Dihydroxyl Groups Research Articles

An Efficient Strategy for Protecting Dihydroxyl Groups of Catechols

A novel strategy for protecting dihydroxyl groups of catechols has been developed. Base-mediated cyclizations of catechols with 1,3-dibromopropane provided the corresponding benzo[b]1,4-dioxepans, and herefrom the protecting group was easily cleaved by aluminum chloride. The preparation of the antibacterial and antifungal agent 4-(2-aminothiazol-4-yl)benzene-1,2-diol from catechol reliably verified its availability amenable to various harsh reaction conditions.

Synthesis of partially biobased polymer-bearing reactive epoxy groups in the side chains by radical copolymerization of limonene oxide with methyl acrylate

A radical copolymerization behavior of limonene oxide and methylacrylate was investigated, by which a partially biobased polymer-bearing reactive epoxy groups in the side chains was obtained in 43 % yield in the maximum. Degree of LO incorporation into the copolymer was determined to be 34–37 % when 5.0 mol % of 2,2′-azobis(isobutyronitrile) was employed, despite initial feed ratios. Reactivity of the epoxy groups in the side chains was investigated by two different methods. One is ring-opening of the epoxy groups with benzyl thiol, giving the corresponding polymer with β-hydroxyl sulfide moieties in 95 % yield. Another one is hydrolyzation of the epoxy groups in HCl aqueous solution at room temperature, providing a quantitative formation of the dihydroxyl groups in the side chains.

Molecular Docking, Kinetics Study, and Structure–Activity Relationship Analysis of Quercetin and Its Analogous as Helicobacter pylori Urease Inhibitors

It was disclosed in our group for the first time that the flavonoids in Lonicera japonica Thunb. are related to its therapy for gastric ulcer. Based on this finding, 20 flavonoids were selected for Helicobacter pylori urease inhibitory activity evaluation, and quercetin showed excellent potency with IC(50) of 11.2 ± 0.9 μM. Structure-activity relationship analysis revealed that removal of the 5-, 3-, or 3'-OH in quercetin led to a sharp decrease in activity. Thus, 3- and 5-OH as well as 3',4'-dihydroxyl groups are believed to be the key structural characteristics for active compounds, which was supported by the molecular docking study. Meanwhile, the results obtained from molecular docking and enzymatic kinetics research strongly suggested that quercetin is a noncompetitive urease inhibitor, indicating that quercetin may be able to tolerate extensive structural modification irrespective of the shape of the active site cavity and could be used as a lead candidate for the development of novel urease inhibitors.

Isolation of Bilberry Anthocyanidin 3-Glycosides Bearing ortho-Dihydroxyl Groups on the B Ring by Forming an Aluminum Complex and Their Antioxidant Activity

Bilberry anthocyanin bearing an ortho-dihydroxyl group on the B ring was selectively isolated by complex formation with flavocommelin and aluminum ions (Al(3+)). The interaction between the anthocyanins, flavocommelin, and Al(3+) might have happened in a manner similar to rigid supramolecules, such as commelinin, protocyanin, and other complex pigments. Complex blue pigment (CP, 8.85 ± 0.26 mg) with Al(3+) was formed from 18.6 mg (15 μmol) of bilberry pigment, 18.2 mg (30 μmol, 2.0 equiv) of flavocommelin, and 0.03 mL of 0.5 M aluminum chloride aqueous solution (15 μmol, 1.0 equiv), yielding 36.5 ± 0.7% recovery of anthocyanins in the complex after precipitation by ethanol. Consequently, anthocyanins bearing ortho-dihydroxyl groups on the B rings (delphinidin 3-glycosides, cyanidin 3-glycosides, and petunidin 3-glycosides) predominating (98.0 ± 0.2%) in the complex were selectively isolated in a dose-dependent manner by the addition of Al(3+), increasing the antioxidative activity of the mixture of anthocyanins.

3',4'-Dihydroxyl Groups in Luteolin are Important for Its Inhibitory Activities against ADAMTS-4

A disintegrin and metalloprotease with thrombospondin domains (ADAMTS) are a member of peptidase and involved in processing of von Willebrand factor as well as cleavage of aggrecan, versican, brevican and neurocan. Among 19 subfamilies of human ADAMTS, ADAMTS-4 is a zinc-binding metalloprotease and is a famous therapeutic target for arthritis. It has been reported that a flavonoid luteolin shows inhibitory activity against ADMATS-4. In this study, we verified that luteolin is a potent inhibitor of ADAMTS-4 and probed the molecular basis of its action. On the basis of a docking study, we proposed a binding model between luteolin and ADAMTS-4 in which 3',4'-dihydroxyl groups in luteolin formed hydrogen bonding with ADMATS-4 and these interactions are important for its inhibitory activity against ADAMTS-4.

