Kinetic study of the reaction of thiophene-tocopherols with peroxyl radicals enlightenings the role of O˙⋯S noncovalent interactions in H-atom transfer.

Three new α-tocopherol thiophene derivatives were efficiently synthesized, characterized and used for the first time as chain-breaking antioxidants for the inhibition of the autoxidation of reference oxidizable substrates. The rate constant of the reaction with alkylperoxyl (ROO˙) radicals and the stoichiometry of radical trapping (n) for the thiophene-tocopherol compounds were determined by measuring the oxygen consumption during the autoxidation of styrene or isopropylbenzene, using a differential pressure transducer. The measurement of the reaction with ROO˙ radicals in an apolar solvent at 30 °C showed inhibition rate constants (kinh) in the order of 104 M-1 s-1. To rationalise the kinetic results, the effect of the thiophene ring on the H-atom donation by O-H groups of the functionalized tocopherols was investigated by theoretical calculations. The importance of noncovalent interactions (including an unusual O˙⋯S bond) for the stability of the conformers has been shown, and the O-H bond dissociation enthalpy (BDE(OH)) of these derivatives was determined. Finally, the photophysical properties of these new compounds were investigated to understand if the addition of thiophene groups changes the absorption or emission spectra of the tocopherol skeleton for their possible application as luminescent molecular probes.

Organocatalytic hydrogen bond donor/Lewis base (HBD/LB) synthesis and chiroptical properties of thiabridged [5]helicenes.

Thiabridged [5]helicenes are obtained from thioaryl-N-phthalimido benzo[a]phenothiazines using a hydrogen bond donor/Lewis base organocatalytic approach. Resolution of [5]helicenes using either (1S)-(-)-camphanic acid as a chiral auxiliary or CSP-HPLC is reported. Thiabridged [5]helicenes show an exceptional configurational stability with racemization energy barriers higher than 40 kcal mol-1. Electronic circular dichroism and TD-DFT calculations permit the assignment of the absolute configuration, demonstrating that the sign of optical rotation is not easily related to the M or P structure. Separated enantiomers show circularly polarized luminescence with high dissymmetry ratio.

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.

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.

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.

Proton-Coupled Electron Transfer from Hydrogen-Bonded Phenols to Benzophenone Triplets.

Phenols with intramolecular hydrogen bond between a pendant base and the phenolic OH group react differently in polar and non-polar environments with electron/proton acceptors. This was demonstrated by using time resolved chemically induced dynamic nuclear polarization (TR CIDNP) and theoretical calculations. In benzene, those phenols undergo a concerted electron-proton transfer (EPT) that yields neutral ketyl and phenoxyl radicals. In polar acetonitrile, the reaction mechanism turns into an electron transfer from the phenol to the triplet ketone, accompanied by the shift of a proton from the phenolic OH group to the nitrogen atom of the pendant base to form a distonic radical cation. This behavior is similar to that of tyrosine H-bonded to basic residues in some radical enzymes. This solvent-induced mechanism switch in proton-coupled electron transfers is important in different biological systems, in which the same metabolites and intermediates can react differently depending on the specific local environments.

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.

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.

Linking an α-tocopherol derivative to cobalt(0) nanomagnets: magnetically responsive antioxidants with superior radical trapping activity and reduced cytotoxicity.

Covalent attachment of a phenolic antioxidant analogue of α-tocopherol to graphite-coated magnetic cobalt nanoparticles (CoNPs) provided a novel magnetically responsive antioxidant capable of preventing the autoxidation of organic materials and showing a reduced toxicity toward human cells.

Structural and medium effects on the reactions of the cumyloxyl radical with intramolecular hydrogen bonded phenols. The interplay between hydrogen-bonding and acid-base interactions on the hydrogen atom transfer reactivity and selectivity.

A time-resolved kinetic study on the reactions of the cumyloxyl radical (CumO(•)) with intramolecularly hydrogen bonded 2-(1-piperidinylmethyl)phenol (1) and 4-methoxy-2-(1-piperidinylmethyl)phenol (2) and with 4-methoxy-3-(1-piperidinylmethyl)phenol (3) has been carried out. In acetonitrile, intramolecular hydrogen bonding protects the phenolic O-H of 1 and 2 from attack by CumO(•) and hydrogen atom transfer (HAT) exclusively occurs from the C-H bonds that are α to the piperidine nitrogen (α-C-H bonds). With 3 HAT from both the phenolic O-H and the α-C-H bonds is observed. In the presence of TFA or Mg(ClO4)2, protonation or Mg(2+) complexation of the piperidine nitrogen removes the intramolecular hydrogen bond in 1 and 2 and strongly deactivates the α-C-H bonds of the three substrates. Under these conditions, HAT to CumO(•) exclusively occurs from the phenolic O-H group of 1-3. These results clearly show that in these systems the interplay between intramolecular hydrogen bonding and Brønsted and Lewis acid-base interactions can drastically influence both the HAT reactivity and selectivity. The possible implications of these findings are discussed in the framework of the important role played by tyrosyl radicals in biological systems.

Spin polarized current in chiral organic radical monolayers.

