Free Phenolic Hydroxyl Research Articles

Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity

Focusing on the importance of the free phenolic hydroxyl moiety, a family of 23 alkylresorcinol-based compounds were developed and evaluated for their cannabinoid receptor binding properties. The non-symmetrical hexylresorcinol derivative 29 turned out to be a CB2-selective competitive antagonist/inverse agonist endowed with good potency. Both the olivetol- and 5-(2-methyloctan-2-yl)resorcinol-based derivatives 23 and 24 exhibited a significant antinociceptive activity. Interestingly, compound 24 proved to be able to activate both cannabinoid and TRPV1 receptors. Even if cannabinoid receptor subtype selectivity remained a goal only partially achieved, results confirm the validity of the alkylresorcinol nucleus as skeleton for the identification of potent cannabinoid receptor modulators.

Chemical and Pharmacological Aspects of Caffeic Acid and Its Activity in Hepatocarcinoma.

Caffeic acid (CA) is a phenolic compound synthesized by all plant species and is present in foods such as coffee, wine, tea, and popular medicines such as propolis. This phenolic acid and its derivatives have antioxidant, anti-inflammatory and anticarcinogenic activity. In vitro and in vivo studies have demonstrated the anticarcinogenic activity of this compound against an important type of cancer, hepatocarcinoma (HCC), considered to be of high incidence, highly aggressive and causing considerable mortality across the world. The anticancer properties of CA are associated with its antioxidant and pro-oxidant capacity, attributed to its chemical structure that has free phenolic hydroxyls, the number and position of OH in the catechol group and the double bond in the carbonic chain. Pharmacokinetic studies indicate that this compound is hydrolyzed by the microflora of colonies and metabolized mainly in the intestinal mucosa through phase II enzymes, submitted to conjugation and methylation processes, forming sulphated, glucuronic and/or methylated conjugates by the action of sulfotransferases, UDP-glucotransferases, and o-methyltransferases, respectively. The transmembrane flux of CA in intestinal cells occurs through active transport mediated by monocarboxylic acid carriers. CA can act by preventing the production of ROS (reactive oxygen species), inducing DNA oxidation of cancer cells, as well as reducing tumor cell angiogenesis, blocking STATS (transcription factor and signal translation 3) and suppression of MMP2 and MMP-9 (collagen IV metalloproteases). Thus, this review provides an overview of the chemical and pharmacological parameters of CA and its derivatives, demonstrating its mechanism of action and pharmacokinetic aspects, as well as a critical analysis of its action in the fight against hepatocarcinoma.

<p>Metabolic profile and structure–activity relationship of resveratrol and its analogs in human bladder cancer cells</p>

Purpose: Resveratrol (RV), a promising anti-cancer candidate, is limited in application for its poor bioavailability. However, the better bioavailability has been found in some RV derivatives. So in this paper, we explore the structure–activity relationship and the metabolic profiles of RV and its analogs (polydatin [PD], oxyresveratrol [ORV], acetylresveratrol [ARV]) in human bladder cancer T24 cells, and then evaluate their active forms and key chemical functional groups which may determine the fate of tumor cells.Methods: Drug sensitivity is evaluated by MTT assay, HE staining and flow cytometry analysis after T24 cells treated with RV, PD, ORV and ARV, respectively. Then the drug metabolites, in alive and dead T24 cells, also in T24 cell supernatant and lysates, are qualitatively and quantitatively analyzed by high-performance liquid chromatography, liquid chromatography coupled with tandem mass spectrum and high-resolution mass spectrometry technologies, respectively.Results: RV, ORV and ARV inhibit bladder cancer cells growth in a dose- and time-dependent manner, and exert the anti-tumor potency to T24 cells in order of ORV>ARV>RV>PD. Meanwhile, similar metabolic profiles of the above compounds are found not only in cell supernatant and lysate, but also in dead and alive T24 cells after drug treatment, and the main metabolites of RV, ORV and PD are their prototypes, but ARV is mainly metabolized to RV.Conclusion: The inhibitory potencies to T24 cells in the order of ORV>ARV>RV>PD are related to the structure and metabolism of RV and its analogs. Meanwhile, the number and position of free phenolic hydroxyl groups play a prominent role in antitumor activities. Therefore, protecting phenolic hydroxyl groups, and inhibiting drug metabolism to keep phenolic hydroxyl groups free would be the promising strategies to ensure the bioactivity of RV and its analogs, and thus to improve RV’s bioactivity and promote RV clinical translation.