Theoretical and experimental studies on the structure-antioxidant activity relationship of synthetic 4-methylcoumarins

The development of antioxidants as useful drugs for the treatment of neurodegenerative diseases such as Alzheimer’s is extremely challenging in medicinal chemistry. Coumarins have attracted great attention as possible therapeutic tools against oxygen radicals in human degenerative diseases. In order to establish the possible structure-antioxidant activity relationship, a series of twenty four 4-methylcoumarin derivatives were examined by employing reducing power measurements, and comparison with bond dissociation enthalpy and ionization potential calculations. Based on the reducing potency of 4-methylcoumarin derivatives with respect to trolox, these compounds were classified into five groups as “most active”, “more active”, “moderately active”, “less active” and “inactive” derivatives. The presence of hydroxyl groups is an essential requirement for the activity, and substitution of hydroxyl groups by methoxy groups leads to non-active derivatives. The results revealed that dihydroxyl groups in the ortho position show a better antioxidant activity with respect to dihydroxyl groups in the meta position. This is ascribed to the ability to construct more stable 4-methylcoumarin radical intermediates by rearrangement of intra-molecular hydrogen bonding. Our findings indicate that other important factors to enhance the antioxidant activity of coumarins are the number of hydroxyl groups, the presence of ester substitutions and a thiono functional group on the pyrone ring. However, bond dissociation enthalpy and ionization potential calculations alone are not sufficient to identify the best antioxidant structures. As a result, chemical and functional properties of molecules such as 4-methylcoumarins should be examined as a whole entity, considering all substitutions versus a single substitution to design functional compounds with good antioxidant activity.

Study on Scale Inhibition Performance of Polyaspartic Acid Derivatives with Dihydroxyl Group on CaCO<sub>3</sub>

An environment-friendly and multifunctional agent for industry circulation cooling water, polyaspartic acid derivatives with dihydroxyl group(DHPAP) was synthesized in aqueous solution. The FTIR spectrum of DHPAP was analyzed. Static experiments were carried out to validate scale inhibition performance of DHPAP. The scale inhibition ratios exceed 90% when 8 and 10 mg/L DHPAP under solution temperatures of 80 and 60°C, respectively. The scale inhibition ratios increase by increasing the DHPAP concentration with 6 and 8 mg/L under heating times of 10 and 6h, respectively. And the scale inhibition ratios are over 90%.

Effects of red wine flavonoid components on biomembranes and cell proliferation

Effects of red wine flavonoid components on biomembranes and cell proliferation Hironori TsuchiyaDepartment of Dental Basic Education, Asahi University School of Dentistry, Mizuho, Gifu, JapanBackground: In order to understand the antiproliferative effect of red wine in mechanistic terms, the membrane interactions of flavonoid components and their related structures were compared using liposomal biomimetic membranes prepared with different phospholipids and cholesterol.Methods and results: A series of fluorescence polarization measurements revealed that anthocyanidins, flavones, flavonols, flavanones, flavanonols, isoflavones, catechins, and chalcones interact with biomimetic membranes in a structure-dependent manner to decrease their fluidity at concentrations of 1–10 µM by preferentially acting in the deeper regions of the lipid bilayers. In the structure and membrane interactivity relationship, greater membrane-interacting potency was associated with a 3-hydroxyl group and a double bond between the 2-carbon and 3-carbon of the C ring, 3’,4’-dihydroxyl groups of the B ring, and 5,7-dihydroxyl groups of the A ring. Cyanidin, quercetin, and (–)-epigallocatechin gallate meet these structural requirements, and were effective in inhibiting the proliferation of tumor cells, showing inhibition rates of 16.4% and 35.4%, 23.3% and 74.3%, and 31.3% and 75.5%, respectively, after culture for 24 and 48 hours. These antiproliferative flavonoids simultaneously decreased the membrane fluidity of tumor cells depending on culture time. The rank order of cell membrane rigidification [(–)-epigallocatechin gallate > quercetin > cyanidin] was consistent with inhibition of cell proliferation.Conclusion: Membrane interaction is very likely to underlie the antiproliferative effects of wine flavonoids. Membrane-interactive flavonoid components would contribute to the functionality of red wine.Keywords: red wine, flavonoid, membrane interaction, fluidity change, antiproliferative effect

Structural characterization of chitosan and oxidized carboxymethyl cellulose based freeze-dried films

