4651-67-6Relevant academic research and scientific papers
An improved synthesis of 6α-ethylchenodeoxycholic acid (6ECDCA), a potent and selective agonist for the Farnesoid X Receptor (FXR)
Yu, Donna,Mattern, Daniell L.,Forman, Barry M.
, p. 1335 - 1338 (2012)
The active, potent, and selective Farnesoid X Receptor (FXR) agonist 6α-ethylchenodeoxycholic acid (6ECDCA) has been synthesized in improved yield compared to the published methodologies. The synthesis employed selective oxidation of one of the two hydroxyls of the readily-available starting material chenodeoxycholic acid (CDCA) as a key step. After protection of the remaining hydroxyl, LDA/HMPA/EtI/PPTS provided an efficient deprotonation/ethylation/ deprotection sequence. The two synthetic improvements that allow a productive yield are the use of PCC in the oxidation step, and the use of HMPA/ethyl iodide in the stereoselective alkylation step. This synthesis offers an economical and efficient strategy which provides a simple and cost-effective procedure for potential large-scale production of this promising FXR agonist, which is a research tool and potential drug substance of current interest.
An expedient synthesis of 6α-fluoroursodeoxycholic acid
Koenigsberger, Kurt,Chen, Guang-Pei,Vivelo, James,Lee, George,Fitt, John,McKenna, Joseph,Jenson, Todd,Prasad, Kapa,Repic, Oljan
, p. 665 - 669 (2002)
Optimization of the synthesis of 6α-fluoroursodeoxycholic acid 1 is described starting from the commercially available 2. The penultimate intermediate 16 was made in eight synthetic steps but in only four operations in an overall yield of 57%. The highlights are flourination of hydroxyketo acid 11 using Selectfluor through the intermediacy of silyl enol ether 12, conversion of 13 to 14 via equilibration of fluoroketone, esterification, and acylation. The drug substance 1 was prepared from mesylate 16 using potassium superoxide followed by a mild reductive workup using methoxydiethylborane.
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.
(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells
Dracinsky, Martin,Drastik, Martin,Kaspar, Miroslav,Klepetarova, Blanka,Kronenberger, Thales,Kudova, Eva,Micuda, Stanislav,Pavek, Petr,Stefela, Alzbeta
, (2021/09/08)
Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15?μM/EC50 = 26?nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.
Preparation method of low-cost, high-yield and high-purity 7-ketolithocholic acid
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Paragraph 0048-0055, (2020/07/24)
The invention discloses a preparation method of low-cost, high-yield and high-purity 7-ketolithocholic acid, which is characterized by comprising the following steps: adding chenodeoxycholic acid intoa mixed solution of an organic solvent and water, and performing stirring to dissolve; adding bromide and acid, and performing stirring and dissolving; adding bromate for reaction; adding a terminating agent, and performing stirring to terminate the reaction; adding water to crystallize the product; and carrying out solid-liquid separation, washing a solid product with water for multiple times, and performing drying to obtain 7-ketolithocholic acid. According to the method, a common and safe reagent is adopted, chenodeoxycholic acid is selectively oxidized into 7-ketolithocholic acid under arelatively mild condition, the product purity is greater than 98.0%, and the yield is greater than 85%. The method has the advantages of cheap reagents, simple operation, high process reproducibility,simple post-treatment, high product purity and the high yield, and can easily implement industrial production.
A method of synthesis of ursodesoxycholic acid(UDCA) using bile salt hydrolase(BSH) from Porcine intestinal flora Bifidobacterium thermophilum
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Paragraph 0045-0046, (2020/07/11)
The present invention relates to a method for synthesizing ursodesoxycholic acid (UDCA) from porcine bile acid by using bile salt hydrolase (BSH) derived from Bifidobacterium thermophilum in porcine gut microbiota. The present inventors have found that, compared to existing synthesis methods involving repeated purification processes, an UDCA synthesis method using the BSH of Bifidobacterium thermophilum in porcine gut microbiota is simple and time-saving; provides remarkable advantages in terms of high-throughput production and stability; is significantly more economical; and can increase an UDCA yield. In addition, the present invention is expected to provide a significant economic advantage in that it provides high-value added UDCA effective in improving hepatic functions, alleviating fatigue through liver improvement, cholesterol reduction, gallstone dissolution, primary biliary cirrhosis, and the like by utilizing porcine waste by-products.(AA) First step : Extract bile acid derived from by-products(BB) Second step : Extract BSH enzyme(CC) Third step : Extract CDCA(DD) Fourth step : Synthesize and purify UDCA(EE) Fifth step : Analyze UDCA(FF) Process of extracting bile acid for use in UDCA synthesis in by-products, Extract bile acid soluble by use of organic solvent methanol and evaporate methanol to obtain bile acid(GG) Extract BSH enzyme by expression and purification of BSH from lactic acid bacteria having BSH enzyme used in CDCA extraction(HH) Extract bile acid from CDCA as a measure to increase the purity and yield of UDCA from extracted bile acid(II) Synthesize UDCA by redox reaction using CDCA from the bile acid extracted from respective by-products(JJ) Analyze CLA via HPLC in order to confirm the synthesis and yield of synthesized UDCACOPYRIGHT KIPO 2020
SYNTHETIC DERIVATIVES OF CHOLIC ACID 7-SULFATE AND USES THEREOF
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Paragraph 00340-00341, (2020/07/05)
The compositions and methods provided herein are related, in part, to the discovery of cholic acid 7-sulfate as a treatment for diabetes. Provided herein is a method for treating a metabolic disorder (e.g., diabetes, obesity), or an inflammatory disease (e.g., Crohn's disease, inflammatory bowel disease, ulcerative colitis, pancreatitis, hepatitis, appendicitis, gastritis, diverticulitis, celiac disease, food intolerance, enteritis, ulcer, gastroesophageal reflux disease (GERD), psoriatic arthritis, psoriasis, and rheumatoid arthritis) in a subject in need thereof comprising administering to a subject a compound of Formulae (I)-(XVII).
