Urushiol Derivatives Research Articles

Natural resin-derived urushiol-based phosphorylation derivative towards flame-retardant and mechanically strong epoxy resin

Biobased flame retardants have attracted great attention owing to their environmental friendliness and easy availability. Urushiol, extracted from natural resin-raw lacquer, has been capped with diphenylphosphoryl chloride to afford a biobased flame retardant, namely urushiol-based phosphonate (U-DC). As an additive this material is effective in reducing flammability while maintaining good mechanical strength for epoxy resins (EP). Impressively, an EP/9 %U-DC blend exhibits a UL-94 V-0 rating, and an LOI of 37.1 % for combustion. Further, compared to that for EP, the peak heat release rate (pHRR) and total heat release (THR) for the EP/9 %U-DC blend was lower by 40.5 % and 26.6 %. Through analysis of volatile products formed and char residue produced during polymer degradation, a mode of flame retardant action for U-DC has been proposed. Further, EP/U-DC blends display better mechanical properties than those of unmodified EP. Tensile strength of EP containing 7 wt% U-DC (81.6 MPa) is greater than that for unmodified EP (64.4 MPa). This may be ascribed to the presence of abundant rigid benzene units in U-DC and chain entanglement between the long side chain of U-DC and the epoxy macromolecular chain. These observations provide a basis for the utilization of new urushiol derivatives in the production of high-performance EP.

Design, synthesis, and biological evaluation of novel urushiol derivatives as potentclass I histone deacetylase inhibitors.

In the present study, a novel series of 11 urushiol-based hydroxamic acid histone deacetylase (HDAC) inhibitors were designed, synthesized, and biologically evaluated. Compounds 1-11 exhibited good to excellent inhibitory activities against HDAC1/2/3 (IC50: 42.09-240.17 nM) and HDAC8 (IC50: 16.11-41.15 nM) in vitro, with negligible activity against HDAC6 (>1409.59 nM). Considering HDAC8, docking experiments revealed some important features contributing to inhibitory activity. According to western blot analysis, select compounds could notably enhance the acetylation of histone H3 and SMC3 but not-tubulin, indicating their privileged structure is appropriate for targeting class I HDACs. Furthermore, antiproliferation assays revealed that six compounds exerted greater in vitro antiproliferative activity against four human cancer cell lines (A2780, HT-29, MDA-MB-231, and HepG2, with IC50 values ranging from 2.31-5.13 µM) than suberoylanilide hydroxamic acid; administration of these compounds induced marked apoptosis in MDA-MB-231 cells, with cell cycle arrest in the G2/M phase. Collectively, specific synthesized compounds could be further optimized and biologically explored as antitumor agents.

Urushiol derivatives as biomass-based photocatalysts for the transition-metal-free synthesis of 1,2-amino alcohols

We report the design and synthesis of urushiol derivatives as biomass-based catalysts for photocatalytic, transition-metal-free access to 1,2-amino alcohols.

Acaricide activity of extract and an isolated compound of Lithraea brasiliensis on Rhipicephalus microplus and selectivity actions against a non-target organism

Rhipicephalus microplus, known as the cattle tick, is a cause of great economic losses for dairy cattle farming because of its high frequency of occurrence and the difficulty in controlling it. This research characterized the chemical profile and evaluated the in vitro toxicity of crude Lithraea brasiliensis extract and its isolated compound against acaricide-resistant and acaricide-susceptible R. microplus strains. Acaricidal activity was evaluated using a larval immersion test and the selectivity against non-target organisms was assessed on Artemia salina assay. The chemical investigation by high-performance liquid chromatography coupled with mass spectrometry (i.e., HPLC-MS) analysis showed the presence of hydrolysable tannins as well as urushiol derivatives. Column chromatography (CC) was carried out on the extract to obtain fractions and an isolated compound. The extract exhibited significant activity against acaricide-resistant (LC50 0.64 mg/mL) and acaricide-susceptible (LC50 0.76 mg/mL) strains of R. microplus larvae. The isolated compound from the extract (urushiol II), exhibited LC50 of 1.11 mg/mL for acaricide-resistant larvae. For acute toxicity in A. salina, the extract showed LC50>100 μg/mL. Thus, our findings represent the first effort to demonstrate the potential of L. brasiliensis extract and urushiol II as potential natural acaricides to replace or to be integrated into the conventional control of R. microplus larvae.

