Resorcinol Moiety Research Articles

Is the Interfacial Electrochemical Behavior of Quercetin the Same as That of Catechol Plus Resorcinol?

Background: Electrodeposition of functional films from polyphenol-containing solutions has emerged as a new field of surface functionalization from bio-sourced molecules. There is, however, almost no knowledge about the chemical structure of such complex films. It is the aim of this research to use the known electrodeposition of films made from catechol and resorcinol, two isomers of dihydroxybenzene, to understand the electrodeposition of a more complex polyphenol, quercetin, which is constituted from a fused catechol and resorcinol moiety. The aim of this article is hence to introduce some methodology in the interpretation of the electrochemical behavior of complex polyphenols starting from their building blocks. Methods: Cyclic voltammetry (CV) is used to deposit films from quercetin and from equimolar blends of catechol and resorcinol on amorphous carbon and gold working electrodes. The main experimental parameter was the potential sweep rate used during the CVs. Results: The CV of quercetin is not the exact sum of the CV of the catechol + resorcinol blends, but the major features are conserved, namely the presence of two main oxidation peaks affiliated to those of catechol and resorcinol but shifted to less anodic potentials. In addition, the anodic electron transfer coefficients of the two oxidation waves of quercetin are higher than those measured in the catechol resorcinol blend. However, film deposition ability is reduced with quercetin compared to catechol + resorcinol blend in probable relationship to steric hindrance occurring during the non-electrochemical crosslinking of the deposit. The quercetin-based films deposited at 10 mV·s−1 on gold electrodes are conformal and display some antioxidant activity.

Asymmetric Synthesis of (-)-Cannabidiol (CBD), (-)-Δ9-Tetrahydrocannabinol (Δ9-THC) and Their cis Analogs Using an Enantioselective Organocatalyzed Diels-Alder Reaction.

Herein we describe an asymmetric synthesis of the pharmacologically relevant natural (-)-trans-CBD and psychoactive (-)-trans-Δ9-THC, as well as their synthetic cis diastereomers. The key step is an enantioselective Diels-Alder reaction catalyzed by a prolinol-based catalyst, which provides the cyclohexene carbaldehyde intermediate in good yield and high enantiomeric excess. Optimization of the substituted resorcinol protecting groups to avoid harsh and low-yield deprotection of the acid sensitive resorcinol moiety is also described.

Microbiocidal Studies of Some Azo Dyes

Microbiocidal potential of some azo dyes has been studied. Polydentate azo dyes viz. 1-(2’-carbo xyphenylazo)-2-naphthol, 5-(2’-carboxyphenylazo)-8-hydroxyquinoline, 5-(2’-carboxyphenylazo)salicylic acid and 4-(2’-carboxyphenylazo)resorcinol were synthesized and characterized by elemental analysis, infrared (FTIR) and 1H NMR spectral studies. The dyes were screened for antibacterial sensitivities against the Gram positive bacteria Staphylococcus aureus and Gram negative bacteria Enterobacter aerogenes and Escherichia coli at four concentrations of the dyes viz. 0.5, 1.0, 1.5 and 2.0 mg/ml, in acetone. Results revealed a high to low potency of the dyes as antibacterials. 5-(2’-carboxyphenylazo)salicylic acid and 4-(2’-carboxyphenylazo) resorcinol in the concentration range of 1 to 2mg/ml, were found to be more potent in inhibiting the bacterial growth uniformly towards all the three bacteria. A possible role of salicylate or resorcinol moieties, in addition to azo group of these dyes in their higher microbiocidal activities may be envisaged. These azo dyes may, thus, be of medicinal value.

First enantioselective total synthesis of human MAO inhibitor (+)-Colveol A

We present the first enantioselective total synthesis of the human MAO inhibitor (+)-colveol A and preliminary studies toward the synthesis of (+)-colveol B. Three strategies, centered on Sharpless asymmetric dihydroxylation, were explored to construct the vicinal syn-dihydroxyl system. The initial attempt involving direct asymmetric dihydroxylation of a chalcone derivative was unsuccessful. Alternatively, successful synthetic routes for (+)-colveol A involved Sharpless dihydroxylation of a cinnamyl ester, a Grignard addition of a resorcinol moiety, Wittig reaction and BBr3-mediated global deprotection of MOM ethers as key steps. The synthesis of (+)-colveol A was accomplished in 30 % yield over 7 steps.

