6160-80-1Relevant academic research and scientific papers
Chirality influence of zaltoprofen towards UDP-glucuronosyltransferases (UGTs) inhibition potential
Jia, Lin,Hu, Cuimin,Wang, Haina,Liu, Yongzhe,Liu, Xin,Zhang, Yan-Yan,Li, Wei,Wang, Li-Xuan,Cao, Yun-Feng,Fang, Zhong-Ze
, p. 359 - 363 (2015)
Abstract Zaltoprofen (ZLT) is a nonsteroidal antiinflammation drug, and has been clinically employed to treat rheumatoid arthritis, osteoarthritis, and other chronic inflammatory pain conditions. The present study aims to investigate the chirality influence of zaltoprofen towards the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation system was employed to investigate the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT isoforms. The inhibition difference capability was observed for the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT1A8 and UGT2B7, but not for other tested UGT isoforms. (R)-zaltoprofen exhibited noncompetitive inhibition towards UGT1A8 and competitive inhibition towards UGT2B7. The inhibition kinetic parameters were calculated to be 35.3 μM and 19.2 μM for UGT1A8 and UGT2B7. (R)-zaltoprofen and (S)-zaltoprofen exhibited a different inhibition type towards UGT1A7. Based on the reported maximum plasma concentration of (R)-zaltoprofen in vivo, a high drug-drug interaction between (R)-zaltoprofen and the drugs mainly undergoing UGT1A7, UGT1A8, and UGT2B7-catalyzed glucuronidation was indicated. Chirality 27:359-363, 2015.
A new synthetic route to 4-methylumbelliferyl-β-D-glucopyranosiduronic acid (MUG)
López-López, Miguel A.,Balbuzano-Deus, Alexander,Rodríguez-Domínguez, Juan C.,Hernández, Miriam Mesa,Villalobo, Anais Fernández,Reyes, Yulianela Ibarra,Kirsch, Gilbert
, p. 649 - 651 (2007)
A synthetic route to prepare 4-methylumbelliferyl-β-D- glucopyranosiduronic acid (MUG) from 4-methylumbelliferyl-β-D- glucopyranoside (MUGluc) was developed. The primary hydroxyl group in MUGluc was protected by tritylation followed by acetylation of secondary hydroxyls. The triphenylmethyl group was selectively removed by treatment with iodine-methanol in benzene and the free hydroxyl was transformed into the carboxylic acid by phase-transfer oxidation with sodium hypochlorite and TEMPO as catalyst. Finally, the acetate groups were removed by reaction with barium methoxide in methanol to afford the MUG with an overall yield of 37% from the MUGluc. Georg Thieme Verlag Stuttgart.
Enzymatic Synthesis of Bioactive O-Glucuronides Using Plant Glucuronosyltransferases
Yue, Tian,Chen, Ridao,Chen, Dawei,Liu, Jimei,Xie, Kebo,Dai, Jungui
, p. 6275 - 6284 (2019/06/13)
Many O-glucuronides exhibiting various pharmacological activities have been found in nature and in drug metabolism. The glucuronidation of bioactive natural products or drugs to generate glucuronides with better activity and druggability is important in drug discovery and research. In this study, by using two uridine diphosphate (UDP)-dependent glucuronosyltransferases (GATs, UGT88D4 and UGT88D7) from plants, we developed two glucuronidation approaches, pure enzyme catalysis in vitro and recombinant whole-cell catalysis in vivo, to efficiently synthesize bioactive O-glucuronides by the glucuronidation of natural products. In total, 14 O-glucuronides with different structures, including flavonoids, anthraquinones, coumarins, and lignans, were obtained, 7 of which were new compounds. Furthermore, one of the biosynthesized O-glucuronides, kaempferol-7-O-β-d-glucuronide (3a), potently inhibited protein tyrosine phosphatase (PTP) 1B with an IC50 value of 8.02 × 10-6 M. Some of the biosynthesized O-glucuronides also exhibited significant antioxidant activities.