Synthesis method of intermediate 3 α - hydroxyl -7 - ketone - 5 5 5 beta-cholestane -24 - acid of obeticholic acid
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Paragraph 0102; 0115-0116, (2021/01/24)
The invention discloses a chemical synthesis method for an intermediate 7-ketone lithocholic acid(3alpha-hydroxy-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, and belongs to the field of organic chemical synthesis. The method comprises the following steps: cholic acid is taken as a raw material, and the intermediate 7- ketone lithocholic acid of the obeticholic acid is synthesized through the selective oxidation of 7alpha-hydroxy, the benzyl esterification of side chain carboxyl, the etherification of 3alpha-hydroxy, the methanesulfonic acid esterification of 12alpha-hydroxy, elimination, hydrogenation, hydrolysis and the like. The method disclosed by the invention has the advantages of novel synthetic method, low cost, high yield, environment friendliness and convenience in industrial production since the cheap cholic acid is taken as the raw material.
Preparation method of ursodeoxycholic acid
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Paragraph 0023, (2020/06/24)
The invention discloses a preparation method of ursodesoxycholic acid, which comprises the following steps:using chenodeoxycholic acid as a raw material, oxidizing with sodium hypochlorite to obtain an intermediate 3alpha-hydroxy-7beta-carbonyl-5 beta-cholanic acid, carrying out hydrogenation reduction hydrogenation by using Raney nickel as a catalyst to obtain an ursodesoxycholic acid crude product, and carrying out triethylamine salifying refining to obtain the ursodesodesoxycholic acid bulk drug. The preparation method of ursodesoxycholic acid is stable and reliable in raw material source,high in reaction selectivity, easy in finished product refining, high in quality and short in process route; the method has the advantages of short synthesis steps, mild reaction conditions and cleanprocess, and is suitable for industrial production.
Flavin Oxidoreductase-Mediated Regeneration of Nicotinamide Adenine Dinucleotide with Dioxygen and Catalytic Amount of Flavin Mononucleotide for One-Pot Multi-Enzymatic Preparation of Ursodeoxycholic Acid
Chen, Xi,Cui, Yunfeng,Feng, Jinhui,Wang, Yu,Liu, Xiangtao,Wu, Qiaqing,Zhu, Dunming,Ma, Yanhe
, p. 2497 - 2504 (2019/03/28)
Ursodeoxycholic acid (UDCA), a pharmaceutical ingredient widely used in clinics, can be prepared from chenodeoxycholic acid (CDCA) by the epimerization of the 7α-OH group. In this study, a nicotinamide adenine dinucleotide (NAD+) regeneration system was developed by using flavin oxidoreductase (FR) and flavin mononucleotide (FMN). Only catalytic amount of FMN is required for the effective NAD+ recycling. FR/FMN system was then applied in the oxidation of CDCA to 7-ketolithocholic acid (7-keto-LCA) by NAD+-dependent 7α-hydroxysteroid dehydrogenase (Bs-7α-HSDH) from Brevundimonas sp., which showed extremely high enzyme activity toward CDCA (kcat/Km=8050 s?1 ? mM?1). When Escherichia coli whole cells coexpressing Bs-7α-HSDH and FR genes were used as biocatalyst, CDCA (50 mM) was completely converted to 7-keto-LCA with the turnover number of FMN being 227 and 58.8 g ? L?1 ? d?1 space-time yield of 7-keto-LCA. For the reduction of 7-keto-LCA, nicotinamide adenine dinucleotide phosphate (NADPH)-dependent 7-β-hydroxysteroid dehydrogenase (Cm-7β-HSDH) from Clostridium sp. Marseille was employed with alcohol dehydrogenase from Thermoanaerobacter brockii (TbADH) and iso-propanol as co-factor regeneration system. When E. coli whole cells coexpressing Cm-7β-HSDH and TbADH genes were used as biocatalyst, 40 mM 7-keto-LCA was reduced to UDCA with 26.8 g ? L?1 ? d?1 space-time yield. The oxidation and reduction were then carried in a one-pot concurrent mode, 12.5 mM CDCA was completely converted to UDCA. The epimerization of CDCA to UDCA proceeded to completion at the substrate concentration of 30 mM in the one-pot sequential process. Therefore, the complete conversion of CDCA to UDCA in one-pot has been realized by employing 7α-HSDH and 7β-HSDH of different co-factor specificities with independent co-factor recycling systems. The cholic acids, especially UDCA, exert inhibitive effect on the activities of these enzymes, preventing the complete epimerization of 7α-OH at higher substrate loading. This inhibition issue should be solvable by engineering the involved enzymes, that is currently pursued in our laboratory. (Figure presented.).