Copper-catalyzed intramolecular cross dehydrogenative coupling approach to coumestans from 2'-hydroxyl-3-arylcoumarins.

A copper-catalyzed intramolecular cross dehydrogenative C–O coupling reaction of 2′-hydroxyl-3-arylcoumarins was developed. This protocol provided a facile and efficient strategy for the construction of natural coumestans and derivatives in moderate to high yields. This transformation exhibited good functional group compatibility and was amenable to substrates with free phenolic hydroxyl groups.

Asymmetric Boron-Cored Aggregation-Induced Emission Luminogen with Multiple Functions Synthesized through Stepwise Conversion from a Symmetric Ligand.

Multifunction luminogens have emerged as promising candidates in high-performance sensor and imaging systems. Concise approaches to the synthesis of such molecules are urgently required both for fundamental research and technological applications. In this study, a new symmetric ligand of di(2-hydroxyphenyl)phthalazine with multiple binding sites around a phthalazine unit was readily synthesized, which could be converted efficiently into an asymmetric luminogen (OBN-DHPP) through the formation of oxygen-boron-nitrogen bonding. This molecule has a twistable π-extended backbone with a tetracoordinated boron core bearing two bulky phenyl groups, giving it abundant optical properties including a large Stokes shift piezochromism and aggregation-induced emission enhancement. Importantly, the presence of a free phenolic hydroxyl group in the backbone of OBN-DHPP enables the incorporation of various functional moieties into the asymmetric luminogen. As an example, polyethylene glycol (PEG)-modified luminogen (OBN-DHPP-PEG45) was synthesized. In the aqueous medium, OBN-DHPP-PEG45 could self-assemble into spherical nanoparticles with low cytotoxicity and excellent emission performance as well as high solubility. The results of flow cytometry and fluorescence microscopy reveal that these nanoparticles could be internalized successfully by HeLa cells, demonstrating their potential application in bioimaging.

Pyrogallol-based benzoxazines with latent catalytic characteristics: The temperature-dependent effect of hydrogen bonds on ring-opening polymerization

Two kinds of pyrogallol-based di-benzoxazines (PG-FA and PG-A) with a free phenolic hydroxyl between two oxazine rings attaching to the same benzene were synthesized. The chemical structures of PG-FA and PG-A were identified by 1H NMR, 13C NMR and FTIR tests. The ring-opening polymerization (ROP) behavior of PG-FA and PG-A was monitored by DSC, TGA, FTIR and in situ FTIR measurements. The pyrogallol-containing benzoxazines showed latent catalytic activity as they reached melting condition. The inter- and intramolecular hydrogen bonds from the phenolic hydroxyl and oxygen or nitrogen were converted into weak OH⋯π intramolecular hydrogen bonding, which easily released the free phenolic hydroxyl. Then, the free hydroxyl could accelerate the breakage of oxazine ring. The para-position of free phenolic hydroxyl in pygarollol-based benzoxazines was preferentially polymerized with the carbocations. The temperature-dependent evolution of the chemical structure of PG-FA and PG-A on ROP was consistent with the change of hydrogen bonds.

