Sterically Hindered Phenols Research Articles

Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis.

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.

Discovery of sterically-hindered phenol compounds with potent cytoprotective activities against ox-LDL–induced retinal pigment epithelial cell death as a potential pharmacotherapy

Late-stage dry age-related macular degeneration (AMD) or geographic atrophy (GA) is an irreversible blinding condition characterized by degeneration of retinal pigment epithelium (RPE) and the associated photoreceptors. Clinical and genetic evidence supports a role for dysfunctional lipid processing and accumulation of harmful oxidized lipids in the pathogenesis of GA. Using an oxidized low-density lipoprotein (ox-LDL)-induced RPE death assay, we screened and identified sterically-hindered phenol compounds with potent protective activities for RPE. The phenol-containing PPARγ agonist, troglitazone, protected against ox-LDL–induced RPE cell death, whereas other more potent PPARγ agonists did not protect RPE cells. Knockdown of PPARγ did not affect the protective activity of troglitazone in RPE, confirming the protective function is not due to the thiazolidine (TZD) group of troglitazone. Prototypical hindered phenol trolox and its analogs potently protected against ox-LDL–induced RPE cell death whereas potent antioxidants without the phenol group failed to protect RPE. Hindered phenols preserved lysosomal integrity against ox-LDL–induced damage and FITC-labeled trolox was localized to the lysosomes in RPE cells. Analogs of trolox inhibited reactive oxygen species (ROS) formation induced by ox-LDL uptake in a dose-dependent fashion and were effective at sub-micromolar concentrations. Treatment with trolox analog 2,2,5,7,8-pentamethyl-6-chromanol (PMC) significantly induced the expression of the lysosomal protein NPC-1 and reduced intracellular cholesterol level upon ox-LDL uptake. Our data indicate that the lysosomal-localized hindered phenols are uniquely potent in protecting the RPE against the toxic effects of ox-LDL, and may represent a novel pharmacotherapy to preserve the vision in patients with GA.

Synthesis of Triazole Derivatives with Sterically Hindered Phenol Fragments

In recent decades, the chemistry of functionally substituted 1,2,4-triazoles and the fused heterocyclic systems based on them have received significant attention due to their structural and biologi...

Comparative characteristics of sterically hindered phenols and nitroxide radicals as stabilizers of polyethylene photodegradation

Introduction. Polymeric materials (PM) are increasingly used in various industries and agriculture. Under the action of UV light, PM are destroyed. UV stabilizers are used to protect PM from photodegradation. Their action is based on the absorption of the photoactive sunlight component or on the deactivation of excited molecules that have already absorbed a light quantum, as well as on the inhibition of dark light-induced reactions. The work objective is to provide a comparative analysis of compounds of the sterically hindered phenols (SHP) series and nitroxide radicals (NR) as the PM photodegradation inhibitors. Materials and Methods . Reagents of the “purum” grade, LDPE premium grade 15803-020 polyethylene film were used for the investigations. The stabilizer was applied to the film by dipping. Carbonyl groups in polyethylene were determined by IR spectroscopy. IR spectra were recorded on Varian-640 instrument. Research Results. 2,4,6-tri-tert-amylphenol (1), 2-methyl-4,6-di-tert-butylphenol (2), 4-acetylamino-2,2,6,6-tetramethylpiperidin-1-oxyl (3), 3-carboxamido-2,2,5,5-tetramethylpyrrolin-1-oxyl (4) were tested as stabilizers for photo-oxidative degradation of polyethylene. It is known that the accumulation of carbonyl and hydroxyl groups is recorded in PM samples under irradiation in the process of photodegradation through the IR spectroscopy. The absorption band of the carbonyl group at 1720 cm - 1 appears in the IR spectra of oxidized polyethylene. The IR spectra analysis shows that the content of carbonyl groups in the check samples is significantly higher than in the samples treated by stabilizer solutions. Discussion and Conclusions . The experiments show that ni-troxide radicals of 3-carboxamido-2,2,5,5-tetramethylpyrrolin-1-oxyl series and 4-acetylamino-2,2,6,6-tetramethylpiperidin-1-oxyl are the best photostabilizers of polyethylene. Moreover, there is no significant difference between the radicals of the 2,2,6,6-tetramethylpiperidine and 2,2,5,5-tetramethylpyrroline series. Sterically hindered phenols, under photodegradation, have a far smaller stabilizing effect, falling short of nitroxide radicals.