Synthesis method for Beta-glucuronidase precipitation type fluorometric substrate
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Paragraph 0054; 0060-0063, (2019/06/07)
The invention discloses a synthesis method for a Beta-glucuronidase precipitation type fluorometric substrate based on 2-(benzothiazole-2'-yl)-4-bromophenol. The synthesis method comprises the following three steps of reaction: (1) glycosylation reaction; (2) aromatic cyclization reaction; (3) protecting group removal reaction. The yield of each step of reaction in the synthesis method can reach the medium level or more and even up to more than 90 percent, the reaction conversion rate of materials with high prices or preparation costs is relatively high, the total yield of the three steps canreach 37 percent, moreover, the reaction condition is mild, and the synthesis method is easy to implement. Furthermore, the step of glycosylation reaction and the step of protecting group removal reaction in the synthesis method can be applied.
Based on 4 - methyl [...] synthesis method of a plurality of glycoside
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, (2018/10/11)
The invention discloses a method for synthesizing various glucosides on a basis of 4-methylumbelliferone. According to the invention, a glycosyl donor peracetyl saccharide and a glycosyl acceptor 4-methylumbelliferone are subjected to a glycosylation reaction under room temperature or under heating with dichloromethane or 1,2-dichloroethane as a solvent and with the combined effect of Lewis acid boron trifluoride ethyl ether and organic alkali triethylamine or pyridine; and protecting groups are removed, such that various glucosides based on 4-methylumbelliferone can be obtained. The glucosides include 4-methylumbelliferone-beta-D-glucopyranosiduronide, 4-methylumbelliferone-beta-D-glucopyranoside, 4-methylumbelliferone-beta-D-xylopyranoside, 4-methylumbelliferone-beta-D-ribofuranoside, 4-methylumbelliferone-alpha-D-galactopyranoside, and 4-methylumbelliferone-alpha-D-mannopyranoside. The method is simple, and can produce a beta or alpha single-configuration target. A glycosylation reaction yield can reach 17-93%.
An improved helferich method for the α/β-stereoselective synthesis of 4-methylumbelliferyl glycosides for the detection of microorganisms
Wei, Xianhu,Ma, Yanxia,Wu, Qingping,Zhang, Jumei,Cai, Zhihe,Lu, Mianfei,Ferro, Vito
, p. 21681 - 21699 (2016/01/25)
An improved Helferich method is presented. It involves the glycosylation of 4-methyl-umbelliferone with glycosyl acetates in the presence of boron trifluoride etherate combined with triethylamine, pyridine, or 4-dimethylaminopyridine under mild conditions, followed by deprotection to give fluorogenic 4-methylumbelliferyl glycoside substrates. Due to the use of base, the glycosylation reaction proceeds more easily, is uncommonly α- or β-stereoselective, and affords the corresponding products in moderate to excellent yields (51%-94%) under appropriate conditions.
The Escherichia coli glucuronylsynthase promoted synthesis of steroid glucuronides: Improved practicality and broader scope
Ma, Paul,Kanizaj, Nicholas,Chan, Shu-Ann,Ollis, David L.,McLeod, Malcolm D.