A novel bio‐based phthalonitrile resin derived from catechin: synthesis and comparison of curing behavior with petroleum‐based counterpart

AbstractThe development of bio‐based thermosetting resins with good thermal stability can potentially afford sustainable polymers as replacements for petroleum‐based polymers. We report a practical route to a novel catechin‐based phthalonitrile resin precursor (CA‐Ph), which contains free phenolic hydroxyl groups that result in ‘self‐curing’ at elevated temperatures to afford a thermostable polymer. Comparison of the performance of this CA‐Ph resin with that of a conventional petroleum‐based bisphenol A phthalonitrile resin (BPA‐Ph; containing 5 wt% of the curing agent 4,4′‐diaminodiphenylsulfone) revealed that CA‐Ph exhibits a lower melting point and curing temperature. Cured CA‐Ph resin retains 95% of its weight at 520 °C under a nitrogen atmosphere, which compares favorably with results obtained for BPA‐Ph resin that retains 95% of its weight at a lower temperature of 484 °C. Kinetic results indicated that the curing reactions of both CA‐Ph and BPA‐Ph systems follow an autocatalytic mechanism. These results suggest that catechin is a useful bio‐based feedstock for the preparation of self‐curing and thermally stable phthalonitrile resins for advanced technological applications. © 2017 Society of Chemical Industry

Crystal Structure, Synthesis and Biological Activity of Ether and Ester <i>Trans</i>-Ferulic Acid Derivatives

The structures of methoxymethyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate, 2; (E)-3-(3-methoxy-4-(methoxymethoxy)phenyl)acrylic acid, 3; methyl (E)- 3-(4-(benzyloxy)-3-methoxyphenyl)acrylate, 4; benzyl (E)-3-(4-(benzyloxy)- 3-methoxyphenyl)acrylate, 6; and (E)-3-(4-(benzyloxy)-3-methoxyphenyl)- acrylic acid, 7; were established by spectroscopic and X-ray diffraction studies. Structure 2 is a new com-pound. Compounds with free phenolic hydroxyls v.gr. methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate 1, 2 and ben-zyl(E)-3-(4-hydroxy-3-methoxyphenyl)acrylate 5, showed scavenging free- radical and antioxidant activity while moderate scavenging free-radical was observed in compound 3. Moderate inhibition of lipid peroxidation was observed for 7. Compound 5 exerted significant inhibition of cell growth in PC-3, K562 tumor cell lines and 4 exhibited the largest cytotoxic effect upon the K562 cell line.

Fast pyrolysis bio‐oil as precursor of thermosetting epoxy resins

Fast pyrolysis bio‐oil was employed as a source of phenolic compounds in the production of a bio‐based polymeric network. The bio‐oil was reacted with epichlorohydrin in alkaline medium using benzyltriethylammonium chloride as a phase transfer catalyst. The amount of free phenolic hydroxyl groups before and after modification was quantified through 31P‐NMR spectroscopy; and the epoxy content of the bio‐oil upon the chemical functionalization was measured by means of a titration using HBr in acetic acid solution. Grafting of epoxy functions onto the monomer`s structure was studied by FTIR. Likewise, α‐resorcylic acid was also modified with reactive epoxy moieties, and used as low molecular weight comonomer. The epoxidized derivatives of the bio‐oil were cured in epoxy polymers with 4‐dimethylaminopyridine. Thermo‐mechanical characterization showed that the obtained materials behave as thermoset amorphous polymers, exhibiting modulus values ranging from approximately 1.5–3.4 GPa at room temperature and glass transition temperatures above 100°C. POLYM. ENG. SCI., 58:1296–1307, 2018. © 2017 Society of Plastics Engineers

Polybenzoxazines: Thermal Responsiveness of Hydrogen Bonds and Application as Latent Curing Agents for Thermosetting Resins.

This work aims at exploring the application of polybenzoxazines as thermal latent curing agents for epoxy resins. Thorough studies have shown that hydrogen bonds of polybenzoxazines block the reactivity of phenolic hydroxyl at ambient temperatures and break at elevated temperatures to release the free phenolic hydroxyl. On the basis of these findings, polybenzoxazines are used as thermal latent curing agents. Mixtures of polybenzoxazines and epoxy resins exhibit a long shelf life at room temperature, and the corresponding copolymers possess enhanced properties. This novel insight into using polybenzoxazines as thermal latent curing agents for epoxy resins is anticipated to help researchers explore novel latent curing agents and apply polybenzoxazines more widely.