Molecular and Crystal Structure of Indole and Camfora with Sterically Hindered Phenol Fragments

Molecular and crystal structure of the antioxidant 4-[3,3-bis(3,5-di-tert-butylphenyl-4- hydroxybenzyl)-3H-indole-2-ilmethylene]-2,6-di-tert-butylcyclohex-2,5-dienone (1) and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N′-((1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2-ylidene)propane hydrazide (2) is studied. It is shown that sterically hindered phenols do not form hydrogen bonds in any of these molecules. In crystal 2, amide groups form a pseudo-centrosymmetric dimer due to N-H…O hydrogen bonds. The chiral camphene basis of molecule 2 prevents the formation of a centrosymmetric supramolecular synthon that usually appears in racemic compounds with amide groups, while the pseudo-centrosymmetric geometry of propane hydrazide chains hinders packing within the space group of the second-order rotational symmetry. As a result, molecules 2 crystallize into non-centrosymmetric crystals with two independent molecules.

Biocatalytic Synthesis and Polymerization via ROMP of New Biobased Phenolic Monomers: A Greener Process toward Sustainable Antioxidant Polymers

Antioxidant norbornene-based monomers bearing biobased sterically hindered phenols (SHP)—NDF (norbornene dihydroferulate) and NDS (norbornene dihydrosinapate)—have been successfully prepared through biocatalysis from naturally occurring ferulic and sinapic acids, respectively, in presence of Candida antarctica Lipase B (Cal-B). The ring opening metathesis polymerization (ROMP) of these monomers was investigated according to ruthenium catalyst type (GI) vs. (HGII) and monomer to catalyst molar ratio ([M]/[C]). The co-polymerization of antioxidant functionalized monomer (NDF or NDS) and non-active norbornene (N) has also been performed in order to adjust the number of SHP groups present per weight unit and tune the antioxidant activity of the copolymers. The polydispersity of the resulting copolymers was readily improved by a simple acetone wash to provide antioxidant polymers with well-defined structures. After hydrogenation with p-toluenesulfonylhydrazine (p-TSH), the radical scavenging ability of the resulting saturated polymers was evaluated using α,α-diphenyl-β-picrylhydrazyl (DPPH) analysis. Results demonstrated that polymers bearing sinapic acid SHP exhibited higher antiradical activity than the polymer bearing ferulic acid SHP. In addition it was also shown that only a small SHP content was needed in the copolymers to exhibit a potent antioxidant activity.

Antioxidants for biodiesel: Additives prepared from extracted fractions of bio-oil

Unlike petroleum diesel, the chemical structure of biodiesel makes it prone to oxidation during long-term storage, thus involving fuel quality deterioration. Therefore, the addition of antioxidants is usually required to meet the quality standards for biodiesel commercialization. Synthetic sterically-hindered phenols have been usually employed for this purpose as free radical scavenging antioxidants. However, naturally occurring phenolics are also available, for example, in the bio-oil produced in the pyrolysis of lignocellulosic biomass. In this work, the antioxidant potential of extracted fractions of lignocellulosic bio-oil has been evaluated. Different organic solvents were tested as extraction agents, acetate esters being the best ones for incorporating bio-oil antioxidant compounds into biodiesel. In the best case, the incorporation of a small concentration of bio-oil compounds (<4wt.%) led to an improvement of the biodiesel oxidation stability of 475% which, in our case, was enough to meet the European standard requirement.

