3749-87-9Relevant academic research and scientific papers
Engineering Regioselectivity of a P450 Monooxygenase Enables the Synthesis of Ursodeoxycholic Acid via 7β-Hydroxylation of Lithocholic Acid
Grobe, Sascha,Badenhorst, Christoffel P. S.,Bayer, Thomas,Hamnevik, Emil,Wu, Shuke,Grathwol, Christoph W.,Link, Andreas,Koban, Sven,Brundiek, Henrike,Gro?johann, Beatrice,Bornscheuer, Uwe T.
supporting information, p. 753 - 757 (2020/12/01)
We engineered the cytochrome P450 monooxygenase CYP107D1 (OleP) from Streptomyces antibioticus for the stereo- and regioselective 7β-hydroxylation of lithocholic acid (LCA) to yield ursodeoxycholic acid (UDCA). OleP was previously shown to hydroxylate testosterone at the 7β-position but LCA is exclusively hydroxylated at the 6β-position, forming murideoxycholic acid (MDCA). Structural and 3DM analysis, and molecular docking were used to identify amino acid residues F84, S240, and V291 as specificity-determining residues. Alanine scanning identified S240A as a UDCA-producing variant. A synthetic “small but smart” library based on these positions was screened using a colorimetric assay for UDCA. We identified a nearly perfectly regio- and stereoselective triple mutant (F84Q/S240A/V291G) that produces 10-fold higher levels of UDCA than the S240A variant. This biocatalyst opens up new possibilities for the environmentally friendly synthesis of UDCA from the biological waste product LCA.
Chenodeoxycholic acid derivative or pharmaceutically acceptable salt thereof, and preparation method and applications thereof
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Paragraph 0042; 0043; 0044, (2020/03/12)
The invention discloses a chenodeoxycholic acid derivative with a structure as shown in general formula I or a medicinal salt thereof, and a preparation method and application of the chenodeoxycholicacid derivative. The chenodeoxycholic acid derivative can up-regulate the transcription levels of FXR mRNA and SHP mRNA, can obviously activate FXR, and can be used for preparing drugs for treating orpreventing hyperlipidemia, atherosclerosis, non-alcoholic steatohepatitis, type II diabetes mellitus and other diseases related to blood fat.
Chemical Synthesis of Rare Natural Bile Acids: 11α-Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids
Namegawa, Kazunari,Iida, Kyoko,Omura, Kaoru,Ogawa, Shoujiro,Hofmann, Alan F.,Iida, Takashi
, p. 403 - 411 (2018/06/08)
A method for the preparation of 11α-hydroxy derivatives of lithocholic and chenodeoxycholic acids, recently discovered to be natural bile acids, is described. The principal reactions involved were (1) elimination of the 12α-mesyloxy group of the methyl esters of 3α-acetate-12α-mesylate and 3α,7α-diacetate-12α-mesylate derivatives of deoxycholic acid and cholic acid with potassium acetate/hexamethylphosphoramide; (2) simultaneous reduction/hydrolysis of the resulting △11-3α-acetoxy and △11-3α,7α-diacetoxy methyl esters with lithium aluminum hydride; (3) stereoselective 11α-hydroxylation of the △11-3α,24-diol and △11-3α,7α,24-triol intermediates with B2H6/tetrahydrofuran (THF); and (4) selective oxidation at C-24 of the resulting 3α,11α,24-triol and 3α,7α,11α,24-tetrol to the corresponding C-24 carboxylic acids with NaClO2 catalyzed by 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and NaClO. In summary, 3α,11α-dihydroxy-5β-cholan-24-oic acid and 3α,7α,11α-trihydroxy-5β-cholan-24-oic acid have been synthesized and their nuclear magnetic resonance (NMR) spectra characterized. These compounds are now available as reference standards to be used in biliary bile acid analysis.
Chenodeoxycholic acid derivatives, preparation method thereof and medical application thereof
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Paragraph 0042; 0043; 0044, (2018/06/26)
The invention relates to the field of medicinal chemistry, relates to chenodeoxycholic acid derivatives, a preparation method thereof and a medical application thereof, in particular to a kind of chenodeoxycholic acid derivatives with a general formula of (I), a preparation method thereof, a pharmaceutical composition comprising the compounds and medical application thereof, especially used as drugs for preventing or treating hyperlipidaemia, type II diabetes, atherosis and non-alcoholic steatohepatitis. The formula is shown in the description.
