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1.
Front Chem ; 8: 772, 2020.
Article in English | MEDLINE | ID: mdl-33102431

ABSTRACT

A preliminary study to develop a novel synthetic method for 3-aryl-5-azaisocoumarins was performed herein. The cycloisomerization of N-pyranonyl propargylamines in the AgOTf-catalyzed system efficiently afforded the desired 3-aryl-5-azaisocoumarins in a highly regioselective manner. This unprecedented method is expected as an expedient alternative synthetic route to 5-azaisocoumarins because the regioselectivity problem is circumvented, and it is easier to introduce substituents on the pyridine ring compared to previously reported intramolecular lactonization approaches.

2.
J Asian Nat Prod Res ; 22(10): 966-975, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32820958

ABSTRACT

Herein, we report a concise and efficient method for the synthesis of p-hydroxyphenyl caffeate, a novel natural caffeic acid ester derivative isolated from Wedelia trilobata. The key feature of this synthesis is the Verley-Doebner modification of the Knoevenagel condensation of the p-hydroxyphenyl malonate intermediate. The synthesized p-hydroxyphenyl caffeate enhanced interleukin 2 production by murine lymph node T cells, and suppressed interleukin 13 production by murine epidermal T cells. This implies that p-hydroxyphenyl caffeate might be a novel immunomodulatory drug candidate, specifically targeting T helper 2 cell type responses in skin diseases such as atopic dermatitis and vitiligo. [Formula: see text].


Subject(s)
Asteraceae , Wedelia , Animals , Mice , Molecular Structure
3.
Eur J Pharm Biopharm ; 130: 143-151, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29940226

ABSTRACT

The objectives of this study were to formulate microcrystals of entecavir-3-palmiate (EV-P), a palmitic acid ester of entecavir (EV), and evaluate the influence of particle size on its pharmacokinetic behavior following subcutaneous (SC) injection. Systemic toxicity and local tolerability of the hepatitis B anti-viral suspension were further evaluated in normal rats. EV-P microcrystals possessing median diameters of 2.1, 6.3, and 12.7 µm were fabricated using anti-solvent crystallization technique with polysorbate 20 and polyethylene glycol 4000 as steric stabilizer. Dissolution rate of EV-P microcrystals was controlled by adjusting the particle size, under sink condition. Pharmacokinetic profiles of 2.1 µm-sized and 6.3 µm-sized EV-P microcrystals were quite comparable (1.44 mg/kg as EV), over 46 days in rats. The absorption rate and extent of EV after SC injection of 12.7 µm-sized microcrystals were significantly retarded, due to its slower dissolution rate in aqueous media. No single-dose systemic toxicity was observed after SC injection of high dose of EV-P microcrystal suspension (30-300 mg/kg as EV). The microcrystals were tolerable in the injected site, showing mild inflammatory responses at a dose of 30 mg/kg. Therefore, the novel microcrystal system with median particle size of below 6.3 µm is expected to be a unique long-acting system of the anti-viral agent, improving patient's compliance with chronic disease.


Subject(s)
Antiviral Agents/administration & dosage , Drug Delivery Systems , Guanine/analogs & derivatives , Palmitic Acids/chemistry , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Chemistry, Pharmaceutical/methods , Crystallization , Delayed-Action Preparations , Guanine/administration & dosage , Guanine/chemistry , Guanine/pharmacokinetics , Injections, Subcutaneous , Male , Particle Size , Polyethylene Glycols/chemistry , Polysorbates/chemistry , Rats , Rats, Sprague-Dawley , Suspensions
4.
Int J Pharm ; 543(1-2): 52-59, 2018 May 30.
Article in English | MEDLINE | ID: mdl-29597034

ABSTRACT

Entecavir (EV), an anti-viral agent for hepatitis B infection, should be administered under fasted state, as intestinal absorption of this hydrophilic compound is markedly decreased under post-prandial conditions. Herein, in order to improve therapeutic adherence, a parenteral sustained delivery system was constructed, by synthesizing water-insoluble ester prodrugs of the nucleotide analogous with fatty acids. EV-3-palmitate (named EV-P), exhibited the lowest solubility in phosphate buffered saline (pH 7.4, 1.1 µg/ml), with extended release profile compared with EV, EV-3-myristate, and EV-3-stearate, was selected as a candidate to formulate drug suspension. The crystalline suspension was fabricated using anti-solvent crystallization technique, with a mean particle size of 7.7 µm. After subcutaneous (SC) injection in beagle dogs (0.43 mg/kg as EV), the plasma concentrations of EV were markedly protracted with lowered maximum plasma concentration (Cmax, 4.7 ng/ml), extended time required to reach Cmax (Tmax, 9.0 days), and lengthened elimination half-life (T1/2, 129.3 h) compared with those after oral administration (0.0154 mg/kg, Cmax, 15.4 ng/ml; Tmax, 0.01 days; T1/2, 4.1 h). The systemic exposure of the lipidic prodrug was below 0.1% compared with that of EV following SC injection, denoting that EV-P was rapidly converted into the parent compound in blood. Therefore, SC delivery of EV-P microsuspension can be an alternative to oral EV therapy, offering prolonged pharmacokinetic profile after single injection.