Facile Green Synthesis of Magnetic Porous Organic Polymers for Rapid Removal and Separation of Methylene Blue

Herein, magnetic porous organic polymers composites (MOPs) with abundant free phenolic hydroxyl group were synthesized via a simple and green azo coupling reaction under mild conditions in water. Remarkably, Fe3O4@SiO2 nanoparticles were encapsulated in the disordering porous organic polymers during the coupling reaction. The prepared MOPs possessed excellent stability, high special surface areas, controllable magnetism, and high adsorption capacity (1153 mg g–1) toward cationic dye methylene blue. Moreover, the MOPs could be easily and rapidly recovered from the solution by using a magnet due to their superparamagnetic property and could be reused at least 5 times without decreasing the adsorption capacity, demonstrating a potential application in pollutants removal.

Aqueous organic solvent fractionation as means to improve lignin homogeneity and purity

Lignin’s heterogeneous polymeric structure limits its utilisation in high-value applications. This paper describes a protocol for kraft lignin precipitation fractionation from aqueous ethanol, acetone and propyleneglycol monomethyl ether solution by adding water as nonsolvent. The solvent-insoluble fractions possessed high molar mass (Mw 4300–18900g/mol), high polydispersity (2.2–5.6), high nitrogen (0.15–0.43%) and low sulphur (0.7–1.5%) content. Even lignin aggregation was observed in acetone-based process. The molar mass of the precipitated fractions depended on the amount of water added in the precipitation step. The highly soluble lignin fractions possessed very low molar mass (Mw 1100–1200g/mol), more free phenolic hydroxyl groups (3.95–4.05mmol/g), carboxylic acid groups (0.56–0.71mmol/g), higher amount of sulphur (1.6k2.9%) and more carbohydrates (5.3–6.1%) than other lignin fractions. The presented protocol provides a selection of green solvents for a simple and easily scalable and tunable lignin fractionation process to produce lignin with constant quality and high purity.

Effects of Solvation and Ionization on 13C NMR Spectra of Lignin Model Compounds, Spruce Milled Wood Lignin and Kraft Lignin

The effects of alkali and polar aprotic solvent on the aromatic carbons signals in 13C NMR (Carbon-13 nuclear magnetic resonance) spectra of lignin model compounds and spruce milled wood lignin (MWL) were studied. It was found that in 1 M aqueous NaOH signal shifts of C-1 and C-4 carbon atoms in the aromatic ring were the most noticeable in lignin models with free phenolic hydroxyl groups, which are ionized under the conditions. A similar effect in the spectra of the studied model compounds was observed in 0.5 M aqueous NaOD-deuterated dimethyl sulfoxide (DMSO) mixture (DMSO: water ratio 3:7 v/v). The model data help explaining changes in the 13C NMR spectra of MWL and lignin in situ dissolved in spruce kraft black liquor caused by ionization. In the 13C NMR spectra of spruce black liquor the signals of phenolic and non-phenolic lignin units are clearly separated and do not overlap with the signals of the carbon atoms of carbohydrates and other aliphatic products of wood degradation. The data obtained are useful in understanding the important role of solvation and ionization processes leading to lignin solubilization.

Antioxidation and mechanism of phosphites including the free phenolic hydroxyl group in polypropylene

