- Design, synthesis, and evaluation of phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents
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In this paper, we designed and synthesized a series of novel phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents. The best compound 10 had relatively high affinity for the GABAA receptor and low affinity for thirteen other off-target receptors. In three animal models (mice, rats, and rabbits), compound 10 exerted potent hypnotic effects (HD50 = 5.2 mg/kg in rabbits), comparable duration of the loss of righting reflex (LORR), and significant shorter recovery time (time to walk) than propanidid. Furthermore, compound 10 (TI = 18.1) showed higher safety profile than propanidid (TI = 14.7) in rabbits. Above results suggested that compound 10 may have predictable and rapid recovery profile in anesthesia.
- Qi, Zhaoyang,Li, Ziying,Zhu, Mo,Zhang, Xiaohua,Zhang, Guisen,Zhuang, Tao,Chen, Yin,Huang, Ling
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- Specific Residues Expand the Substrate Scope and Enhance the Regioselectivity of a Plant O-Methyltransferase
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An isoeugenol 4-O-methyltransferase (IeOMT), isolated from the plant Clarkia breweri, can be engineered to a caffeic acid 3-O-methyltransferase (CaOMT) by replacing three consecutive residues. Here we further investigated functions of these residues by constructing the triple mutant T133M/A134N/T135Q as well as single mutants of each residue. Phenolics with different chain lengths and different functional groups were investigated. The variant T133M improves the enzymatic activities against all tested substrates by providing beneficial interactions to residues which directly interact with the substrate. Mutant A134N significantly enhanced the regioselectivity. It is meta-selective or even specific against most of the tested substrates but para-specific towards 3,4-dihydroxybenzoic acid. The triple mutant T133M/A134N/T135Q benefits from these two mutations, which not only expand the substrate scope but also enhance the regioselectivity of IeOMT. On the basis of our work, regiospecific methylated phenolics can be produced in high purity by different IeOMT variants.
- Tang, Qingyun,Bornscheuer, Uwe T.,Pavlidis, Ioannis V.
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p. 3227 - 3233
(2019/07/04)
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- Phenylacetic acid ester compound and use thereof
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The invention relates to a phenylacetate compound as shown in a general formula (I) and a pharmaceutical composition containing the phenylacetate compound, as well as application in anesthesia and sedation.
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Paragraph 0059; 0065; 0066
(2019/03/02)
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- Biological evaluation of natural and synthesized homovanillic acid esters as inhibitors of intestinal fatty acid uptake in differentiated Caco-2 cells
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With raising prevalence of obesity, the regulation of human body fat is increasingly relevant. The modulation of fatty acid uptake by enterocytes represents a promising target for body weight maintenance. Recent results demonstrated that the trigeminal active compounds capsaicin, nonivamide, and trans-pellitorine dose-dependently reduce fatty acid uptake in differentiated Caco-2 cells as a model for the intestinal barrier. However, non-pungent alternatives have not been investigated and structural determinants for the modulation of intestinal fatty acid uptake have not been identified so far. Thus, based on the previous results, we synthesized 23 homovanillic acid esters in addition to the naturally occurring capsiate and screened them for their potential to reduce intestinal fatty acid uptake using the fluorescent fatty acid analog Bodipy-C12 in differentiated Caco-2 cells as an enterocyte model. Whereas pre-incubation with 100 μM capsiate did not change fatty acid uptake by Caco-2 enterocytes, a maximum inhibition of ?47% was reached using 100 μM 1-methylpentyl-2-(4-hydroxy-3-methoxy-phenyl)acetate. Structural analysis of the 24 structural analogues tested in the present study revealed that a branched fatty acid side chain, independent of the chain length, is one of the most important structural motifs associated with inhibition of fatty acid uptake in Caco-2 enterocytes. The results of the present study may serve as an important basis for designing potent dietary inhibitors of fatty acid uptake.
