- De novo biosynthesis and whole-cell catalytic production of paracetamol on a gram scale in Escherichia coli
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The synthetic drug paracetamol is one of the most commonly used analgesic, antipyretic agents around the world. Global massive demand promoted its synthesis in large quantities. Chemical synthesis is the main approach for paracetamol production. However, the reaction process contributes toward environmental pollution, and the reaction conditions are harsh. Herein, we reported the construction of the paracetamol de novo biosynthetic pathway in Escherichia coli. Five enzymes from different microbial sources were heterologously expressed into E. coli to construct the APAP (1) producing strain PA1. Through protein engineering of ABH (4-aminobenzoate hydroxylase) and PANAT (arylamine N-acetyltransferase), enhancement of the host cell resistance to the substrate or final product, and utilizing synthetic protein scaffolds to optimize the metabolic flux, the engineered strain could produce 942.5 mg L-1 (6.24 mM) paracetamol in a fed-batch 5 L fermenter directly from glucose or glycerol, which circumvents the fossil fuel resource use. Moreover, we established a whole-cell cascade biocatalytic synthesis way to paracetamol and analogues. Using p-aminobenzoate as the substrate, 4.2 g L-1 (27.7 mM) paracetamol can be formed after 9 h (95% conversion rate). After metabolic engineering, enzyme molecular modification, and other optimizations, we created the biotransformation strategy to manufacture paracetamol on a gram scale. This study provides a promising green and efficient alternative to the traditional chemical manufacturing method.
- Hou, Feifei,Huang, Wei,Xian, Mo
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p. 8280 - 8289
(2021/11/01)
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- Hydrohalogenation of N-acetyl(aroyl)-1,4-benzoquinone monoimines
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New N-acetyl-1,4-benzoquinone monoimines alkyl-substituted in the quinoid ring were synthesized. The hydrohalogenation of N-acetyl(aroyl)-1,4-benzoquinone monoimines proceeds exclusively in keeping with the 1,4-addition. The hydrochlorination occurs along the ionic mechanism, in the hydrobromination grows the role of the radical mechanism.
- Avdeenko,Konovalova,Ludchenko,Ledeneva,Vakulenko
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scheme or table
p. 214 - 229
(2011/05/05)
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- Bisacetamide hydrochloride: A chemoselective and inexpensive N-acetylating reagent for aminophenols
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A facile and chemoselective acetylation of aminophenols using bisacetamide hydrochloride under conventional heating and microwave irradiation has been developed. Also, a rapid method for the microwave-assisted preparation of aminophenols is described herein.
- Peng, Yanqing,Song, Gonghua,Ding, Fang
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p. 2021 - 2023
(2007/10/03)
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- Therapeutic amines
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Compounds of formula I, and their pharmaceutically acceptable salts, STR1 in which R1 and R2 are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl or alkenyl; or NR1 R2 is a heterocyclic group; A is trimethylene optionally substituted by alkyl and the phenyl ring is optionally substituted by substituents such as halogeno, alkenyl, amino, cyano, ureido, alkyl, carbamoylalkyl, alkanoylamino, alkoxycarbonyl, N-alkyl-alkanoylamino, alkanoyl and amines thereof; are inhibitors of squalene synthese and hence useful in treating diseases in which a lowering of cholesterol is desirable. As well as the use of these compounds in medicine, novel compounds, processes for their preparation and pharmaceutical compositions are also referred to.
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- Novel thiopyrano[3,2-b] and cycloalkeno[1,2-b]indole derivatives with high inhibitory properties in LTB4 production
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Series of thiopyrano[3,2-b] and cycloalkeno[1,2-b]indoles were synthesized and evaluated in order to determine the necessary structural requirements for high leukotrienes biosynthesis inhibition. In vitro experiments showed that compounds 11b and 12b belonging to the second series were the most active and selective compounds on LTB4 production. Further in vivo investigations have shown additional very significant activity in the acute phorbol ester induced mouse ear swelling which is predictive of potential antipsoriatic properties.
