tocopherols may have a potential role as a therapeutic support against intestinal chronic inflammation, in which TNFα represents an important proinflammatory mediator.

Groundwater quality trend and trend reversal assessment in the European Water Framework Directive context: an example with nitrates in Italy.

Groundwater resources are of utmost importance in sustaining water related ecosystems, including humans. The long-lasting impacts from anthropogenic activities require early actions, owing to the natural time lag in groundwater formation and renewal. The European Union (EU) policy, within the implementation of the Water Framework Directive (WFD), requires Member States to identify and reverse any significant and sustained upward trend in the concentration of pollutants, defining specific protection measures to be included in the River Basin Management Plans (RBMP). In Italy, official guidelines for trend and trend reversal assessment have been published recently. Statistical methods, such as the Mann-Kendall test for trend analysis and the Sen's method for estimating concentration scenarios, should be applied at the fixed terms stated by the WFD implementation cycles to identify upward trends, while the Pettitt test is proposed for the identification of trend reversal. In this paper, we present an application of a slightly modified version of the Italian Guidelines to a groundwater body in Northern Italy featuring nitrate pollution and discuss its advantages and limitations. In addition to Pettitt test, for the trend reversal analysis, we apply the Mann-Kendall test in two sections and compare the results. We conclude that this method seems more reliable than Pettitt test to identify a reversal point in quality time series. The overall procedure can be easily applied to any groundwater body defined at risk across Europe, for the assessment of the upward trends of pollutants and their reversal, even with little chemical monitoring data. Although focused on the EU legislative framework, this procedure may be relevant for a wider context, allowing to individuate upward trend as early warning for contamination processes in an integrated water resources management context.

A New NT4 Peptide-Based Drug Delivery System for Cancer Treatment.

The development of selective tumor targeting agents to deliver multiple units of chemotherapy drugs to cancer tissue would improve treatment efficacy and greatly advance progress in cancer therapy. Here we report a new drug delivery system based on a tetrabranched peptide known as NT4, which is a promising cancer theranostic by virtue of its high cancer selectivity. We developed NT4 directly conjugated with one, two, or three units of paclitaxel and an NT4-based nanosystem, using NIR-emitting quantum dots, loaded with the NT4 tumor-targeting agent and conjugated with paclitaxel, to obtain a NT4-QD-PTX nanodevice designed to simultaneously detect and kill tumor cells. The selective binding and in vitro cytotoxicity of NT4-QD-PTX were higher than for unlabeled QD-PTX when tested on the human colon adenocarcinoma cell line HT-29. NT4-QD-PTX tumor-targeted nanoparticles can be considered promising for early tumor detection and for the development of effective treatments combining simultaneous therapy and diagnosis.

Magnetic nanoantioxidants with improved radical-trapping stoichiometry as stabilizers for inhibition of peroxide formation in ethereal solvents.

Graphite-coated magnetic cobalt nanoparticles (CoNPs) decorated with hindered phenolic antioxidant analogues of 2,6-di-tert-butyl-4-methylphenol (BHT, E321) provided easily removable nanoantioxidants capable of preventing the autoxidation of organic solvents as tetrahydrofuran (THF).

Chain Breaking Antioxidant Activity of Heavy (S, Se, Te) Chalcogens Substituted Polyphenols.

Polyphenols are probably the most important family of natural and synthetic chain-breaking antioxidants. Since long ago, chemists have studied how structural (bioinspired) modifications can improve the antioxidant activity of these compounds in terms of reaction rate with radical reactive oxygen species (ROS), catalytic character, multi-defence action, hydrophilicity/lipophilicity, biodistribution etc. In this framework, we will discuss the effect played on the overall antioxidant profile by the insertion of heavy chalcogens (S, Se and Te) in the phenolic skeleton.

Blocking the FKBP12 induced dendrimeric burst in aberrant aggregation of α-synuclein by using the ElteN378 synthetic inhibitor.

α-Synuclein (α-syn), a disordered cytoplasmatic protein, plays a fundamental role in the pathogenesis of Parkinson's disease (PD). Here, we have shown, using photophysical measurements, that addition of FKBP12 to α-syn solutions, dramatically accelerates protein aggregation, leading to an explosion of dendritic structures revealed by fluorescence and phase-contrast microscopy. We have further demonstrated that this aberrant α-syn aggregation can be blocked using a recently discovered non-immunosuppressive synthetic inhibitor of FKBP12, ElteN378. The role of FKBP12 and of ElteN378 in the α-syn aggregation mechanism has been elucidated using molecular dynamics simulations based on an effective coarse-grained model. The reported data not only reveal a new potent synthetic drug as a candidate for early stage treatment of α-syn dependent neurodegenerations but also pave the way to a deeper understanding of the mechanism of action of FKBP12 on α-syn oligomeric aggregation, a topic which is still controversial.

Ditocopheryl Sulfides and Disulfides: Synthesis and Antioxidant Profile.

Symmetrical ditocopheryl disulfides (Toc)2 S2 and symmetrical and unsymmetrical ditocopheryl sulfides (Toc)2 S were simply prepared under remarkably mild conditions with complete control of the regiochemistry by using δ-, γ-, and ß-tocopheryl-N-thiophthalimides (Toc-NSPht) as common starting materials. The roles of sulfur atom(s), H-bond and aryl ring substitution pattern on the antioxidant profile of these new compounds, which were assembled by linking together two tocopheryl units, are also discussed.