Voltammetric determination of sterically hindered phenols in surfactant-based self-organized media

Tert-butylhydroquinone (TBHQ), butylhydroxyanisole (BHA), and butylhydroxytoluene (BHT) are irreversibly oxidized on a glassy-carbon electrode in a medium of acetonitrile-Britton-Robinson buffer solution (1: 9, pH 3.0) at 0.61, 0.79, and 1.1 V, respectively, to give quinones. Micellar media of Triton X100,Brij® 35, and sodium dodecyl sulfate affect their oxidation. The splitting and suppression of the oxidation steps for sterically hindered phenols (SHP) is observed in the presence of nonionic surfactants. Sodium dodecyl sulfate considerably enhances anodic currents and also shifts positive potentials to lower values. The conditions of the differential-pulse voltammetric determination of SHP in a 0.1 M sodium dodecyl sulfate supporting electrolyte are found. The calibration graphs are linear in the ranges 2.02–1010, 2.34–1170, and 6.15–615 μM and the detection limits (S/N = 3) are 0.23, 0.18, and 3.5 μM for TBHQ, BHA, and BHT, respectively. The possibility of determining SHP in TBHQ-BHT and BHA-BHT mixtures in wide ranges of component concentration is demonstrated. A method is developed for the extraction-voltammetric determination of BHT in vegetable oils.

Synthesis, Toxicity, and Antituberculosis Activity of Isoniazid Derivatives Containing Sterically Hindered Phenols

The toxicity and tuberculostatic activity of new isoniazid derivatives containing sterically hindered phenols were investigated. The investigated isoniazid derivatives exhibited lower activity and toxicity than isoniazid.

ChemInform Abstract: Transition Metal Complexes with Redox Ligands Based on Sterically Hindered Phenols

ChemInform Abstract: Transition Metal Complexes with Redox Ligands Based on Sterically Hindered Phenols

Aggregation of dextran hydrophobically modified by sterically-hindered phenols in aqueous solutions: Aggregates vs. single molecules

The hydrodynamic properties of dextrans hydrophobically modified by sterically-hindered phenols in aqueous solution were characterized by a combination of Cryogenic Transmission Electron Microscopy (Cryo-TEM), fluorescent spectroscopy, and Dynamic Light Scattering (DLS). All solutions investigated contained aggregates the structure, shape, and critical aggregation concentration of which are influenced by the amount of the inserted phenol groups in the polymer matrix. We found that increasing of temperature enhances aggregation. It was established that the critical aggregation concentration could be well approximated by a logarithmic function of the substitution degree of the glycoside units. The results suggest that the proportion of aggregates is nevertheless negligible in comparison with the proportion of single molecules.

SYNTHESIS OF NOVEL BI-FUNCTIONAL COPOLYMER BEARING STERICALLY HINDERED PHENOL AND HINDERED AMINE GROUPS VIA RING-OPENING METATHESIS POLYMERIZATION

Norbornene derivatives exo,endo-2-[2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-acetoxy]methyl-5-norbornene (M1) and 3,3,5,5- etramethyl-4-piperidinyl 5-norbornene-exo,endo-2-carboxylate (M2) were synthesized and polymerized by RuCl2 (=CHPh)(PCy3)2 to prepare a novel kind of bi-functional polymer bearing sterically hindered phenol (SHP) and hindered amine (HLAS) groups via ring-opening metathesis polymerization (ROMP). The resulting copolymers were characterized by gel permeation chromatography (GPC), 1H-NMR and differential scanning calorimetry (DSC). The number average molecular weight (Mn) and functional unit content of the resulting copolymer could be regulated by varying the concentration of catalyst and monomer feed.

Synthesis and radical scavenging ability of new polymers from sterically hindered phenol functionalized norbornene monomers via ROMP

Norbornene derivatives, including four novel structure compounds, bearing sterically hindered phenol (SHP) were prepared as functional monomers (1–3). The ring-opening metathesis polymerization (ROMP) of these functional monomers was carried out with typical ruthenium catalyst [bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride] that was so called as first-generation Grubbs catalyst to prepare hindered phenol functionalized polymers possessing radical scavenging function. The resulting polymers were characterized by means of gel permeation chromatography (GPC), 1H and 13C NMR, and differential scanning calorimetry (DSC). The radical scavenging ability of polymer was evaluated by determining RSA using the α,α-diphenyl-β-picrylhydrazyl (DPPH) free radical. The results show that the resulting polymers have different radical scavenging ability with the difference in structure of side chain. Polymers bearing 3,5-di-tert-butyl-4-hydroxyphenyl-propionate (DBHP) side chain have a higher radical scavenging ability than the polymers bearing 3,5-di-tert-butyl-4-hydroxy-benzoate (DBHB) as side chain. The molecular weight of polymers is dependent on the ratio of molar concentration of monomer to catalyst ([M]/[C]); monomers bearing DBHP group have a higher activity for ROMP than the monomers bearing DBHB group comparatively.