Novel C15 Triene Triazole, D-A Derivatives Anti-HepG2, and as HDAC2 Inhibitors: A Synergy Study.

A series of novel C15 urushiol derivatives were designed by introducing a pechmann structure and F-, Cl-, and Br-nitro substituents with different electronic properties into its alkyl side chain, as well as a triazolyl functional group in its aromatic oxide. Their chemical structures were determined based on the analysis of the NMR (nuclear magnetic resonance) spectroscopic and mass spectrometric data. The results showed that compound 4 exhibited a strong inhibition of the HepG2 cell proliferation (half maximal inhibitory concentration (IC50): 2.833 μM to human hepatocellular carcinoma (HepG2), and 80.905 μM to human normal hepatocytes (LO2)). Furthermore, it had an excellent synergistic effect with levopimaric acid. The nitrogen atom of the triazole ring formed a hydrogen-bonding interaction with Gly103, Gly154, and Tyr308, which made compound 4 bind to histone deacetylase (HDAC)2 more tightly. One triazole ring and His33 formed a π–π stacking effect; the other, whose branches were deep into the pocket, further enhanced the interaction with HDAC2. Meanwhile, compound 4 involved a hydrophobic interaction with the residues Phe210 and Leu276. The hydrophobic interaction and π–π stacking provided powerful van der Waals forces for the compounds.

Molecular identification of Asian lacquers from different trees using Py‐GC/MS and ToF‐SIMS

Traditional Asian lacquers are natural products with highly valued properties, including beauty, gloss, and durability. Pyrolysis‐gas chromatography/mass spectrometry is the technique of choice to study insoluble polymeric lacquer films. In the present study, pyrolysis‐gas chromatography/mass spectrometry results showed that the pyrolysis products of lacquer films were different for all of the studied trees, with urushiol derivatives detected in Toxicodendron vernicifluum from China, Japan, and Korea; laccol in Toxicodendron succedaneum from Vietnam; and thitsiol in Gluta usitata from Myanmar. Time‐of‐flight secondary ion mass spectrometry (ToF‐SIMS) was also used to characterize the Asian lacquers, avoiding the time‐consuming and destructive processes of other techniques. The ToF‐SIMS spectra provided structural characterization of a series of urushiol, laccol, and thitsiol derivatives for T vernicifluum from China, Japan, and Korea; T succedaneum from Vietnam; and G usitata from Myanmar, respectively. To differentiate the ToF‐SIMS results for the different Asian lacquer films, principal component analysis was used because it can extract differences in the spectra and indicate what peaks are responsible for these differences. The results indicate that lacquer films from different lacquer trees can be very different. Therefore, ToF‐SIMS with principal component analysis is suitable for the characterization and differentiation of Asian lacquer films in cultural heritage applications.

Synthesis and Evaluation of C15 Triene Urushiol Derivatives as Potential Anticancer Agents and HDAC2 Inhibitor.

A series of C15 triene urushiol derivatives were synthesized and evaluated for their anti-HepG2 aggregation in vitro. The results indicated that all compounds had an effective anti-HepG2 vitality. Compound 1 was a potent inhibitor of HepG2 with IC50 of 7.886 μM and 150 μM against LO2. Moreover, compound 1 increased the apoptosis of HepG2. Compound 1’s thiol sulfur formed hydrogen bonding interactions with Gly154 and Tyr308, respectively, and made it bound more closely to HDAC2. In addition, it also formed hydrophobic interactions with the residues His33, Pro106, Val107, Gly154, Phe155, and His183, and was provided with a strong van der Waals force by the hydrophobic action.