- Lieder, Barbara,Hans, Joachim,Hentschel, Fabia,Geissler, Katrin,Ley, Jakob
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- Electrochemical Lignin Degradation in Ionic Liquids on Ternary Mixed Metal Electrodes
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Lignin is the second most abundant natural polymer and a promissing feedstock for the generation of renewable aromatic chemicals. We present an fundamental approach for the electrocatalytic cleavage of lignin dissolved in a recoverable, inexpensive ionic liquid using mixed metal oxide electrodes of different compositions. The distribution of depolymerization products generated by electrochemical oxidation were analyzed by means of mass spectrometry. The distribution and yield of the cracked species was found to depended strongly on the implemented metal catalyst and therefore offers the potential to tailor the amount and composition of the low molecular weight cleavage products. This approach could help to provide a more sustainable valorization of lignin for the potential production of high value aromatic compounds due to synergistic effects.
- Rauber, Daniel,Dier, Tobias K.F.,Volmer, Dietrich A.,Hempelmann, Rolf
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p. 189 - 208
(2017/12/18)
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- Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach
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Lamellarin K is a complex pyrrole natural product and member of the lamellarin family – a group of natural products known for their potent biological activities, such as, antiproliferative activity and inhibition of P-gp mediated drug efflux pumps. We herein describe the synthesis of the N-benzyl-des-D ring analogue of lamellarin K using a route that centres on an acyl-Claisen reaction to eventually prepare a highly-functionalised 1-aryl-4-methyl-1,4-diketone. Paal-Knorr pyrrole formation using this diketone undergoes auto-oxidation to give a fully-substituted 5-formyl pyrrole which was converted into the natural lactone B ring. Antiproliferative testing of the N-benzyl-des-D ring analogue gave an IC50 of 2.63?μM against the MDA-MB-231 breast cancer cell line.
- Dittrich, Nora,Pilkington, Lisa I.,Leung, Euphemia,Barker, David
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p. 1881 - 1894
(2017/03/11)
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- METHOD FOR BIOCATALYTIC SYNTHESIS OF SUBSTITUTED OR UNSUBSTITUTED PHENYLACETIC ACIDS AND KETONES HAVING ENZYMES OF MICROBIAL STYRENE DEGRADATION
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The present invention relates to a method for the biocatalytic synthesis of substituted and unsubstituted phenylacetic acids and ketones from styrenes and bicyclic aromatic hydrocarbons using enzymes of microbial styrene degradation in a whole-cell sensor, as well as a kit for the biocatalytic synthesis of substituted and unsubstituted phenylacetic acids and ketones containing a whole-cell catalyst and the use of the method, wherein the method comprises the following steps: a) providing at least one type of whole-cell catalyst, containing genes which code for the enzymes of styrene degradation and are under the functional control of a regulatable promoter, in an aqueous component,b) activating the whole-cell catalyst with an inducer and/or an activator, leading to expression of the gene,c) bringing the activated whole-cell catalyst into contact with a substrate,d) isolating the reaction products produced, which are advantageously not further metabolized by the whole-cell cat and advantageously accumulate in the aqueous component.
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- New synthesis of vanillin by degradation of lignin in presence of functional basic ionic liquid
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The degradation of lignin catalyzed by functional basic ionic liquid was investigated. Higher conversion of lignin and simpler degradation product composition were obtained in the presence of basic ionic liquid, comparing with that under traditional NaOH
- Yi, Fengping,Jiang, Xiaoyan,Niu, Jihua,Zhang, Lirong,Wang, Zhen
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p. 885 - 888
(2015/02/05)
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- The effect of hydroxytyrosol and its nitroderivatives on catechol-O-methyl transferase activity in rat striatal tissue
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Hydroxytyrosol is a well-known phenolic compound with antioxidant properties that is found in virgin olive oil. Studies have shown that virgin olive oil has neuroprotective effects in rats; thus the purpose of the present study was to investigate the neuroprotective effect of hydroxytyrosol in rats. Additionally, this study aimed to investigate the neuroprotective potential of a homologous series of compounds with better lipophilic profiles in order to increase the assortment of compounds with a putative effect against Parkinson's disease (PD). In this context, the inhibition of catechol-O-methyl transferase (COMT) activity by hydroxytyrosol, nitrohydroxytyrosol, nitrohydroxytyrosol acetate and ethyl nitrohydroxytyrosol ether was investigated by measuring intracellular dopamine and its metabolite levels in the corpus striatum by high performance liquid chromatography (HPLC) with electrochemical detection. The animals received an acute (single dose; 20 mg kg-1; i.p.) or chronic (one daily dose for 5 days; 20 mg kg-1; i.p.) treatment of hydroxytyrosol and its nitroderivatives. For comparison, a commercial COMT inhibitor, Ro 41-0960, was also included. Our data show that acute and chronic systemic administration of these compounds produced a clear and statistically significant increase in the intracellular levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid. The increase in dopamine levels was very similar to the increase seen with Ro 41-0960 treatment. The effect of chronic treatment was stronger than that of acute treatment. With respect to the intracellular level of homovanillic acid, Ro 41-0960 produced a statistically significant decrease which it was not observed when hydroxytyrosol and its nitroderivatives were systemically administered. However, the chronic homovanillic acid treatment effect was stronger than the acute treatment. The results suggest that these compounds could inhibit COMT activity.