Safety assessment and redox status in rats after chronic exposure to cannabidiol and cannabigerol

Cannabidiol (CBD) and cannabigerol (CBG) are the two main non-psychotropic phytocannabinoids with high application potential in drug development. Both substances are redox-active and are intensively investigated for their cytoprotective and antioxidant action in vitro. In this study, we focused on an in vivo safety evaluation and the effect of CBD and CBG on the redox status in rats in a 90-d experiment. The substances were administered orogastrically in a dose of 0.66 mg synthetic CBD or 0.66 mg/1.33 mg CBG/kg/day. CBD produced no changes in the red or white blood count or biochemical blood parameters in comparison to the control. No deviations in the morphology or histology of the gastrointestinal tract and liver were observed. After 90 d of CBD exposure, a significant improvement in redox status was found in the blood plasma and liver. The concentration of malondialdehyde and carbonylated proteins was reduced compared to the control. In contrast to CBD, total oxidative stress was significantly increased and this was accompanied by an elevated level of malondialdehyde and carbonylated proteins in CBG-treated animals. Hepatotoxic (regressive changes) manifestations, disruption in white cell count, and alterations in the ALT activity, level of creatinine and ionized calcium were also found in CBG-treated animals. Based on liquid chromatography-mass spectrometry analysis, CBD/CBG accumulated in rat tissues (in the liver, brain, muscle, heart, kidney and skin) at a low ng level per gram. Both CBD and CBG molecular structures include a resorcinol moiety. In CBG, there is an extra dimethyloctadienyl structural pattern, which is most likely responsible for the disruption to the redox status and hepatic environment. The results are valuable to further investigation of the effects of CBD on redox status and should contribute towards opening up critical discussion on the applicability of other non-psychotropic cannabinoids.

Aromatase inhibitors isolated from a flowering tea, snow Chrysanthemum (the capitula of Coreopsis tinctoria Nutt.).

Methanol extract from the capitula of Coreopsis tinctoria Nutt. (Asteraceae), which is also known as a flowering tea or blooming tea "Snow Chrysanthemum," was found to inhibit the enzymatic activity of aromatase. A total of 24 known isolates (1-24) were identified from the extract, including three chalcones (1-3), an aurone (4), five flavanones (5-9), four flavanols (10-13), a flavonol (14), and two biflavanones (15, 16). Among them, okanin (1, Ki = 1.6μM), (2S)-naringenin (5, 0.90μM), isookanin (6, 0.81μM), (2S)-7,3',5'-trihydroxyflavaone (7, 0.13μM), and (2S)-5,7,3',5'-tetrahydroxyflavanone (8, 0.32μM) exhibited relatively potent competitive inhibition. Specifically, the isolates 7 and 8, having a common 3',5'-resorcinol moiety at the B ring in their flavanone skeleton, exhibited potent inhibitory activities compared to those of a clinically applied aminoglutethimide (0.84μM) and naturally occurring flavone, chrysin (0.23μM), which is a common non-steroidal aromatase inhibitor. Importantly, the active flavonoid constituents (1 and 5-8) did not inhibit the activity of 5α-reductase enzyme, which normally reacts with the same substrate "testosterone," thus, these compounds were suggested to be specific to aromatase.

Structural dynamics and susceptibility of isobutylamido thiazolyl resorcinol (ThiamidolTM) against human and mushroom tyrosinases

Tyrosinase, a key enzyme catalyzing a rate-limiting step of the melanin production, has been the most promising target for suppressing hyperpigmentation. Although a number of tyrosinase inhibitors have been developed, most of those lack clinical efficacy as they were identified from using mushroom tyrosinase (mTyr) as the target. Previous study revealed that the inhibitory effect of isobutylamido thiazolyl resorcinol (ThiamidolTM) on human tyrosinase (hTyr) is ∼100 times higher than that on mTyr. In the present study, we aimed to investigate the structural dynamics and susceptibility of ThiamidolTM against hTyr and mTyr at the atomic level using molecular docking, molecular dynamics simulation, and free energy calculation based on the molecular mechanics/Poisson-Boltzmann surface area method. The obtained results revealed that the resorcinol moiety of ThiamidolTM was found to be embedded in the catalytic copper center, interacting with H180, H202, H211, F386, and H390 residues of hTyr as well as with F264 residue of mTyr, mostly through van der Waals interactions. However, the number of destabilizing residues was found to be more pronounced in the ThiamidolTM/mTyr complex than the ThiamidolTM/hTyr system, supported by the lower binding affinity of ThiamidolTM/mTyr complex as well as the higher water accessibility and the lower number of atomic contacts at the active site of mTyr. Altogether, the structural and energetic information from this work would be useful for further optimization of more potent human tyrosinase inhibitors based on ThiamidolTM scaffold. Communicated by Ramaswamy H. Sarma