Design, virtual screening, molecular docking and molecular dynamics studies of novel urushiol derivatives as potential HDAC2 selective inhibitors

Three series of novel urushiol derivatives were designed by introducing a hydroxamic acid moiety into the tail of an alkyl side chain and substituents with differing electronic properties or steric bulk onto the benzene ring and alkyl side chain. The binding affinity toward HDAC2 of the compounds was screened by Glide docking. The best scoring compounds were processed further with molecular docking, MD simulations and binding free energy studies to analyze the binding modes and mechanisms. Six compounds, 21, 23, 10, 19, 9 and 30, gave Glide scores of −7.9 to −8.5, which revealed that introducing F, Cl, triazole, benzamido, formamido, hydroxyl or nitro substituents onto the benzene ring could increase binding affinity significantly. Molecular docking studies revealed that zinc ion coordination, hydrogen bonding and hydrophobic interactions contributed to the high calculated binding affinities of these compounds toward HDAC2 and that His145, His146, Gly154, Glu103, His183, Asp104, Tyr308 and Phe155 contributed favorably to the binding. MD simulations and binding free energy studies showed that all complexes possessed good stability as characterized by low RMSDs; low RMSFs of residues, moderate hydrogen bonding and zinc ion coordination; and low values of binding free energies. van der Waals and electrostatic interactions provided major contributions to the stability of these complexes. These results show the promising potential of urushiol derivatives as potent HDAC2 binding lead compounds.

Novel urushiol derivatives as HDAC8 inhibitors: rational design, virtual screening, molecular docking and molecular dynamics studies

Three series of novel urushiol derivatives were designed by introducing a hydroxamic acid moiety into the tail of an alkyl side chain and substituents with differing electronic properties or steric bulk onto the benzene ring and alkyl side chain. The compounds’ binding affinity toward HDAC8 was screened by Glide docking. The highest-scoring compounds were processed further with molecular docking, MD simulations, and binding free energy studies to analyze the binding modes and mechanisms. Ten compounds had Glide scores of −8.2 to −10.2, which revealed that introducing hydroxy, carbonyl, amino, or methyl ether groups into the alkyl side chain or addition of –F, –Cl, sulfonamide, benzamido, amino, or hydroxy substituents on the benzene ring could significantly increase binding affinity. Molecular docking studies revealed that zinc ion coordination, hydrogen bonding, and hydrophobic interactions contributed to the high calculated binding affinities of these compounds toward HDAC8. MD simulations and binding free energy studies showed that all complexes possessed good stability, as characterized by low RMSDs, low RMSFs of residues, moderate hydrogen bonding and zinc ion coordination and low values of binding free energies. Hie147, Tyr121, Phe175, Hip110, Phe119, Tyr273, Lys21, Gly118, Gln230, Leu122, Gly269, and Gly107 contributed favorably to the binding; and Van der Waals and electrostatic interactions provided major contributions to the stability of these complexes. These results show the potential of urushiol derivatives as HDAC8 binding lead compounds, which have great therapeutic potential in the treatment of various malignancies, neurological disorders, and human parasitic diseases.

Antimicrobial activity of the synthesized non-allergenic urushiol derivatives.

Synthesized urushiol derivatives possessing different carbon atomic length in the alkyl side chain inhibited the growth of food spoilage and pathogenic microorganisms. Particularly, non-allergenic 3-pentylcatechol showed a broad antimicrobial spectrum on an agar plate. Most food spoilage and pathogenic microorganisms were sensitive to urushiol derivatives in the liquid culture. The morphologies of the microorganisms were changed after treatment of 3-pentylcatechol.

Modification of Urushiol Derivatives by Liquid Crystal Epoxy Resin

Urushiol derivatives have vast potentials for using as coating materials. However, the cured coatings are quite brittle, limiting their applications. In this study, urushiol-furfural (UFUR) was chosen as an example of urushiol derivatives and a liquid crystal (LC) epoxy resin, tetramethylbiphenyl diglycidyl ether (TMBPDE), was for the first time utilized to modify UFUR. Fourier transform infrared spectroscopy and solid-state13C nuclear magnetic resonance showed the reactions between TMBPDE and UFUR after the UFUR/TMBPDE composite resin was cured. Differential scanning calorimetry analysis showed that theTgsignificantly increased after the addition of TMBPDE. Thermogravimetry analysis indicated that the cured UFUR/TMBPDE composite resin exhibited increasing thermodecomposition temperature as the TMBPDE concentration increased, indicating its great potential for high temperature applications. Moreover, the presence of TMBPDE enhanced the toughness of UFUR as observed by impact test and reflected in the morphologies observed from SEM images of fracture surfaces. It would also be novel and effective to modify urushiol derivatives by the LC polymer.