- Gallardo, Elena,Madrona, Andrs,Palma-Valds, Roco,Trujillo, Mariana,Espartero, Jos Luis,Santiago, Marti
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p. 61086 - 61091
(2015/02/19)
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- 2-Diazo-1-(4-hydroxyphenyl)ethanone: A versatile photochemical and synthetic reagent
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α-Diazo arylketones are well-known substrates for Wolff rearrangement to phenylacetic acids through a ketene intermediate by either thermal or photochemical activation. Likewise, α-substituted p-hydroxyphenacyl (pHP) esters are substrates for photo-Favorskii rearrangements to phenylacetic acids by a different pathway that purportedly involves a cyclopropanone intermediate. In this paper, we show that the photolysis of a series of α-diazo-p- hydroxyacetophenones and p-hydroxyphenacyl (pHP) α-esters both generate the identical rearranged phenylacetates as major products. Since α-diazo-p-hydroxyacetophenone (1a, pHP N2) contains all the necessary functionalities for either Wolff or Favorskii rearrangement, we were prompted to probe this intriguing mechanistic dichotomy under conditions favorable to the photo-Favorskii rearrangement, i.e., photolysis in hydroxylic media. An investigation of the mechanism for conversion of 1a to p-hydroxyphenyl acetic acid (4a) using time-resolved infrared (TRIR) spectroscopy clearly demonstrates the formation of a ketene intermediate that is subsequently trapped by solvent or nucleophiles. The photoreaction of 1a is quenched by oxygen and sensitized by triplet sensitizers and the quantum yields for 1a-c range from 0.19 to a robust 0.25. The lifetime of the triplet, determined by Stern-Volmer quenching, is 31 ns with a rate for appearance of 4a of k = 7.1 × 10 6 s-1 in aq. acetonitrile (1:1 v:v). These studies establish that the primary rearrangement pathway for 1a involves ketene formation in accordance with the photo-Wolff rearrangement. Furthermore we have also demonstrated the synthetic utility of 1a as an esterification and etherification reagent with a variety of substituted α-diazo-p- hydroxyacetophenones, using them as synthons for efficiently coupling it to acids and phenols to produce pHP protect substrates. The Royal Society of Chemistry and Owner Societies.
- Senadheera, Sanjeewa N.,Evans, Anthony S.,Toscano, John P.,Givens, Richard S.
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p. 324 - 341
(2014/02/14)
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- DEPOLYMERIZATION OF LIGNIN USING SOLID ACID CATALYSTS
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The invention provides for a process for the depolymerization of lignin in an inert atmosphere to result in substituted phenolic monomer compounds. The process is catalysed by heterogeneous solid acid catalysts and is carried out in batch or continuous mode.
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Page/Page column 6; 7
(2012/12/13)
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- Substituted Isoquinolinones and Quinazolinones
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The invention relates to substituted nitrogen containing bicyclic heterocycles of the formula (I) wherein Z is CH2 or N—R4 and X, R1, R2, R4, R6, R7 and n are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of MDM2 and/or MDM4, or variants thereof.
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Page/Page column 72
(2011/10/10)
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- P-Hydroxyphenacyl photoremovable protecting groups Robust photochemistry despite substituent diversity
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A broadly based investigation of the effects of a diverse array of substituents on the photochemical rearrangement of p-hydroxyphenacyl esters has demonstrated that common substituents such as F, MeO, CN, CO2R, CONH2, and CH3 have little effect on the rate and quantum efficiencies for the photo-Favorskii rearrangement and the release of the acid leaving group or on the lifetimes of the reactive triplet state. A decrease in the quantum yields across all substituents was observed for the release and rearrangement when the photolyses were carried out in buffered aqueous media at pHs that exceeded the ground-state pKa of the chromophore where the conjugate base is the predominant form. Otherwise, substituents have only a very modest effect on the photoreaction of these robust chromophores.