ABSTRACTInhibiting the degradation of polypropylene (PP) in melt processing and usage is an important issue in the plastic industry. It is becoming more and more urgent to increase the antioxidation of phosphites alone while maintaining the water resistance. In this study, one phosphite antioxidant, named bis‐2,2′‐methyl‐4,6‐di‐tert‐butylphenyl phosphite (BM46TBPP), which contains a water‐resistant inner ring and a free phenolic hydroxyl group together, was synthesized. Then, antioxidation in PP was characterized with multiple extrusions and oxidation induction times (OITs). Finally, the hydrogen‐donating ability of this antioxidant was tested with 2,2‐diphenyl‐1‐picrylhydrazyl radical colorimetry to explain the antioxidation mechanism. The results show that the phosphite BM46TBPP displays better antioxidation than tris(2,4‐di‐tert‐butylphenyl) phosphite (Irgafos 168) in melt processing and OIT testing. Furthermore, the priority of this antioxidant was more obvious when it was used in the presence of oxygen, so the antioxidant even made the PP stabilized by it alone show a longer OIT value than the PP stabilized by the complex system including Irgafos 168 and 2,4‐di‐tert‐butylphenol because there was a free phenolic hydroxyl group in the BM46TBPP antioxidant molecule and the hydroxyl group made the antioxidant show intermolecular synergistic antioxidation through hydrogen donation to radicals. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 44696.

Exploiting fluorescein based drug conjugates for fluorescent monitoring in drug delivery

Anticancer drugs connected to fluorescein based chemosensors by different biodegradable linkers were investigated for fluorescent monitoring in drug delivery models. The drug release triggered by chemo- and bio-hydrolytic environments was visualized on the basis of "switch on" fluorescence of the fluorophore moiety of fluorescein-drug conjugates. The conjugation of free phenolic hydroxyl of fluorescein chemosensor to the hydroxyl group of the drugs was employed by biodegradable oxy- and amino acrylate linkers. The chemosensor also possesses a free carboxylic group for potential conjugation to a specific carrier for targeted drug delivery applications. Fluorescent monitoring of drug release, quantum yield and other spectroscopic characteristics of our novel fluorescein-drug conjugates were measured and discussed. The work offers a versatile fluorophore platform for the fluorescent observation of drug delivery.

A tryptamine-paeonol hybridization compound inhibits LPS-mediated inflammation in BV2 cells

In the present study, we synthesized and evaluated the anti-inflammatory effects of three tryptamine (Trm) hybrid compounds, HBU-375, HBU-376 and HBU-379. The Click reaction between the azido-Trm and 2- or 4-propazylated paeonol moiety resulted in HBU-376 and HBU-375, respectively. HBU-379 was generated by hybridizing Trm with propazylated acetyl-syringic acid. HBU-376 and HBU-375 dose-dependently inhibited LPS and caused nitric oxide (NO) generation in BV2 cells, whereas HBU-379 minimally inhibited NO generation, indicating that the paeonol unit plays an important role in the anti-inflammatory effect of Trm hybrid compounds. Although HBU-375 and HBU-376 demonstrated a similar inhibitory effect on LPS-induced NO generation, HBU-376 resulted in less cellular toxicity presumably due to the free phenolic hydroxyl group of paeonol. Therefore, HBU-376 may be a promising anti-inflammatory agent conferring minimal cytotoxicity. HBU-376 significantly and dose-dependently inhibited LPS-induced NO products, NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6, MCP-1 and interleukin-1β mRNA expressions and iNOS and COX-2 protein expressions. However, at the same concentrations, Trm or paeonol individually did not inhibit LPS-mediated production of inflammatory molecules. HBU-376 inhibited both LPS-induced STAT-3 phosphorylation and nuclear factor-kappa B (NF-κB) activation. Furthermore, LPS-mediated DNA binding of c-Rel, p50 and p52 to the NF-κB binding site of the iNOS promoter was inhibited by HBU-376, whereas Trm and paeonol did not inhibit LPS-induced NF-κB activation and DNA binding of c-Rel, p50 and p52. Overall, our data suggest that the Trm-paeonol hybrid compound down-regulates inflammatory responses by inhibiting NF-κB and NF-κB-dependent gene expression. This suggests that it is a potential therapeutic agent for inflammatory diseases of the central nervous system.

Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates.

Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a 'lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs. Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of β-carotene bleaching, at 1-200μm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50μm) assays. Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of β-carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay. Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment.

Correlation between lignin physicochemical properties and inhibition to enzymatic hydrolysis of cellulose.