Preparation and Characterization of Urushiol Methylene Acetal Derivatives with Various Degrees of Unsaturation in Alkyl Side Chain

Preparation of urushiol derivatives was carried out in response to the drug industry’s increasing demand for new synthetic anticancer agents. Urushiol methylene acetal derivatives were synthesized in high yields by reaction of urushiol with methylene chloride under the catalytic action of NaOH. Four kinds of urushiol methylene acetal monomers were separated by silica-gel column and preparative HPLC, and their structures were elucidated by extensive spectroscopic methods, including 1D-NMR and 2D-NMR (1H,13C-NMR,1H-1HCOSY, HSQC, and HMBC) as well as TOF-MS. They were identified as 3-[pentadecyl] benzene methylene ether (compound 1), 3-[8′-pentadecatrienyl] benzene methylene ether (compound 2), 3-[8′,11′-pentadecatrienyl] benzene methylene ether (compound 3), and 3-[8′,11′,14′-pentadecatrienyl] benzene methylene ether (compound 4). This research provides a theoretical reference for exploration of these interesting and potentially bioactive compounds.

Nonallergenic urushiol derivatives inhibit the oxidation of unilamellar vesicles and of rat plasma induced by various radical generators

Urushiols consist of an o-dihydroxybenzene (catechol) structure and an alkyl chain of 15 or 17 carbons in the 3-position of a benzene ring and are allergens found in the family Anacardiaceae. We synthesized various veratrole (1,2-dimethoxybenzene)-type and catechol-type urushiol derivatives that contained alkyl chains of various carbon atom lengths, including –H, –C1H3, –C5H11, –C10H21, –C15H31, and –C20H41, and investigated their contact hypersensitivities and antioxidative activities. 3-Decylcatechol and 3-pentadecylcatechol displayed contact hypersensitivity, but the other compounds did not induce an allergic reaction, when the ears of rats were sensitized by treatment with the compounds every day for 20 days. Catechol-type urushiol derivatives (CTUDs) exerted very high radical-scavenging activity on the 1,1-diphenyl-2-picrylhydrazyl radical and inhibited lipid peroxidation in a methyl linoleate solution induced by 2,2′-azobis(2,4-dimethylvaleronitrile) (AMVN). However, veratrole-type urushiol derivatives did not scavenge or inhibit lipid peroxidation. CTUDs also acted as effective inhibitors of lipid peroxidation of the egg yolk phosphatidylcholine large unilamellar vesicle (PC LUV) liposome system induced by various radical generators such as AMVN, 2,2′-azobis(2-amidino-propane) dihydrochloride, and copper ions, although their efficiencies differed slightly. In addition, CTUDs suppressed formation of cholesteryl ester hydroperoxides in rat blood plasma induced with copper ions. CTUDs containing more than five carbon atoms in the alkyl chain showed excellent lipophilicity in a n-octanol/water partition experiment. These compounds also exhibited high affinities to the liposome membrane using the ultrafiltration method of the PC LUV liposome system. Therefore, CTUDs seem to act as efficient antioxidative compounds against membranous lipid peroxidation owing to their localization in the phospholipid bilayer. These results suggest that nonallergenic CTUDs act as antioxidants to protect against oxidative damage of cellular and subcellular membranes.

Analysis of Urushiols by Liquid Chromatography/Atmospheric Pressure Chemical Ionization‐Ion Trap Mass Spectrometry

Urushiol derivatives in a natural polymeric paint (urushi), obtained from Korean tapping lacquer trees were separated by reverse phase liquid chromatography and analyzed by on‐line atmospheric pressure chemical ionization ion trap mass spectrometry (LC/APCI‐ITMS). The molecular weight and molecular structure information for each peak were obtained from full scan spectrum and collision induced dissociation (CID) spectrum, respectively. Each urushiol isomer was identified, based on the pseudomolecular ion, the pattern of product ions by CID of pseudomolecular ions, and the elution order of urushiols on the C18 stationary phase. The elution order was the result of other researchers by a preparative separation and NMR. For composition analysis, the relative peak area ratios of components over total urushiol constituents were calculated from each peak area of urushiol components.