The conversion of dihydroxyl groups to dialdehyde by periodate oxidation is a useful method widely used in derivatization of cellulose. Periodate oxidation is a highly specific reaction to convert 1,2-dihydroxyl groups to paired aldehyde groups without significant side reactions. This reaction cleaves the C2–C3 bond; the resulting compound is the dialdehyde cellulose (DAC). These aldehyde groups of carboxymethyl cellulose interact with amino group of chitosan and their interaction results in the formation Schiff’s base with enhanced properties of both the polymers, i.e., of chitosan and carboxymethyl cellulose. Interaction of chitosan and oxidized carboxymethyl cellulose (OCMC) has been carried out with three combinations, i.e., 5, 10, and 15 wt% OCMC with rest of chitosan in 2% lactic acid solution. This new compound is covalently crosslinked which has been analyzed by various techniques like FTIR, TGA, XRD, and SEM.

Inhibition Kinetics of Flavonoids on Yeast α-Glucosidase Merged with Docking Simulations

Flavonoids, also called vitamin P, are widely distributed in plants fulfilling many functions. Yeast α-glucosidase (YAGH; EC 3.2.1.20), as extensively used target protein for screening bioactive compounds from medicine plants, was selected to explore the possible mechanisms of multiple biological function of flavonoids. The results in this study indicated that flavonoids, as mixed-type inhibitors, quenched the intrinsic fluorescence of YAGH by a mixed fluorescence quenching mechanism. The interaction information between flavonoids and YAGH was analyzed using a flexible docking method (AutoDock) and showed that 3', 4' dihydroxyl groups of B ring and 3-OH of C ring played a more important role in the inhibition activity than other hydroxyl groups, because the 3', 4' dihydroxyl groups of B ring directly interacted with the active-site residues of YAGH to inhibit enzyme activity and 3-OH of C ring seemed to be necessary to maintain the proper binding orientation of flavonoid molecules, thereby making the hydroxyl groups of B ring interact with active-site residues tightly in the hydrophobic pocket of YAGH. The results supply a basis for understanding the mechanisms of multiple biological functions of flavonoids.

Synthesis of flavonoids and their effects on aldose reductase and sorbitol accumulation in streptozotocin-induced diabetic rat tissues.

Aldose reductase, the key enzyme of the polyol pathway, and oxidative stress are known to play important roles in the complications of diabetes. A drug with potent inhibition of aldose reductase and oxidative stress, therefore, would be a most promising drug for the prevention of diabetic complications. The purpose of this study was to develop new compounds with these dual-effects through synthesis of chalcone derivatives and by examining the structure-activity relationships on the inhibition of rat lens aldose reductase as well as on antioxidant effects. A series of 35 flavonoid derivatives were synthesized by Winget's condensation, oxidation, and reduction of appropriate acetophenones with appropriate benzaldehydes. The inhibitory activity of these derivatives on rat lens aldose reductase and their antioxidant effects, measured using Cu2+ chelation and radical scavenging activities on 1,1-diphenyl-picrylhydrazyl in-vitro, were evaluated. Their effect on sorbitol accumulation in the red blood cells, lenses and sciatic nerves of streptozotocin-induced diabetic rats was also estimated. Among the new flavonoid derivatives synthesized, those with the 2',4'-dihydroxyl groups in the A ring such as 2,4,2',4'-tetrahydroxychalcone (22), 2,2',4'-trihydroxychalcone (11), 2',4'-dihydroxy-2,4-dimethylchalcone (21) and 3,4,2',4'-tetrahydroxychalcone (18) were found to possess the highest rat lens aldose reductase inhibitory activity in-vitro, their IC50 values (concentration of inhibitors giving 50% inhibition of enzyme activity) being 1.6 x 10(-7), 3.8 x 10(-7), 4.0 x 10(-7) and 4.6 x 10(-7) M, respectively. All of the chalcones tested except 3, 18, 23 with o-dihydroxy or hydroquinone moiety showed a weak free radical scavenging activity. In the in-vivo experiments, however, compound 18 with o-dihydroxy moiety in the B ring showed the strongest inhibitory activity in the accumulation of sorbitol in the tissues. It also showed the strongest activity in transition metal chelation and free radical scavenging activity. Of the 35 4,2'-dihydroxyl and 2',4'-dihydroxyl derivatives of flavonoid synthesized, including chalcone, flavone, flavanone, flavonol and dihydrochalcone, some chalcone derivatives synthesized were found to possess aldose reductase inhibition and antioxidant activities in-vitro as well as inhibition in the accumulation of sorbitol in the tissues in-vivo. 3,4,2',4'-Tetrahydroxychalcone (18, butein) was the most promising compound for the prevention or treatment of diabetic complications.