supporting information, p. 6208 - 6214 (2014/08/05)
A library of steroid glucuronides was prepared using the glucuronylsynthase derived from Escherichia coli β-glucuronidase, followed by purification using solid-phase extraction. A representative range of steroid substrates were screened for synthesis on t
UDP-glucuronic acid binds first and the aglycone substrate binds second to form a ternary complex in UGT1A9-catalyzed reactions, in both the presence and absence of bovine serum albumin
Manevski, Nenad,Yli-Kauhaluoma, Jari,Finel, Moshe
, p. 2192 - 2203 (2013/01/15)
The presence of bovine serum albumin (BSA) largely modulates the enzyme kinetics parameters of the human UDP-glucuronosyltransferase (UGT) 1A9, increasing both the apparent aglycone substrate affinity of the enzyme and its limiting reaction velocity (Drug Metab Dispos 39:2117-2129, 2011). For a better understanding of the BSA effects and an examination of whether its presence changes the catalytic mechanism, we have studied the enzyme kinetics of 4-methylumbelliferone glucuronidation by UGT1A9 in the presence and absence of 0.1% BSA, using bisubstrate enzyme kinetic experiments, in both the forward and reverse directions, as well as product and dead-end inhibition. The combined results strongly suggest that the reaction mechanism of UGT1A9, and presumably other human UGTs as well, involves the formation of a compulsory-order ternary-complex, with UDP-α-D-glucuronic acid (UDPGA) as the first binding substrate. Based on the enzyme kinetic parameters measured for the forward and reverse reactions, the equilibrium constant of the overall reaction was calculated (Keq = 574) and the relative magnitudes of the reaction rate constants were elucidated. The inclusion of BSA in the bisubstrate kinetic experiments quantitatively changed the apparent enzyme kinetic parameters, presumably by removing internal inhibitors that bind to the binary enzyme-UDPGA (E-UDPGA) complex, as well as to the ternary E-UDPGA-aglycone complex. Nevertheless, the underlying compulsory-order ternary-complex mechanism with UDPGA binding first is the same in both the absence and presence of BSA. The results offer a novel understanding of UGT enzyme kinetic mechanism and BSA effects. Copyright
Critical roles of residues 36 and 40 in the phenol and tertiary amine aglycone substrate selectivities of UDP-glucuronosyltransferases 1A3 and 1A4
Kubota, Takahiro,Lewis, Benjamin C.,Elliot, David J.,Mackenzie, Peter I.,Miners, John O.
, p. 1054 - 1062 (2008/09/16)
Despite high sequence identity, UGT1A3 and UGT1A4 differ in terms of substrate selectivity. UGT1A3 glucuronidates the planar phenols 1-naphthol (1-NP) and 4-methylumbelliferone (4-MU), whereas UGT1A4 converts the tertiary amines lamotrigine (LTG) and trifluoperazine (TFP) to quaternary ammonium glucuronides. Residues 45 to 154 (which incorporate 21 of the 35 amino acid differences) and 45 to 535 were exchanged between UGT1A3 and UGT1A4 to generate UGT1A3-4(45-535), UGT1A3-4(45-154)-3, UGT1A4-3 (45-535), and UGT1A4-3(45-154)-4 hybrid proteins. Although differences in kinetic parameters were observed between the parent enzymes and chimeras, UGT1A4-3(45-535) and UGT1A4-3(45-154)-4 [but not UGT1A3-4(45-535) and UGT1A3-4(45-154)-3] retained the capacity to glucuronidate LTG and TFP. Likewise, UGT1A3-4(45-535) and UGT1A3-4(45-154)-3 retained the capacity to glucuronidate 1-NP and 4-MU, but UGT1A4-3(45-535) and UGT1A4-3(45-154)-4 exhibited low or absent activity. Within the first 44 residues, UGT1A3 and UGT1A4 differ in sequence at positions 36 and 40. "Reciprocal" mutagenesis was performed to generate the UGT1A3(I36T), UGT1A3(H40P), UGT1A4(T36I), and UGT1A4 (P40H) mutants. The T36I and P40H mutations in UGT1A4 reduced in vitro clearances for LTG and TFP glucuronidation by >90%. Conversely, the I36T and H40P mutations in UGT1A3 reduced the in vitro clearances for 1-NP and 4-MU glucuronidation by >90%. Introduction of the single H40P mutation in UGT1A3 conferred LTG and TFP glucuronidation, whereas the single T36I mutation in UGT1A4 conferred 1-NP and 4-MU glucuronidation. Thus, residues 36 and 40 of UGT1A3 and UGT1A4 are pivotal for the respective selectivities of these enzymes toward planar phenols and tertiary amines, although other regions of the proteins influence binding affinity and/or turnover. Copyright
Profiling of glycosidase activities using coumarin-conjugated glycoside cocktails
Park, Sungjin,Shin, Injae
, p. 619 - 622 (2007/10/03)
Glycosidases are a large subgroup of carbohydrate-processing enzymes that hydrolytically cleave the glycosidic bond. Glycans formed by the action of glycosidases are involved in various biological processes. Genetic abnormalities in glycosidases are associated with inherited diseases. Thus, characterization of the catalytic activities of glycosidases is of great importance. Herein, we describe a simple and rapid approach for determining glycosidase activity profiles using coumarin-conjugated glycoside cocktails.