Subject(s)
Antiviral Agents/administration & dosage , Fatty Acids/administration & dosage , Guanine/analogs & derivatives , Prodrugs/administration & dosage , Animals , Antiviral Agents/pharmacokinetics , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Dogs , Drug Liberation , Esters , Fatty Acids/pharmacokinetics , Guanine/administration & dosage , Guanine/pharmacokinetics , Injections, Subcutaneous , Male , Prodrugs/pharmacokinetics , Suspensions
5.
Appl Environ Microbiol ; 80(9): 2754-62, 2014 May.
Article in English | MEDLINE | ID: mdl-24561591

ABSTRACT

Plants produce two flavonoid O-pentoses, flavonoid O-xyloside and flavonoid O-arabinoside. However, analyzing their biological properties is difficult because flavonoids are not naturally produced in sufficient quantities. In this study, Escherichia coli was used to synthesize the plant-specific flavonoid O-pentosides quercetin 3-O-xyloside and quercetin 3-O-arabinoside. Two strategies were used. First, E. coli was engineered to express components of the biosynthetic pathways for UDP-xylose and UDP-arabinose. For UDP-xylose biosynthesis, two genes, UXS (UDP-xylose synthase) from Arabidopsis thaliana and ugd (UDP-glucose dehydrogenase) from E. coli, were overexpressed. In addition, the gene encoding ArnA (UDP-l-Ara4N formyltransferase/UDP-GlcA C-4″-decarboxylase), which competes with UXS for UDP-glucuronic acid, was deleted. For UDP-arabinose biosynthesis, UXE (UDP-xylose epimerase) was overexpressed. Next, we engineered UDP-dependent glycosyltransferases (UGTs) to ensure specificity for UDP-xylose and UDP-arabinose. The E. coli strains thus obtained synthesized approximately 160 mg/liter of quercetin 3-O-xyloside and quercetin 3-O-arabinoside.


Subject(s)
Arabinose/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Flavonoids/metabolism , Metabolic Engineering , Xylose/metabolism , Arabidopsis/enzymology , Arabidopsis/genetics , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Biosynthetic Pathways , Carboxy-Lyases/genetics , Carboxy-Lyases/metabolism , Flavonoids/chemistry , Glycosyltransferases/genetics , Glycosyltransferases/metabolism , Uridine Diphosphate Glucose Dehydrogenase/genetics , Uridine Diphosphate Glucose Dehydrogenase/metabolism , Uridine Diphosphate Sugars/metabolism
6.
Appl Environ Microbiol ; 78(12): 4256-62, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22492444

ABSTRACT

Most flavonoids exist as sugar conjugates. Naturally occurring flavonoid sugar conjugates include glucose, galactose, glucuronide, rhamnose, xylose, and arabinose. These flavonoid glycosides have diverse physiological activities, depending on the type of sugar attached. To synthesize an unnatural flavonoid glycoside, Actinobacillus actinomycetemcomitans gene tll (encoding dTDP-6-deoxy-L-lyxo-4-hexulose reductase, which converts the endogenous nucleotide sugar dTDP-4-dehydro-6-deoxy-L-mannose to dTDP-6-deoxytalose) was introduced into Escherichia coli. In addition, nucleotide-sugar dependent glycosyltransferases (UGTs) were screened to find a UGT that could use dTDP-6-deoxytalose. Supplementation of this engineered strain of E. coli with quercetin resulted in the production of quercetin-3-O-(6-deoxytalose). To increase the production of quercetin 3-O-(6-deoxytalose) by increasing the supplement of dTDP-6-deoxytalose in E. coli, we engineered nucleotide biosynthetic genes of E. coli, such as galU (UTP-glucose 1-phosphate uridyltransferase), rffA (dTDP-4-oxo-6-deoxy-d-glucose transaminase), and/or rfbD (dTDP-4-dehydrorahmnose reductase). The engineered E. coli strain produced approximately 98 mg of quercetin 3-O-(6-deoxytalose)/liter, which is 7-fold more than that produced by the wild-type strain, and the by-products, quercetin 3-O-glucose and quercetin 3-O-rhamnose, were also significantly reduced.


Subject(s)
Biosynthetic Pathways/genetics , Escherichia coli/genetics , Escherichia coli/metabolism , Glycosides/biosynthesis , Metabolic Engineering , Quercetin/biosynthesis , Aggregatibacter actinomycetemcomitans/enzymology , Aggregatibacter actinomycetemcomitans/genetics , Escherichia coli/enzymology , Glycosyltransferases/genetics , Glycosyltransferases/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sugar Alcohol Dehydrogenases/genetics , Sugar Alcohol Dehydrogenases/metabolism
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