- Givens, Richard S.,Stensrud, Kenneth,Conrad, Peter G.,Yousef, Abraham L.,Perera, Chamani,Senadheera, Sanjeewa N.,Heger, Dominik,Wirz, Jakob
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scheme or table
p. 364 - 384
(2011/06/22)
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- Conversion of dehydrodiferulic acids by human intestinal microbiota
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Plant cell wall associated dehydrodiferulic acids (DFA) are abundant components of cereal insoluble dietary fibers ingested by humans. The ability of human intestinal microbiota to convert DFA was studied in vitro by incubating 8-O-4- and 5-5-coupled DFA with fecal suspensions. 8-O-4-DFA was completely degraded by the intestinal microbiota of the majority of donors, yielding homovanillic acid, 3-(3,4-dihydroxyphenyl)propionic acid, and 3,4-dihydroxyphenylacetic acid as the main metabolites. The transient formation of ferulic acid and presumably 3-(3-hydroxy-4-methoxyphenyl)pyruvic acid suggests an initial cleavage of the ether bond. In contrast to 8-O-4-DFA, the 5-5-coupled DFA was not cleaved into monomers by any of the fecal suspensions. Only the side chains were hydrogenated and the methoxy groups were demethylated. The cleavage of DFA by human intestinal microbiota, which depended on their coupling type, may affect both the bioavailability of DFA and the degradability of DFA-coupled fiber in the gut.
- Braune, Annett,Bunzel, Mirko,Yonekura, Reiko,Blaut, Michael
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experimental part
p. 3356 - 3362
(2010/06/16)
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- Syntheses of NAMDA derivatives inhibiting NO production in BV-2 cells stimulated with lipopolysaccharide
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Sixteen derivatives of N-acetyl-3-O-methyldopamine (NAMDA), an inhibitor of BH4 synthesis, were designed and synthesized. The ability of these derivatives to inhibit NO and BH4 production by lipopolysaccharide- stimulated BV-2 microglial cells was determined. While NAMDA at 100 μM inhibited NO and BH4 production by only about 20%, its catecholamide 8, indole 23 derivative, 13, and N-acetyl tetrahydroisoquinoline 25 inhibited the NO production by >50% at the same concentration. In particular, 13 and 25 inhibited both NO and BH4 production to similar degrees, which suggested that these compounds might inhibit NO production by blocking BH 4-dependent dimerization of the newly synthesized iNOS monomer.
- Jai, Woong Seo,Srisook, Ekaruth,Hyo, Jin Son,Hwang, Onyou,Cha, Young-Nam,Dae, Yoon Chi
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p. 3369 - 3373
(2007/10/03)
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- New Phototriggers: Extending the p-Hydroxyphenacyl π-π* Absorption Range
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(Matrix Presented) Introducing 3-methoxy or 3,5-dimethoxy substituents on the 4-hydroxyphenacyl (pHP) photoremovable protecting group has been explored with two excitatory γ-amino acids, L-glutamic acid and γ-amino butyric acid (GABA). These substituents significantly extend the absorption range of the pHP chromophore, e.g., the tail of absorption bands of 2a,b extend above 400 nm, well beyond the absorptions of aromatic amino acids and nucleotides. Irradiation releases the amino acids with rate constants of ~107 s-1 and appearance efficiencies (Φapp) of 0.03-0.04. The photoproducts are formed through the pHP excited triplet and are primarily products of photoreduction and photohydrolysis. 1a,b also rearranged to the phenylacetic acid 3.
- Conrad II, Peter G.,Givens, Richard S.,Weber, J?rg F. W.,Kandler, Karl
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p. 1545 - 1547
(2007/10/03)
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- Reactivity of ferulic acid and its derivatives toward hydrogen peroxide and peracetic acid
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The reactions of ferulic acid and its derivatives with hydrogen peroxide and peracetic acid in lignin-retaining bleaching conditions have been investigated to determine their susceptibility to oxidative degradation. The conjugated side chain of ferulic acid and its etherified or esterified derivative was shown to be fairly stable, especially to hydrogen peroxide. The major reaction was trans-cis isomerization that possibly involved a radical mechanism but did not cause bond cleavage. The peracetic acid reaction increased the rate of trans-cis isomerization and was also accompanied by a minor cleavage of the side chain. Esterification did not have a substantial effect on the reactivity of ferulic acid, but 4-O- etherification significantly stabilized it against these two oxidants. By contrast, aldehyde substitution tremendously enhanced the susceptibility of the cinnamyl side chain to oxidative degradation, as evidenced by an intensive degradation of coniferaldehyde.