Using isolated organosolv lignins from hardwood poplar and softwood lodgepole pine with varied physicochemical properties (molecular weight, aliphatic hydroxyl, phenolic hydroxyl, and hydrophobicity), the inhibitory effect of the lignins on enzymatic hydrolysis of cellulose was investigated and the relationship between lignin properties and the inhibitory effect was elucidated. The results indicated that the lignin inhibition to enzymatic hydrolysis of cellulose was closely related to the hydrophobicity and the phenolic hydroxyl groups of the lignin. The overall hydrophobicity of the lignin quantified by contact angle could serve as a predictor of the inhibitory effect of lignin. Hydrophilic modification of the lignin by carboxylation and sulfonation reduced the hydrophobicity by 22-30% and thereby removed the lignin inhibition by 76-96%. Phenolic hydroxyl group was a crucial factor affecting the inhibitory effect of lignin. Blocking free phenolic hydroxyl group by chemical reaction such as hydroxypropylation significantly (65-91%) reduced the inhibitory effect of lignin. Biotechnol. Bioeng. 2016;113: 1213-1224. © 2015 Wiley Periodicals, Inc.

Structure-Activity Relationships for DNA Damage by Alkenylbenzenes in Turkey Egg Fetal Liver.

Certain alkenylbenzenes (AB), flavoring chemicals naturally occurring in spices and herbs, are established to be cytotoxic and hepatocarcinogenic in rodents. The purpose of the present study was to determine the DNA damaging potential of key representatives of this class using the Turkey Egg Genotoxicity Assay. Medium white turkey eggs with 22- to 24-day-old fetuses received three injections of nine AB with different carcinogenic potentials: safrole (1, 2 mg/egg), methyl eugenol (2, 4 mg/egg), estragole (20, 40 mg/egg), myristicin (25, 50 mg/egg), elemicin (20, 50 mg/egg), anethole (5, 10 mg/egg), methyl isoeugenol (40, 80 mg/egg), eugenol (1, 2.5 mg/egg), and isoeugenol (1, 4 mg/egg). Three hours after the last injection, fetal livers were harvested for measurement of DNA strand breaks, using the comet assay and DNA adducts formation, using the nucleotide(3) (2)P-postlabeling assay. Estragole, myristicin, and elemicin induced DNA stand breaks. These compounds as well as safrole, methyl eugenol and anethole, at the highest doses tested, induced DNA adduct formation. Methyl isoeugenol, eugenol, and isoeugenol did not induce genotoxicity. The genotoxic AB all had the structural features of either a double bond in the alkenyl side chain at the terminal 2',3'-position, favorable to formation of proximate carcinogenic 1'-hydroxymetabolite or terminal epoxide, or the absence of a free phenolic hydroxyl group crucial for formation of a nontoxic glucuronide conjugate. In contrast, methyl isoeugenol, eugenol and isoeugenol, which were nongenotoxic, possessed chemical features, unfavorable to activation.

Integrated hot-compressed water and laccase-mediator treatments of Eucalyptus grandis fibers: structural changes of fiber and lignin.

Eucalyptus grandis fibers were treated with hot-compressed water (HCW) and laccase mediator to enhance the fiber characteristics and to produce an active lignin substrate for binderless fiberboard production. The composition, morphology, and crystallinity index (CrI) analysis of fibers showed that the HCW treatment increased the CrI and lignin content of the treated fibers through partial removal of hemicelluloses. Simultaneously, the HCW treatment produced some granules and holes on the surface of the fibers, which possibly facilitated the accessibility of the laccase mediator. Milled wood lignins and enzymatic hydrolysis lignins isolated from the control and treated fibers were comparatively characterized. A reduction of molecular weight was observed, which indicated that a preferential degradation of lignin occurred after exposure to the laccase mediator. Quantitative (13)C, 2D-HSQC and (31)P NMR characterization revealed that the integrated treatment resulted in the cleavage of β-O-4' linkages, removal of G' (oxidized α-ketone) substructures, and an increase in the S/G ratio and free phenolic hydroxyls.