Synthesis of 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐thiadiazole Derivatives Containing Fragments of Sterically‐Hindered Phenol.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Derivatives of Δ2‐Imidazolin‐5‐one and Imidazolidine Containing Residues of Sterically‐Hindered Phenols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The Search for Promising Antioxidants and Thermostabilizers for Synthetic Fibres in a Number of Nitrogen-Containing Heterocycle Derivatives

The properties of a series of polynitrogen heterocyclic compounds of different structure were investigated as thermostabilizers for polypropylene and polycaproamide. It was found that polyheterocyclic compounds containing a condensed heterocyclic nucleus (1,2,4-triazole, thiazole, thiodiazole) and sterically-hindered phenol residue are the most promising compounds investigated.

Heterocycles Based on Sterically Hindered Phenols and Their Derivatives

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Derivatives of of Δ 2 -Imidazolin-5-one and Imidazolidine Containing Residues of Sterically-hindered Phenols

1-Substituted 4-benzylidene-2-{β-[3,5-di(tert-butyl)-4-hydroxyphenyl]vinyl}-4-benzylidene-Δ2-imidazolin-5-ones have been synthesized by the interaction of azomethines and N-acylhydrazones (derivatives of 3,5-di(tert-butyl)-4-hydroxybenzaldehyde) with 4-benzylidene-2-methyloxazol-5-one. The acylation of 1,2-bis[3,5-di(tert-butyl)-4-hydroxybenzylideneamino]ethane with acid chlorides in acetonitrile in the presence of triethylamine leads to 1,3-diacyl-2-[3,5-di(tert-butyl)-4-hydroxyphenyl]imidazolidine.

Inhibition of Styrene Thermal Polymerization by Formulations Based on Quinone Dioxime and Sterically Hindered Phenols

A formulation based on quinone dioxime and a mixture of sterically hindered phenols tert-butylpyrocatechol-2,2'-methylenebis(6-tert-butyl-4-methylphenol) (Agidol-2) was suggested for inhibiting terpolymerization of styrene.

Effects of some sterically hindered phenols on whole-cell Ca(2+) current of guinea-pig gastric fundus smooth muscle cells.

1. The aim of the present study was to investigate the effects of extracellular application of some sterically-hindered phenols, namely 3-t-butyl-4-hydroxyanisole (BHA), 3,5-di-t-butyl-4-hydroxyanisole (DTBHA) and the dimer of BHA, 2,2'-dihydroxy-3,3'-di-t-butyl-5,5'-dimethoxydiphenyl (DIBHA), on the whole-cell Ca(2+) current (I(Ca)) of freshly isolated smooth muscle cells from the guinea-pig gastric fundus, in the presence of a range of Ca(2+) concentrations (1 -- 5 mM) using the patch-clamp technique. The influx of Ca(2+) had characteristics of L-type I(Ca) (I(Ca(L))). 2. BHA as well as DTBHA inhibited I(Ca(L)) in a concentration-dependent manner, during depolarization to 10 mV from a holding potential of -50 mV. Bath application of BHA (50 microM) and DTBHA (30 microM) decreased I(Ca(L)) by 48.9% and 45.2%, respectively. This inhibition was only partially reversible. In contrast, DIBHA (up to 50 microM) was devoided of effects on I(Ca(L)). 3. BHA inhibition of I(Ca(L)) was voltage-dependent and inversely related to the external concentration of Ca(2+). On the other hand, DTBHA inhibition was only voltage-dependent. 4. BHA and DTBHA shifted the voltage range of the steady-state inactivation curve to more negative potentials by 8 mV at the mid-potential of the curve, without affecting the activation curve. Furthermore, BHA and DTBHA did not modify the time-course of the current decay. 5. We conclude that the inhibition of I(Ca(L)) by BHA and DTBHA is qualitatively similar to that of a Ca(2+) channel blocker and is characterized by the stabilizing effect of the inactivated state of the channel.