- Pan, George X.,Spencer, Liam,Leary, Gordon J.
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p. 3325 - 3331
(2007/10/03)
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- A new system for the reduction of 4-hydroxymandelic acids
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We describe a new reduction of 4-hydroxymandelic acids which is easy to perform with available, cheap and environmentally clean reagents.The reduction of these acids is an important method for the synthesis of (4-hydroxyphenyl)-acetic acids.The new reducing system is constituted of sodium bisulfite or dithionite in catalytic quantities and formic acid in slight excess. - Keywords: 4-hydroxymandelic acid; reduction; sodium bisulfite; sodium dithionite; formic acid
- Vallejos, Jean Claude,Legrand, Olivier,Christidis, Yani
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p. 101 - 104
(2007/10/03)
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- Preparation process for hydroxyphenylacetic acids
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Preparation process for a hydroxyphenylacetic acid of formula (I): STR1 where R=H, alkyl or alkoxyl as well as its salts, in which the corresponding free or salified hydroxymandelic acid of formula (II): STR2 in which R has the meaning given previously and M=H, K or an ammonium group is reacted in an aqueous medium, at a temperature greater than or equal to 50° C., with formic acid in the presence of catalytic quantities of an oxygenated derivative of sulphur having a degree of oxidation from 2 to 4, in order to obtain the hydroxyphenylacetic acid of formula (I) which is isolated or, if desired, is salified according to the usual methods and the hydroxyphenylacetic acid thus obtained.
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- BIOTRANSFORMATION OF 6-GINGEROL AND 6-SHOGAOL BY ASPERGILLUS NIGER
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6-Gingerol and 6-shogaol, the pungent constituents of Zingiber officinalis were biotransformed by Aspergillus niger. 6-Gingerol was converted to the corresponding primary alcohol as major product although a keto group is present in the molecule whereas the double bond and keto group of 6-shogaol were reduced and the terminal methyl group was further oxidized to afford a ketoalcohol and a diol.All metabolites obtained from both substrates are tasteless.The structures of the metabolites have been established by spectral evidence.The metabolic pathways of both substrates will be discussed.
- Takahashi, Hironobu,Hashimoto, Toshihiro,Noma, Yoshiaki,Asakawa, Yoshinori
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p. 1497 - 1500
(2007/10/02)
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- 3-methoxy-4-hydroxyphenylglycol fluorescence polarization immunoassay
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The present invention is directed to a fluoroescence polarization immunoassay for determining the 3-methoxy-4-hydroxyphenylglycol content in body fluids, to the various components needed for preparing and carrying out such an assay, and to methods of making these components. Specifically, tracers, immunogens and antibodies are disclosed, as well as methods for preparing them. The assay is conducted by measuring the degree of polarization of plane polarized light that has been passed through a sample containing antiserum and tracer.
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- Expedient Synthesis of Polyhydroxyisoflavones
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A general and direct synthesis of polyhydroxy isoflavones (3-phenyl-4H-1-benzopyran-4-ones) starting from the corresponding unprotected phenols and arylacetic acids is described.The aryl rings may carry additional alkyl, methoxy and/or halogeno groups.Intermediate polyhydroxydeoxybenzoins (1,2-diphenylethanones) can also be isolated in good yields.
- Waehaelae, Kristiina,Hase, Tapio A.
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p. 3005 - 3008
(2007/10/02)
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- Process for preparation of 3-alkoxy-4-hydroxyphenylacetic acid
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3-Alkoxy-4-hydroxyphenylacetic acid useful as intermediate for preparation of pharmaceuticals is prepared by catalytic reduction with hydrogen using a palladium catalyst of corresponding 3-alkoxy-4-hydroxymandelic acid occurring as the reaction product between 2-alkoxyphenol and glyoxylic acid at high conversion and yield.
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