Lipid accumulation inhibitory activities of novel isoxazole-based chenodeoxycholic acids: Design, synthesis and preliminary mechanism study
Qiu, Rongmao,Luo, Guoshun,Li, Xinyu,Zheng, Fan,Li, Haolin,Zhang, Jin,You, Qidong,Xiang, Hua
, p. 2879 - 2884 (2018/07/25)
In continuation of our drug discovery program on hyperlipidemia, a series of novel isoxazole-chenodeoxycholic acid hybrids were designed, synthesized and evaluated for their lipid-lowering effects. Preliminary screening of all the synthesized compounds was done by using a 3T3-L1 adipocyte model, in which the most active compound 16b could significantly reduce the lipid accumulation up to 30.5% at a nontoxic concentration 10 μM. Further mechanism studies revealed that 16b blocked lipid accumulation via activating FXR-SHP signaling pathway, efficiently down-regulated the expression of key lipogenesis regulator SREBP-1c.
Chemical synthesis of uncommon natural bile acids: The 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids
Iida, Takashi,Namegawa, Kazunari,Nakane, Naoya,Iida, Kyoko,Hofmann, Alan Frederick,Omura, Kaoru
, p. 1397 - 1402 (2016/10/03)
The chemical synthesis of the 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids is reported. For initiating the synthesis of the 9α-hydroxy derivative of chenodeoxycholic acid, cholic acid was used; for the synthesis of the 9α-hydroxy derivative of lithocholic acid, deoxycholic acid was used. The principal reactions involved were (1) decarbonylation of conjugated 12-oxo-Δ9(11)-derivatives using in situ generated monochloroalane (AlH2Cl) prepared from LiAlH4 and AlCl3, (2) epoxidation of the deoxygenated Δ9(11)-enes using m-chloroperbenzoic acid catalyzed by 4,4'-thiobis-(6-tert-butyl-3-methylphenol), (3) subsequent Markovnikov 9a-hydroxylation of the Δ9(11)-enes with AlH2Cl, and (4) selective oxidation of the primary hydroxyl group at C-24 in the resulting 3α,9α,24-triol and 3α,7α,9α,24-tetrol to the corresponding C-24 carboxylic acids using sodium chlorite (NaClO2) in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and sodium hypochlorite (NaOCl). The 1H- and 13C-NMR spectra are reported. The 3α,7α,9α-trihydroxy-5β-cholan-24-oic acid has been reported to be present in the bile of the Asian bear, and its 7-deoxy derivative is likely to be a bacterial metabolite. These bile acids are now available as authentic reference standards, permitting their identification in vertebrate bile acids.
11 -SUBSTITUTED BILE ACID DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND USE OF THESE COMPOUNDS AS MEDICAMENTS
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Paragraph 0053, (2015/06/25)
The present invention discloses a novel bile acid derivatives having substituted nitrogen functionality at C-11 and process for synthesis thereof. These C-11 substituted bile acid derivatives shows anticancer and antimycobacterial activity.
Synthesis, NMR Characterization and Crystal Structure of Methyl 3α,7α-Dihydroxy-12-oxo-5β-cholanate
Tinajero-Delgado, Vernica,Romero-vila, Margarita,Flores-lamo, Marcos,Arteaga, Martn A. Iglesias
, p. 487 - 492 (2015/02/19)
The crystal structure and NMR characterization of methyl 3α,7α-dihydroxy-12-oxo-5β-cholanate are described. The title compound which was obtained from methyl cholanate in a 3-step synthetic sequence that does not alter the starting chirality, crystallizes in the monoclinic system with P 21 space group. While despite the substitution pattern rings A, B and C adopt chair conformations, the 5 membered D ring, that bears the side chain attached to C-17, shows a twisted conformation on C-13-C-14. In the crystal array, classical hydrogen bond interactions O-H···H and intermolecular contacts C-H···O of hydrogen bond type are observed. Graphical Abstract: The crystal structure and NMR characterization of Methyl α,7α-dihydroxy-12-oxo-5β-cholanate are described. [Figure not available: see fulltext.]
PROCESS FOR PREPARING HIGH PURITY URSODEOXYCHOLIC ACID
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Page/Page column 4; 7; 8, (2014/02/16)
The present invention describes a process for the synthesis of ursodeoxycholic acid wherein the purification of the crude ursodeoxycholic acid (containing approximately 13-15% of chenodeoxycholic acid impurity) takes place first passing through a salification with imidazole and a subsequent purification via "methyl ester", which allows a finished product with an extremely low content of known "cheno and "litho" impurities to be obtained. The present invention also describes the recovery steps of cholic acid and 3α-hydroxy-7-ketocholanic acid from the mother liquors of process intermediates.
Stereoselective synthesis of pentacyclic steroids functionalized at C-11
Ibrahim-Ouali, Malika,Romero, Eugenie,Hamze, Khalil
, p. 1092 - 1100 (2012/11/13)
We set out to describe an efficient and versatile method for preparing pentacyclic steroids diversely substituted at C-11 from cholic acid, via a stereoselective epoxidation and the epoxide opening as the key steps. The characteristic 1H and 13C NMR spectroscopic features of the synthesized compounds are reported.