- Kuehm-Caubere, Catherine,Caubere, Paul,Jamart-Gregoire, Brigitte,Pfeiffer, Bruno,Guardiola-Lemaitre, Beatrice,Manechez, Dominique,Renard, Pierre
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- Hydrolysis of N-Acetyl-p-benzoquinone Imines: pH Dependence of the Partitioning of a Tetrahedral Intermediate
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The hydrolysis reactions of N-acetyl-p-benzoquinone imine, 1a, and its 3,5- and 2,6-dimethyl analogues, 1b and 1c, in the pH range 0.3-10.5 are described.At pH 6.0 the carbinolamide intermediates 2a-c can be detected by 1H NMR, UV, and HPLC methods.The pH-dependent partitioning of 2a and 2c can be monitored since the reversion of these intermediates to the protonated N-acylimines 5a and 5c leads to products of the conjugate attack of Cl(-), the 3-chloroacetaminophen derivatives 4a and 4c.A mechanism for the hydrolysis of 1a-c (Scheme I) is proposed which accurately predicts the time dependence of the formation of 2 and the final hydrolysis products, the p-benzoquinones 3, and 4.The alternative O-protonation mechanism (Scheme II) is tentatively rejected on the basis of substituent effect data.The relationship of the hydrolysis reactions of 1a-c to those of ordinary imines is discussed.
- Novak, Michael,Bonham, Gayl A.,Mulero, Julio J.,Pelecanou, Maria,Zemis, Joseph N.,et al.
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p. 4447 - 4456
(2007/10/02)
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- Hydrolysis of the Model Carcinogen N-(Pivaloyloxy)-4-methoxyacetanilide: Involvement of N-Acetyl-p-benzoquinone Imine
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Results of kinetic, 1H NMR, and HPLC studies show that N-(pivaloyloxy)-4-methoxyacetanilide (1a), a model for suspected carcinogenic metabolites of phenacetin (10), decomposes predominately into N-acetyl-p-benzoquinone imine (3) in aqueous solution.The only other product isolated from the decomposition of 1a is 4-methoxyacetanilide (7), which is produced in moderate yield at pH > 6.0.The available evidence indicates that both of these materials are produced by a nitrenium ion mechanism.In aqueous solutions containing KCl at pH 1H NMR results indicate that the intermediate is a carbinolamine (8).At pH > 6.0, the decomposition of 3 becomes very complicated.At high concentrations, 3 decomposes by a non-first order path into a material which appears to be oligomeric.At sufficiently low concentrations (ca. 2.5 x 10-6 M), the decomposition of 3 returns to a first-order process.Under these conditions, the major products of the reaction are 6 and acetaminophen (4).The measured standard reduction potential for 3 of 0.978 +/- 0.001 V indicates that it is a much stronger oxidizing agent than either p-benzoquinone or p-benzoquinone monoimine.However, at this time it is not possible to determine the identity of the species responsible for the reduction of 3 into 4 in aqueous solution.
- Novak, Michael,Pelecanou, Maria,Pollack, Lee
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p. 112 - 120
(2007/10/02)
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- Solvolysis of N-Sulfonoxyacetanilides in Aqueous and Alcohol Solutions: Generation of Electrophilic Species
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A series of ring-substituted N-sulfonoxyacetanilides (1a-f) were synthesized, and their solvolysis reactions in aqueous and alcohol solvents were studied.These compounds serve as models for the carcinogenic metabolites of polynuclear aromatic amides.Kinetic and product studies yielded evidence for solvolysis via N-O bond cleavage in aqueous solution with generation of tight ion pairs and solvent-separated ion pairs.The tight ion pairs, which cannot be trapped by nucleophiles or reducing agents, give rise to o-sulfonoxyacetanilides, while the solvent-separated ion pairs can be trapped by these reagents to yield ring-substituted compounds and reduction products.The para-substituted N-sulfonoxyacetanilides yield substantial amounts of highly electrophilic p-benzoquinone imine derivatives such as 10 during solvolysis in aqueous media.In ethanol these esters solvolyze exclusively via S-O bond cleavage with apparent production of SO3.This study demonstrates that electrophilic species other than nitrenium ions can be generated during the solvolysis of N-sulfonoxy-N-arylamides.These species may play a role in the in vivo activity of these metabolites.
- Novak, Michael,Pelecanou, Maria,Roy, Ajit K.,Andronico, Anthony F.,Plourde, Francine M.,et al.
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p. 5623 - 5631
(2007/10/02)
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