120-36-5Relevant articles and documents
Structural insights into the differences among lactisole derivatives in inhibitory mechanisms against the human sweet taste receptor
Nakagita, Tomoya,Matsuya, Takumi,Narukawa, Masataka,Misaka, Takumi,Kobayashi, Takuya,Ishida, Akiko,Hashimoto, Makoto,Hirokawa, Takatsugu
, (2019)
Lactisole, an inhibitor of the human sweet taste receptor, has a 2-phenoxypropionic acid skeleton and has been shown to interact with the transmembrane domain of the T1R3 subunit (T1R3-TMD) of the receptor. Another inhibitor, 2,4-DP, which shares the same molecular skeleton as lactisole, was confirmed to be approximately 10-fold more potent in its inhibitory activity than lactisole; however the structural basis of their inhibitory mechanisms against the receptor remains to be elucidated. Crystal structures of the TMD of metabotropic glutamate receptors, which along with T1Rs are categorized as class C G-protein coupled receptors, have recently been reported and made it possible to create an accurate structural model for T1R3-TMD. In this study, the detailed structural mechanism underlying sweet taste inhibition was characterized by comparing the action of lactisole on T1R3-TMD with that of 2,4-DP. We first performed a series of experiments using cultured cells expressing the sweet taste receptor with mutations and examined the interactions with these inhibitors. Based on the results, we next performed docking simulations and then applied molecular dynamics-based energy minimization. Our analyses clearly revealed that the (S)-isomers of both lactisole and 2,4-DP, interacted with the same seven residues in T1R3-TMD and that the inhibitory potencies of those inhibitors were mainly due to stabilizing interactions mediated via their carboxyl groups in the vertical dimension of the ligand pocket of T1R3-TMD. In addition, 2,4-DP engaged in a hydrophobic interaction mediated by its o-Cl group, and this interaction may be chiefly responsible for the higher inhibitory potency of 2,4-DP.
Improving the enantioselectivity of candida rugosa lipase in the kinetic resolution of racemic methyl 2-(2,4-dichlorophenoxy)propionate
Cipiciani, Antonio,Cittadini, Massimiliano,Fringuelli, Francesco
, p. 7883 - 7890 (1998)
Racemic methyl 2-(2,4-dichlorophenoxy)propionate (±)-1, was subjected to hydrolysis in water and in a series of two-phase aqueous organic media in the presence of Candida rugosa lipase (CRL). The biocatalytic material used was the commercial preparation and enzyme purified by using different procedures. The (+)-R- and (-)-S-2-(2,4-dichlorophenoxy)propionic acids (3) were obtained in excellent yield and high enantiomeric excess when the hydrolysis of (}-1 was performed in water/benzene in the presence of 2- propanol treated CRL. The kinetic resolution of (±)-1 was scaled-up.
Enantiomer separation by countercurrent chromatography using cinchona alkaloid derivatives as chiral selectors
Lindner,Franco,Oberleitner,Blanc,Maier,Minguillon
, p. 4175 - 4183 (2002)
Cinchona-derived anion-exchange type chiral selectors were used in countercurrent chromatography (CCC) for the separation of enantiomers of N-derivatized amino acids and 2-aryloxypropionicacids. The accurate optimization of the enantioseparation in terms of solvent system composition, pH values, ionic strength, and CCC operating conditions was carried out. Successful resolutions were obtained in systems such as ammonium acetate buffer/tert-amyl alcohol/methanol/heptane and ammonium acetate buffer/methyl isobutyl ketone (MIBK) or diisopropyl ether (DIPE). Different α values were obtained in CCC and HPLC for a given pair of selector/racemate. For n-(3,5-dinitrobenzoyl)-(±)-leucine and N-(3,5-dinitrobenzyloxycarbonyl)-(±)-neopentylglycine, enantioselectivity factors were lower in CCC, while for N-(3,5-dinitrobenzyloxycarbonyl)-(±)-β-phenylalan ine, α values slightly increased. No significant separation was observed for any of the of the aryloxypropionic acid derivatives tested in system containing (MIBK). In contrast, some discriminations for the enantiomers of these compounds was detected when DIPE was used in the binary system. The results exhibited the high potential of CCC as a separative separation technique.
Elucidation of the enantioselective enzymatic hydrolysis of chiral herbicide dichlorprop methyl by chemical modification
Wen, Yuezhong,Li, Chandan,Fang, Zhaohua,Zhuang, Shulin,Liu, Weiping
, p. 1924 - 1930 (2011)
Up to 25% of the current pesticides are chiral, the molecules have chiral centers, but most of them are used as racemates. In most cases, enantiomers of chiral pesticides have different fates in the environment. Knowledge of the function of amino acids of
Design, Synthesis, and Pharmacological Evaluation of Novel β2/3 Subunit-Selective γ-Aminobutyric Acid Type A (GABAA) Receptor Modulators
Stadler, Marco,Monticelli, Serena,Seidel, Thomas,Luger, Denise,Salzer, Isabella,Boehm, Stefan,Holzer, Wolfgang,Schwarzer, Christoph,Urban, Ernst,Khom, Sophia,Langer, Thierry,Pace, Vittorio,Hering, Steffen
, p. 317 - 341 (2018/11/02)
Subunit-selective modulation of γ-aminobutyric acid type A receptors (GABAAR) is considered to exert fewer side effects compared to unselective clinically used drugs. Here, the β2/3 subunit-selective GABAAR modulators valerenic acid (VA) and loreclezole (LOR) guided the synthesis of novel subunit-selective ligands with simplified structures. We studied their effects on GABAARs expressed in Xenopus laevis oocytes using two-microelectrode voltage clamp technique. Five compounds showed significantly more efficacious modulation of GABA-evoked currents than VA and LOR with retained potency and selectivity. Compound 18 [(E)-2-Cyano-3-(2,4-dichlorophenyl)but-2-enamide] induced the highest maximal modulation of GABA-induced chloride currents (Emax: 3114 ± 242%), while 12 [(Z)-3-(2,4-dichlorophenyl)but-2-enenitrile] displayed the highest potency (EC50: 13 ± 2 μM). Furthermore, in hippocampal neurons 12 facilitated phasic and tonic GABAergic inhibition, and in vivo studies revealed significantly more potent protection against pentylenetetrazole (PTZ)-induced seizures compared to VA and LOR. Collectively, compound 12 constitutes a novel, simplified, and subunit-selective GABAAR modulator with low-dose anticonvulsant activity.
A method for preparing chloro-benzene oxygen carboxylic acid (by machine translation)
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Paragraph 0071; 0073; 0074; 0076, (2019/01/08)
The invention provides a method for preparing carboxylic acid chloro-benzene oxygen, comprising the following steps: S1) phenoxy fatty alcohol in the catalyst B A and under the action of the catalyst, and the chlorinating agent to 2 bit and/or 4 bit selective chlorination reaction, to obtain chloro-benzene oxygen fatty alcohol; said catalyst A is Lewis acid; said catalyst B is C5 - 22 of the thioether, thiazole, isothiazole, thiophene or their halogenated derivatives; S2) [...] fatty alcohol and water, under the action of a catalyst, and an oxidizing agent for the selective catalytic oxidation reaction, get chloro-benzene oxygen carboxylic acid. The invention through the re-design of the process route, the catalyst and the chlorinating agent fine screening, effectively reduces the energy consumption, the selectivity of the dichloride to improve at the same time avoiding the losses of the active ingredient, the resulting chloro-benzene oxygen carboxylic acid content can be up to 98.5% or more, the total yield can be up to 99% or more. (by machine translation)