The chirality-induced spin selectivity (CISS) effect is the capability of chiral molecules to act as spin filters, i.e. to selectively sort flowing electrons based on their spin states. The application of this captivating phenomenon holds great promise in the realm of molecular spintronics, where the primary focus lies in advancing technologies based on chiral molecules to regulate the injection and coherence of spin-polarized currents. In this context, we conducted a study to explore the spin filtering capabilities of a monolayer of the thia-bridged triarylamine hetero[4]helicene radical cation chemisorbed on a metallic surface. Magnetic-conductive atomic force microscopy revealed efficient electron spin filtering at exceptionally low potentials. Furthermore, we constructed a spintronic device by incorporating a monolayer of these molecules in between two electrodes, obtaining an asymmetric magnetoresistance trend with signal inversion in accordance with the handedness of the enantiomer involved, indicative of the presence of the CISS effect. Our findings underscore the significance of thia[4]azahelicene organic radicals as promising candidates for the development of quantum information operations based on the CISS effect as a tool to control the molecular spin states.

Regioselective electrophilic access to naphtho[1,2-b:8,7-b']- and -[1,2-b:5,6-b']dithiophenes.

A two-step one purification access to dichloronaphtho[1,2-b:8,7-b'] and [1,2-b:5,6-b']dithiophenes using bis-alkylnaphthyl alkynes and phthalimidesulfenyl chloride as starting materials has been developed. The functionalization of the carbon-chlorine bonds allowed further modification of NDT core, broadening the potential of the methodology.

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.

Optimization of the antioxidant activity of hydroxy-substituted 4-thiaflavanes: a proof-of-concept study.

The design and the synthesis of a new family of hydroxy-4-thiaflavanes, in which the reactive phenolic OH is ortho to the sulfur atom of the benzofused oxathiin ring, allowed to prepare antioxidants that show rate constants for the reaction with peroxyl radicals (k(inh)), and bond dissociation energies (BDE), of the ArO-H group identical to those of α-tocopherol, the main component of vitamin E and the most effective lipophilic antioxidant known in nature. The peculiar conformation of the six-membered heterocyclic ring prevents the formation of an intramolecular hydrogen bond between the OH group and the S atom, while ensuring a good stabilization by electron donation of the phenoxyl radical formed after the reaction with peroxyl radicals. The preparation of these compounds was achieved through an inverse electron demand hetero Diels-Alder reaction of styrenes with o-thioquinones, in turn prepared from accurately designed 1,3-dihydroxy arenes. Properly arranging the substitution pattern on the aromatic ring, as in derivatives 9 and 11, allowed to reach values of k(inh) up to 4.0×10(6) M(-1) s(-1) and BDE((OH)) of 77.2 kcal mol(-1). This approach represents an innovative way to obtain highly active antioxidants without using strongly electron donating alkylamino groups which are associated with adverse toxicological profiles.

Amphiphilic antioxidants from "cashew nut shell liquid" (CNSL) waste.

Hydrogenated cardanol and cardols, contained in industrial grade cardanol oil and obtained by distillation of the raw "cashew nut shell liquid" (CNSL), are easily transformed into efficient 4-thiaflavane antioxidants bearing a long alkyl chain on A ring and a catechol group on B ring.

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.

Hydrogen-atom transfer reactions from ortho-alkoxy-substituted phenols: an experimental approach.

The role of intramolecular hydrogen bonding (HB) on the bond-dissociation enthalpy (BDE) of the phenolic O-H and on the kinetics of H-atom transfer to peroxyl radicals (k(inh)) of several 2-alkoxyphenols was experimentally quantified by the EPR equilibration technique and by inhibited autoxidation studies. These compounds can be regarded as useful models for studying the H-atom abstraction from 2-OR phenols, such as many lignans, reduced coenzyme Q and curcumin. The effects of the various substituents on the BDE(O-H) of 2-methoxy, 2-methoxy-4-methyl, 2,4-dimethoxyphenols versus phenol were measured in benzene solution as -1.8; -3.7; -5.4 kcal mol(-1), respectively. In the case of polymethoxyphenols, significant deviations from the BDE(O-H) values predicted by the additive effects of the substituents were found. The logarithms of the k(inh) constants in cumene were inversely related to the BDE(O-H) values, obeying a linear Evans-Polanyi plot with the same slope of other substituted phenols and a y-axis intercept slightly smaller than that of 2,6-dimethyl phenols. In the cases of phenols having the 2-OR substituent included in a five-membered condensed ring (i.e, compounds 9-11), both conformational isomers in which the OH group points toward or away from the oxygen in position 2 were detected by FTIR spectroscopy and the intramolecular HB strength was thus estimated. The contribution to the BDE(O-H) of the ortho-OR substituent in 9, corrected for intramolecular HB formation, was calculated as -5.6 kcal mol(-1). The similar behaviour of cyclic and non-cyclic ortho-alkoxy derivatives clearly showed that the preferred conformation of the OMe group in ortho-methoxyphenoxyl radicals is that in which the methyl group points away from the phenoxyl oxygen, in contrast to the geometries predicted by DFT calculations.

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.