Low-Energy Electron Interactions with Resveratrol and Resorcinol: Anion States and Likely Dissociation Pathways.

We report a computational study of the anion states of the resveratrol (RV) and resorcinol (RS) molecules, also investigating dissociative electron attachment (DEA) pathways. RV has well-known beneficial effects in human health, and its antioxidant activity was previously associated with DEA reactions producing H2. Our calculations indicate a valence bound state and four resonances ( to ) for that system. While the computed thermodynamic thresholds are compatible with DEA reactions producing H2 at 0 eV, the well-known mechanism involving vibrational Feshbach resonances built on a dipole bound state should not be present in RV. Our results suggest that the shallow valence bound state is expected to account for H2 elimination, probably involving / couplings along the vibration dynamics. The RS molecule is also an oxidant and a subunit of RV. Because two close-lying hydroxyl groups are found in the RS moiety, the H2-elimination reaction in RV should take place at the RS site. Our calculations point out a correspondence between the anion states of RV and RS and even between the thresholds. Nevertheless, the absence of bound anion states in RS, indicated by our calculations, is expected to suppress the H2-formation channel at 0 eV. One is led to conclude that the ethene and phenol subunits in RV stabilize the state, thus switching on the DEA mechanism producing H2.

Structural Analysis of an Octameric Resorcinarene Self-Assembly in Toluene and its Morphological Transition by Temperature.

Calix[4]resorcinarene derivatives such as C-undecylcalix[4]resorcinarene self-assemble into a hexameric capsule-like structure. This structure is expected in any apolar solvent, but we recently found a self-assembled octameric form of resorcinarene in toluene. To understand this unexpected form, we performed small-angle X-ray scattering (SAXS) measurements of the octameric self-assembly. In ab initio shape reconstruction and model fitting of the SAXS profile, a core-shell spherical structure resembling a reverse micelle was found in the octameric self-assembly. The shell and core were composed of alkyl chains and resorcinol moieties, respectively. We also evaluated the temperature dependence of the octameric self-assembly. Above 95 °C, the structure began directly decomposing into unimers, implying the partial cleavage of hydrogen bonds in the octamer core. Meanwhile, below 25 °C, the spherical structure of the octamer partially transformed to a cylindrical structure. This morphological transition could be understood by packing parameter theory, which is often applied to suspected micellar structures.

Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety.

We previously reported (E)-β-phenyl-α,β-unsaturated carbonyl scaffold ((E)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (E)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds 1c (IC50 = 18.09 ± 0.25 μM), 1h (IC50 = 4.14 ± 0.10 μM), and 2a (IC50 = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC50 = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition.

Binding of agonist WAY-267,464 and antagonist WAY-methylated to oxytocin receptor probed by all-atom molecular dynamics simulations

AimsNon-peptide ligands of oxytocin receptor (OTR) have promising potentialities as therapeutic agents with improved pharmacological properties. WAY-267,464 is a non-peptide agonist which loses its agonist activity when its resorcinol moiety is methylated, yielding a partial antagonist (denoted here, WAY-Methylated). This study attempts to rationalize these opposing activities by comparative analyses of structural dynamicsof OTR in complex with these ligands. Main methodsGlide extra precision (XP) docking with and without positional constraints was employed to probe alternative binding poses of both WAY-267,464 and WAY-Methylated. The more preferred configuration of each system was subjected to an extended 2 μs MD simulation and the physics-based Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding energy was used to rank the complexes with improved accuracy, in addition to empirical-based Glide docking score. Network analysis was performed, and the identified critical residues were cross-referenced with the experimental mutagenesis data. Key findingsThe added methyl groups in the antagonist WAY-Methylated enhanced hydrophobicity, resulting in a flipped binding pose deeper in the binding pocket. Interestingly, OTR responded to the methylation by stabilizing the initial inactive conformation, decreasing fluctuations and increasing the overall secondary structural composition. Conversely, the agonist WAY-267,464 produced larger fluctuations to allow the receptor to change from the default inactive state to a state of partial activation. These transitions were further supported by the identified critical residues overlapping with experimental mutagenesis data. SignificanceThese findings provide insights into the activation mechanism of OTR by WAY-267.464 and its antagonism by WAY-Methylated.

