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.
Preparative enantiomer separation of dichlorprop with a cinchona-derived chiral selector employing centrifugal partition chromatography and high-performance liquid chromatography: A comparative study
Gavioli, Blena,Maier, Norbert M.,Minguillon, Cristina,Lindner, Wolfgang
, p. 5837 - 5848 (2004)
A countercurrent chromatography protocol for supportfree preparative enantiomer separation of the herbicidal agent 2-(2,4-dichlorphenoxy)propionic acid (dichlorprop) was developed utilizing a purposefully designed, highly enantioselective chiral stationary-phase additive (CSPA) derived from bis-1,4-(dihydroquinidinyl)phthalazine. Guided by liquid-liquid extraction experiments, a solvent system consisting of 10 mM CSPA in methyl tert-butyl ether and 100 mM sodium phosphate buffer (pH 8.0) was identified as a suitable stationary/mobile-phase combination. This solvent system provided an ideal compromise among stationary-phase retention, enantioselectivity, and well-balanced analyte distribution behavior. Using a commercial centrifugal partition chromatography instrument, complete enantiomer separations of up to 366 mg of racemic dichlorprop could be achieved, corresponding to a sample load being equivalent to the molar amount of CSPA employed. Comparison of the preparative performance characteristics of the CPC protocol with that of a HPLC separation using a silica-supported bis-1,4-(dihydroquinidinyl)phthalazine chiral stationary phase CSP revealed comparable loading capacities for both techniques but a significantly lower solvent consumption for CPC. With respect to productivity, HPLC was found to be superior, mainly due to inherent flow rate restrictions of title CPC instrument. Given that further progress in instrumental design and engineering of dedicated, highly enantioselective CSPAs can be achieved, CPC may offer a viable alternative to CSP-based HPLC for preparative-scale enantiomer separation.
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.
A new biocatalyst for the preparation of enantiomerically pure 2-arylpropanoic acids
Kumar, Ish,Manju, Kavita,Jolly, Ravinder S.
, p. 1431 - 1434 (2001)
A new biocatalyst, a strain of Pseudomonas fluorescens MTCCB0015, is described, which produces ibuprofen, ketoprofen and flurbiprofen as enantiomerically pure (S)-2-arylpropanoic acids from their corresponding racemic esters. 2-Arylpropanoic acids are an important class of non-steroidal anti-inflammatory compounds, whose anti-inflammatory activity is mainly due to the (S)-enantiomer.
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
Access to Optically Enriched α-Aryloxycarboxylic Esters via Carbene-Catalyzed Dynamic Kinetic Resolution and Transesterification
Liu, Bin,Song, Runjiang,Xu, Jun,Majhi, Pankaj Kumar,Yang, Xing,Yang, Song,Jin, Zhichao,Chi, Yonggui Robin
, p. 3335 - 3338 (2020/04/30)
Optically active α-aryloxycarboxylic acids and their derivatives are important functional molecules. Disclosed here is a carbene-catalyzed dynamic kinetic resolution and transesterification reaction for access to this class of molecules with up to 99% yields and 99:1 er values. Addition of a chiral carbene catalyst to the ester substrate leads to two diastereomeric azolium ester intermediates that can quickly epimerize to each other and thus allows for effective dynamic kinetic resolution to be realized. The optically enriched ester products from our reaction can be quickly transformed to chiral herbicides and other bioactive molecules.
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.
New Synthesis of Known Herbicides Based on Aryloxyalkanoic Acids
Latypova,Salikhov, Sh. M.,Legostaeva, Yu. V.,Khusnitdinov,Ishmuratov, G. Yu.,Abdrakhmanov
, p. 1313 - 1318 (2018/11/21)
A new version has been proposed for the synthesis of analogs of the known herbicides mecoprop (MCPP) and dichlorprop (2,4-DP) by ozonolysis of chloro derivatives of (pent-3-en-2-yloxy)benzene.
Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
, p. 1067 - 1078 (2018/08/01)
A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