Peroxynitrite scavenging activity of lithospermate B from Salvia miltiorrhiza.

Peroxynitrite (ONOO-) is produced by the reaction of superoxide (O2-) with nitric oxide. ONOO- damages proteins through nitration or oxidation. For protection from ONOO- induced protein modifications, ONOO- scavengers should be supplemented. Evidence was obtained that lithospermate B extracted from Salvia miltiorrhiza showed the strongest scavenging activity among its constituents. Its ONOO- scavenging activity is via an electron donation mechanism. A dihydroxyl group and a double bond seem to be essential structure requirements. The data from the experiments further confirmed a protective effect of lithospermate B on bovine serum albumin and low-density lipoprotein against ONOO-. This study demonstrated that lithospermate B with hydroxyl groups and double bonds exerts an anti-nitration effect by scavenging ONOO-.

Electrochemical oxidation of the synthetic anthocyanin analogue 4-methyl-7,8-dihydroxyflavylium salt

The oxidation of the synthetic flavylium 4-methyl-7,8-dihydroxyflavylium (analysed for the first time using electrochemical tools) was studied and compared with kuromanin, an anthocyanin present in raspberry Rubus idaeus, using cyclic and square voltammetry. Most studies were done at pH 1 where the dominant species is the flavylium cation. This pH also corresponds to the highly acidic environment of the stomach. For kuromanin, the electrochemical signal is due to the oxidation of the catechol 3′,4′-dihydroxyl groups on ring B and corresponds to a two-electron two-proton reversible reaction coupled to an irreversible homogeneous chemical reaction. A similar behaviour was found for the synthetic flavylium. However, the electrochemical signal can only be due to the oxidation of the o-dihydroxy groups in ring A since no such groups are present on ring B. The oxidation occurs at a potential more favourable than that of the natural compound. This fact may be relevant as to a possible antioxidant role of the synthetic analogues.

Square-wave and cyclic voltammetry of epicatechin gallate on glassy carbon electrode

The mechanism of electrochemical oxidation of (−)-epicatechin (EC) and (−)-epicatechin gallate (ECG) on a glassy carbon electrode was investigated over a wide range of conditions, using cyclic and square-wave voltammetry. Electrochemical behavior of gallic acid has been studied as well, in order to elucidate the influence of catechol and galloyl groups on the overall electrochemical response of ECG. The first oxidation peak of both catechins, ECG and EC, originates primarily from the oxidation of the catechol 3′,4′-dihydroxyl groups. The oxidation of galloyl group in the molecule of ECG constitutes only a minor component of the response, and causes the shift of the ECG peak potential (ca. 20 mV) towards more positive values when compared with the peak potential of EC. The oxidation of the catechol group is a two electron two proton reaction. After successive scans, the oxidation products of EC and ECG adsorb at the electrode surface, forming a polymeric film that undergoes reversible oxidation at a lower potential than the catechol group.

Study on fisetin–aluminium(III) interaction in aqueous buffered solutions by spectroscopy and molecular modeling

Spectroscopic (UV/visible and IR) and theoretical studies were used to assess relevant interaction of fisetin, a tetrahydroxylated flavone molecule, and trivalent aluminium in a wide range of buffered aqueous solutions. The chelation sites, stoichiometry, stability and the dependence of the complexes structures on pH and aluminium/fisetin mole ratios were defined. Obtained results implicated successive formation of two complexes with aluminium(III)-fisetin stoichiometries of 1:1 and 2:1. Considering the fisetin molecular structure, results of vibrational analysis and theoretical calculations, it is possible to implicate 3-hydroxyl-4-carbonyl and 3'4'-dihydroxyl groups as those with the possible chelating power. The equilibrium geometries were optimized in vacuum at the B3LYP/6-31G(d) level of theory, which predict structural modifications between the ligand molecule in free state and in the complex structure. The theoretical model has been validated by both vibrational and electronic spectroscopies.

Studies on depigmenting activities of dihydroxyl benzamide derivatives containing adamantane moiety

Six diphenolic compounds containing adamantane moiety were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in melan-a cells. The inhibitory activity of 4-adamantyl resorcinol 1 was similar to that of 4- n-butyl resorcinol in both assays. However, dihydroxyl benzamide derivatives 6a–e showed different inhibitory patterns. All derivatives significantly suppressed the cellular melanin formation without tyrosinase inhibitory activities. These behaviors indicated that the introduction of amide bond changes the binding mode of dihydroxyl groups to tyrosinase. Among derivatives, 6d (3,4-dihydroxyl compound) and 6e (2,3-dihydroxyl compound) showed stronger inhibitory activities (IC 50 = 1.25 μM and 0.73 μM, respectively) as compared to 4- n-butyl resorcinol (IC 50 = 21.64 μM) and hydroquinone (IC 50 = 3.97 μM). This study showed that the position of dihydroxyl substituent at aromatic ring is important for the intercellular inhibition of melanin formation, and also amide linkage and adamantane moiety enhance the inhibition.