A Fragmentation Study on Four Oligostilbenes by Electrospray Tandem Mass Spectrometry

Oligostilbenes have attracted much interest due to their intricate structures and diverse bioactivities. In this study, two stilbene dimers, (−)-7,8-cis-ε-viniferin (1) and carasiphenol A (2), and two trimers, suffruticosol A (3) and suffruticosol C (4), were investigated by electrospray ionization ion-trap time-of-flight multistage mass spectrometry (ESI-IT-TOF-MSn). Based on the MSn study, the fragmentation pathways and diagnostic ions of four oligostilbenes in both positive and negative modes were proposed. The consecutive elimination of phenol (C6H6O) and resorcinol (C6H6O2) moieties were the particular dissociation for oligostilbenes due to the presence of 1,2-diphenylethylene nucleus. The present MSn fragmentation study will provide valuable information for the fast characterization of oligostilbenes from complicated natural mixtures.Graphical

Resorcinol Functionalized Gold Nanoparticles for Formaldehyde Colorimetric Detection.

Gold nanoparticles functionalized with resorcinol moieties have been prepared and used for detecting formaldehyde both in solution and gas phases. The detection mechanism is based on the color change of the probe upon the aggregation of the nanoparticles induced by the polymerization of the resorcinol moieties in the presence of formaldehyde. A limit of detection of 0.5 ppm in solution has been determined. The probe can be deployed for the detection of formaldehyde emissions from composite wood boards.

Structure-Activity Relationship and Prediction of the Electron-Transfer Potential of the Xanthones Series.

The structure–activity relationships of 31 xanthones were analyzed by using the ferric reducing antioxidant power (FRAP) assay to determine their electron‐transfer (ET) potential. It was proven that the ET potential of xanthones was dominated by four moieties (i.e. hydroquinone moiety, 5,6‐catechol moiety, 6,7‐catechol moiety, and 7,8‐catechol moiety) and was only slightly affected by other structural features, including a single phenolic OH group, the resorcinol moiety, the transannular dihydroxy moiety, a methoxy group, a sugar residue, an isoprenyl group, a cyclized isoprenyl group, and an isopentanol group. The results could be used to predict the ET potentials of other antioxidant xanthones.

Hybrid of Resveratrol and Glucosamine: An Approach To Enhance Antioxidant Effect against DNA Oxidation.

Resveratrol exhibits various pharmacological activities, which are dependent upon phenolic hydroxyl groups. In this work, glucosamine, lipoic acid, or adamantanamine moiety was applied for attaching to ortho-position of hydroxyl group in resorcinol moiety of resveratrol (known as position-2). Antioxidant effects of the obtained hybrids were characterized using DNA oxidative systems mediated by •OH, Cu2+/glutathione (GSH), and 2,2'-azobis(2-amidinopropanehydrochloride) (AAPH), respectively. The glucosyl-appended imine and amine at position-2 of resveratrol were found to show higher inhibitory effects than other resveratrol derivatives against AAPH-induced DNA oxidation. The antioxidative effect was quantitatively expressed by stoichiometric factor ( n, the number of radical-propagation terminated by one molecule of antioxidant). The stoichiometric factors of glucosyl-appended imine and amine of resveratrol increased to 4.74 (for imine) and 4.97 (for amine), respectively, higher than that of resveratrol (3.70) and glucoside of resveratrol (3.49). It was thereby concluded that the combination of resveratrol with glucosamine at position-2 represented a novel pathway for modifying resveratrol structure in the protection of DNA against peroxyl radical-mediated oxidation.