Protective role of benzoselenophene derivatives of resveratrol on the induced oxidative stress in intestinal myofibroblasts and osteocytes.

Resveratrol (RE), a polyphenolic compound present in some food and plants, is characterized by anti-inflammatory and antioxidant properties. However, it is quickly metabolized with consequent loss of its efficacy. In this study, the antioxidant effect of 2-phenyl-benzoselenophene derivatives (VD0, VD1 and VD2) was detected in intestinal myofibroblast and osteocyte cell lines in which the oxidative stress was induced by GSH depletion or starvation, respectively. In fact, the oxidative stress is involved in pathogenesis of inflammatory bowel diseases (IBD) and in increased osteoclastogenesis in osteoporosis. Our results show that these derivatives have major antioxidant power in reducing and/or restoring radical oxygen species to control values than RE itself in both cell types. Moreover, derivatives have different antioxidant capacity in myofibroblasts and in osteocytes and this can be due to different degree of oxidative stress and structural characteristics of these compounds. Some of the synthesized RE analogs have shown anti-bacterial role in IBD and anti-resorptive activity in bone pathologies related to inflammatory and osteoporotic processes. Thus, we suggest benzoselenophene derivatives as good candidates for alternative therapy and/or therapeutic support in these pathologies.

Evaluation of selenide, diselenide and selenoheterocycle derivatives as carbonic anhydrase I, II, IV, VII and IX inhibitors.

A series of selenides, diselenides and organoselenoheterocycles were evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) isoforms hCA I, II, IV, VII and IX, involved in a variety of diseases among which glaucoma, retinitis pigmentosa, epilepsy, arthritis and tumors etc. These investigated compounds showed inhibitory action against these isoforms and some of them were selective for inhibiting the cytosolic over the membrane-bound isoforms, thus making them interesting leads for the development of isoform-selective inhibitors.

Catechol-Containing Hydroxylated Biomimetic 4-Thiaflavanes as Inhibitors of Amyloid Aggregation.

The study of compounds able to interfere in various ways with amyloid aggregation is of paramount importance in amyloid research. Molecules characterized by a 4-thiaflavane skeleton have received great attention in chemical, medicinal, and pharmaceutical research. Such molecules, especially polyhydroxylated 4-thiaflavanes, can be considered as structural mimickers of several natural polyphenols that have been previously demonstrated to bind and impair amyloid fibril formation. In this work, we tested five different 4-thiaflavanes on the hen egg-white lysozyme (HEWL) amyloid model for their potential anti-amyloid properties. By combining a thioflavin T assay, atomic force microscopy, and a cell toxicity assay, we demonstrated that such compounds can impair the formation of high-order amyloid aggregates and mature fibrils. Despite this, the tested 4-thiaflavanes, although non-toxic per se, are not able to prevent amyloid toxicity on human neuroblastoma cells. Rather, they proved to block early aggregates in a stable, toxic conformation. Accordingly, 4-thiaflavanes can be proposed for further studies aimed at identifying blocking agents for the study of toxicity mechanisms of amyloid aggregation.

Role of Noncovalent Sulfur···Oxygen Interactions in Phenoxyl Radical Stabilization: Synthesis of Super Tocopherol-like Antioxidants.

Noncovalent sulfur···oxygen interactions can increase the stability of chalcogen ortho-substituted phenoxyl radicals. This effect contributes to transforming the 7-hydroxybenzo[b]thiophene moiety in a privileged structural motif to enhance the activity of phenolic antioxidants. A cascade of five consecutive electrophilic reactions occurring in one pot afforded potent and biocompatible α-tocopherol-like antioxidants.

Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug.

Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity.

Efficient nonequilibrium method for binding free energy calculations in molecular dynamics simulations.

We introduce an effective technique for the calculation of the binding free energy in drug-receptor systems using nonequilibrium molecular dynamics and application of the Jarzynski theorem. In essence, this novel methodology constitutes the nonequilibrium adaptation of an ancient free energy perturbation technique called Double Annihilation Method, invented more than 25 years ago [J. Chem. Phys. 1988, 89, 3742-3746] and upon which modern approaches of binding free energy computation in drug-receptor systems are heavily based. The proposed computational approach, termed Fast Switching Double Annihilation Methods (FS-DAM) in honor of its ancient ancestor, is applied to a prototypical example system with multiple binding sites, proving its computational potential and versatility in unraveling multiple site or allosteric binding processes.

A Straightforward Route to Potent Phenolic Chain-Breaking Antioxidants by Acid-Promoted Transposition of 1,4-Benzo[b]oxathiines to Dihydrobenzo[b]thiophenes.

The transformation of simple phenols with limited antioxidant activity into potent chain-breaking antioxidants was achieved by a three-step protocol, consisting of the conversion of phenols into 1,4-benzo[b]oxathiines followed by an unprecedented acid-promoted transposition to o-hydroxydihydrobenzo[b]thiophenes, or dihydrobenzo[de]thiochromenes, starting from phenols or naphthols, respectively. These derivatives, bearing a benzo-fused heterocycle with a sulfide sulfur ortho to the phenolic OH, have a rate constant of reaction with alkylperoxyl radicals (kinh ) comparable to that of α-tocopherol. A solid rationale for the transposition mechanism as well as for the structure-antioxidant activity relationship is presented.