Synthesis and Conformational Analysis of Novel 2', 3'-Didehydo-2', 3'-dideoxy-4'-selenonucleosides

The structure of 2',3'-didehydro-2',3'-dideoxynucleosides (d4Ns) was applied to design the novel bioisosteric 4'-seleno-d4Ns as potential inhibitors of human immunodeficiency virus reverse transcriptase (HIV RT). Conversion of 2',3'-dihydroxyl groups of 4'-selenoribofuranosyl pyrimidines into the olefin was accomplished by treatment of cyclic 2',3'-thiocarbonate with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine.

Structural requirements for the flavonoid fisetin in inhibiting fibril formation of amyloid β protein

Fisetin (3,3′,4′,7-tetrahydroxyflavone) has been found to be neuroprotective, induce neuronal differentiation, enhance memory, and inhibit the aggregation of the amyloid β protein (Aβ) that may cause the progressive neuronal loss in Alzheimer's disease. The diverse collection of biological activities of this compound may lead to a new type of therapeutic drug for Alzheimer's disease. As the first step to design even more effective drugs based upon the structure of fisetin, the present study investigated the structural requirements for the anti-amyloidogenic activity of fisetin by comparing the effects of several structurally related flavonoids on Aβ fibril formation in vitro. Aβ1-42 (20 μM) and the flavonoids were incubated for 0–48 h at 37 °C, and fibril formation was quantitatively determined by the thioflavin T fluorescence assay. Among ten flavonoids tested, fisetin, 3′,4′,7-trihydroxylflavone, 3,3′,4′-trihydroxyflavone, luteolin, quercetin and myricetin inhibited Aβ fibril formation. On the other hand, 3,3′,7-trihydroxyflavone, 5-deoxykaempferol, chrysin and kaempferol enhanced Aβ fibril formation. These results suggest that the 3′,4′-dihydroxyl group, but not the 3- or 7-hydroxyl group, is essential for the inhibitory effect of fisetin on Aβ fibril formation.

PH dependency of ligand binding to cellobiohydrolase 1 (Cel7A): Affinity, selectivity and inhibition for designed propranolol analogues

The affinity and enantioselectivity have been determined for designed propranolol derivatives as ligands for Cel7A by capillary electrophoresis (CE) at pH 7.0. These results have been compared to measurements at pH 5.0. In agreement with previous studies, the affinity increased at the higher pH. However, the affinity was not as dependent of the ligand structure at pH 7.0 as at pH 5.0, and the selectivity was generally decreased. Instead, at pH 7.0, the changes in binding were mainly dependent on the presence of additional dihydroxyl groups, indicating an increased importance of the electrostatic interactions. To evaluate the pH dependent variations in binding, changes in both the ligand and in the enzyme had to be taken into account. To ensure that the ligands had the same charge in all measurements, p Ka-values of all compounds were determined. The ligand–protein interaction has also been studied by inhibition experiments at both pHs to evaluate the specific binding to the active site when competing with the substrate p-nitrophenyl lactoside ( pNPL). With support of docking computations we propose a hypothesis on the effect of the ligand structure and pH dependency of the binding and selectivity of amino alcohols to Cel7A.

Nitric acid promoted formation of an N-confused porphyrin-derived porphodimethene and a violinoid

The nitration of free-base N -confused porphyrin led to a novel 5,10-meso-dihydroxy- N -confused porphodimethene and an open-ring N -confused violinoid. The results support nitration occurring first, followed by nucleophilic addition of a hydroxyl group and a parallel reaction of oxygenolysis to cause the ring-opening. The nitro group substituted at the inner carbon of the inverted pyrrole ring is located on both the porphodimethene and violinoid. In the case of the porphodimethene, two dihydroxyl groups with υ( OH ) at 3404 cm−1 are arranged in a syn conformation at the same side with the nitro group. The violinoid exhibits υ( C = O ) at 1659 cm−1. NMR and structure determination suggest that oxygenolysis occurs selectively at the C=C bond between the α-pyrrole and meso carbon closest to the amino NH of the inverted pyrrole ring. The single crystal structure of porphodimethene gave a 50% disorder between the peripheral nitrogen and carbon atom on the inverted pyrrole ring, while a dimeric structure assembled through hydrogen bonding interactions was observed in the crystal lattice of the violinoid.