Quantitative structure‐activity relationships for skin sensitization potential of urushiol analogues

The relative alkylation index (RAI), a theoretically derived parameter intended to quantify the relative extent of carrier haptenation resulting from a given dose of a given sensitizer, has previously been successfully applied to the analysis of relative sensitization potential and dose-response data for a variety of contact allergens which are directly electrophilic. Here the RAI concept is applied to analysis of data on compounds related to urushiol (i.e., 3-substituted catechols), the naturally occurring mixture of allergens responsible for contact allergy to poison ivy and poison oak. These allergens are believed to act as pro-electrophiles, being oxidized to electrophilic orthoquinones in vivo. It is found that the various types of urushiol derivatives fit the same sort of RAI-sensitization relationships as expected theoretically and as found previously with direct acting electrophiles. There is evidence that in many cases, the test conditions were such that overload effects, whereby the degree of sensitization induced decreases with increasing carrier haptenation, applied. It is also concluded that the question as to the relative sensitization potencies of the naturally occurring urushiols remains open. The commonly held view that with these materials, sensitization potential increases with increasing unsaturation in the 3-hydrocarbyl chain of the 3-hydrocarbyl catechols, is based on evidence that is capable of alternative interpretation.

ChemInform Abstract: Synthesis of Urushiol Derivatives by the Fries Rearrangement.

AbstractDie photoinduzierte Fries‐Umlagerung der ungesättigten Ester (Ib)‐(Id) führt ‐ analog der (bekannten) Reaktion von (Ia) zu (IIIa) ‐ zu den o‐Umlagerungsprodukten (IIIb)‐(IIId); neben (IIIc) bzw. (IIId) entstehen auch entsprechende p‐Produkte (IVc) bzw. (IVd).

Synthesis of Urushiol Derivatives by the Fries Rearrangement

The photo- and thermal-induced Fries rearrangement reactions of some unsaturated aliphatic esters of benzene-1,2-diol (catechol) have been studied. Photorearrangement and thermal rearrangement favoured products correspond to ortho and para migration respectively, but the thermal rearrangement may be accompanied by indanones, chromanones and other products which were formed through subsequent side reactions of the double bond. Photoinduced Fries rearrangement of 2-hydroxy-phenyl oleate followed by reduction of the carbonyl group gave monosubstituted catechol derivatives with an unsaturated C18 side chain in either the 3- or the 4-position. These alkenylcatechol derivatives are related in structure to chemical components isolated from oriental lacquer trees, such as urushiol from Rhus verniciflua or thitsiol from Melanorrhoea usitata.

Immunologic Studies of Poisonous Anacardiaceae: I. Production of Tolerance and Desensitization to Poison Ivy and Oak Urushiols Using Esterified Urushiol Derivatives in Guinea Pigs

The development of contact sensitivity to poison ivy urushiol in Hartley guinea pigs was inhibited by i.v. injection of the diacetate esters of poison ivy and oak urushiols into guinea pigs 2 weeks prior to attempted sensitization with homologous antigen. Immune tolerance to urushiols of poison ivy and oak developed in 80% or more of the treated animals and persisted for the duration of the study, 8 weeks. The tolerance was immunologically specific for urushiols since the tolerant animals were sensitizable to the unrelated sensitizer 2, 4-dinitrochlorobenzene. Guinea pigs already sensitive to urushiol were also desensitized or hyposensitizied by i.v. injection of urushiol acetates in successively increasing doses. After receiving the equivalent of 16 mg of poison ivy and oak urushiols in the acetate form over a period of 12 weeks, 54% of a group of guinea pigs were desensitized to poison ivy. all of the remaining 46% of the guinea pigs still sensitive to poison ivy were substantially hyposensitized (no longer responded to 1.5 or 0.80 microgram test doses of PDC). A control group of guinea pigs was not hyposensitized by injection of vehicle, and remained highly sensitive throughout the 15 week study. The majority of treated animals (less than 80%) were also hyposensitized to poison sumac and cashew nut shell liquid allergens.