Chemistry and Pharmacology of Artocarpin: An Isoprenyl Flavone from Artocarpus Species

Artocarpin is an isoprenyl flavone from Artocarpus species (Moraceae). Trees of the genus comprise about 50 species, and are native to tropical and subtropical Asia. First isolated from the root of A. heterophyllus (jackfruit), artocarpin has been reported in other Artocarpus species such as A. altilis, A. chempeden, A. kemando and A. maingayi. Recently, artocarpin has also been isolated from A. incisus, A. chama, A. lowii, A. anisophyllus, A. scortechinii, A. odoratissimus and A. hirsutus. It has a molecular formula of C26H28O6 and a 5,7,2’,4’-tetrahydroxylated structure with three benzene rings. Ring B has a 2’,4’-resorcinol moiety and there is a methoxy group at C-7 of ring A. At C-3 and C-6 of artocarpin are the isoprenyl substituents. Some data on the content of artocarpin in extracts and fractions of different solvents and species of Artocarpus have been presented. Other flavones prenylated at C-3 and C-6 include artelasticin, artelastofuran, cudraflavone C and norartocarpin. The inhibition of tyrosinase and melanogenesis are two skin-whitening activities of artocarpin. It protects UVB-induced skin damage. Besides its cosmeceutical activities of skin-whitening and photo protection, artocarpin possesses other pharmacological properties such as cytotoxic, anti-inflammatory, antioxidant, antimicrobial, antiandrogen, antitubercular, antiplasmodial, neuraminidase inhibitory, termiticidal and wound healing activities. In the conclusion, some research studies of interest for the future have been proposed.

Mechanistic Pathways and Identification of the Electrochemically Generated Oxidation Products of Flavonoid Eriodictyol in the Presence of Glutathione

AbstractThe metabolic oxidation pathways of dietary flavonoid eriodictyol (Er) are not very well‐probed. In the present work, the electrochemical oxidation behavior of Er was studied in aqueous Britton‐Robinson (B‐R) buffer solution using cyclic voltammetry (CV), chronoamperometry (CA), and bulk‐electrolysis (BE). The oxidation products and reaction pathways of Er in the absence and the presence of glutathione (GSH) were proposed and identified in view of the results obtained by ultra‐high‐performance liquid chromatography coupled with mass spectrometry (UPLC‐MS). In the absence of GSH, eriodictyol shows one quasi‐reversible oxidation process at E1/2=0.305 V, followed by a totally irreversible anodic peak at a more positive potential (Epa=1.05 V vs. Ag/AgCl, 3 M KCl). Putatively, the first process corresponds to the oxidation of the catechol moiety on the B ring of Er while the second one is attributed to the oxidation of the resorcinol moiety on the A ring. In the presence of GSH, however, the anodic oxidation of Er was proposed to be an ECEC‐type mechanism. The Er molecule first underwent a two‐electron oxidation coupled with loss of two‐proton to generate the corresponding quinone, which was either reduced to the original Er molecule by GSH, or further interacted with GSH to produce mono‐ and bi‐ glutathione conjugates of Er. The proposed mechanism was confirmed by digital simulation of the cyclic voltammograms.

Sugar moiety has a synergistic effect on hydroxylated xanthone for better antioxidant activity of mangiferin

The structure–antioxidant relationship of mangiferin was elucidated by means of quantum chemistry calculations. The density functional theory level of theory was used for antioxidant pharmacophore selection. According to the obtained geometry by using the DFT/B3LYP/6-31+G(d,p) values, HOMO, ionization potential, bond dissociation energy, stabilization energy, and spin density distribution, the catechol moiety is more important for the antioxidant capacity than the resorcinol moiety. However, the sugar is a strong electron-withdrawing group due to its hydrogen bond formation with the resorcinol moiety of xanthone ring. The hydrogen transfer is more important for the antioxidant activity than the electron transfer. The hydrogen abstractions in the ortho positions are more favored than the meta positions. Thus, our results show a synergistic effect between xanthone and sugar rings.

Methyl trifluoropyruvate – a new solvent for the production of fluorinated organic resorcinol–formaldehyde aerogels

Resorcinol–formaldehyde aerogels obtained in methyl trifluoropyruvate (MTFP) possess a fluorinated matrix due to the mechanism of electrophilic substitution in the resorcinol moiety with the formation of C–C bond. The use of MTFP as a solvent also substantially accelerates the formaldehyde– resorcinol interaction.

Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation

To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diarylaminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC50 values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors.