- Synthesis method of intermediate 3 α - hydroxyl -7 - ketone - 5 5 5 beta-cholestane -24 - acid of obeticholic acid
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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.
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Paragraph 0102-0104
(2021/01/24)
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- SYNTHETIC DERIVATIVES OF CHOLIC ACID 7-SULFATE AND USES THEREOF
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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).
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Paragraph 00332-00333
(2020/07/05)
-
- Insights into the Substrate Promiscuity of Novel Hydroxysteroid Dehydrogenases
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Hydroxysteroid dehydrogenases (HSDHs) are valuable biocatalysts for the regio- and stereoselective modification of steroids, bile acids and other steroid derivatives. In this work, we investigated the substrate promiscuity of this highly selective class of enzymes. In order to reach this goal, a preliminary search of HSDH homologues in in-house or public available (meta)genomes was carried out. Eight novel NAD(H)-dependent HSDHs, showing either 7α-, 7β-, or 12α-HSDH activity, and including, for the first time, enzymes from extremophilic microorganisms, were identified, recombinantly produced, and characterized. Among the novel HSDHs, four highly active (up to 92 U mg?1) NAD(H)-dependent 7β-HSDHs showing negligible similarity towards previously described 7β-HSDHs, were discovered. These enzymes, along with previously characterized HSDHs, were tested as biocatalysts for the stereoselective reduction of a panel of substrates including two α-ketoesters of pharmaceutical interest and selected ketones that partially resemble the structural features of steroids. All the reactions were coupled with a suitable cofactor regeneration system. Regarding the α-ketoesters, nearly all of the tested HSDHs showed a good activity toward the selected substrates, yielding the reduced α-hydroxyester with up to 99% conversions and enantiomeric excesses. On the other hand, only the 7β-HSDHs from Collinsella aerofaciens and Clostridium absonum showed appreciable activity toward more complex ketones, i. e., (±)-trans-1-decalone, but with interesting as well as different selectivity. (Figure presented.).
- Bertuletti, Susanna,Ferrandi, Erica Elisa,Marzorati, Stefano,Vanoni, Marta,Riva, Sergio,Monti, Daniela
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p. 2474 - 2485
(2020/05/06)
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- NAD+-Dependent Enzymatic Route for the Epimerization of Hydroxysteroids
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Epimerization of cholic and chenodeoxycholic acid (CA and CDCA, respectively) is a notable conversion for the production of ursodeoxycholic acid (UDCA). Two enantiocomplementary hydroxysteroid dehydrogenases (7α- and 7β-HSDHs) can carry out this transformation fully selectively by specific oxidation of the 7α-OH group of the substrate and subsequent reduction of the keto intermediate to the final product (7β-OH). With a view to developing robust and active biocatalysts, novel NADH-active 7β-HSDH species are necessary to enable a solely NAD+-dependent redox-neutral cascade for UDCA production. A wild-type NADH-dependent 7β-HSDH from Lactobacillus spicheri (Ls7β-HSDH) was identified, recombinantly expressed, purified, and biochemically characterized. Using this novel NAD+-dependent 7β-HSDH enzyme in combination with 7α-HSDH from Stenotrophomonas maltophilia permitted the biotransformations of CA and CDCA in the presence of catalytic amounts of NAD+, resulting in high yields (>90 %) of UCA and UDCA.
- Tonin, Fabio,Otten, Linda G.,Arends, Isabel W. C. E.
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p. 3192 - 3203
(2018/11/10)
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- Efficient Synthesis of 12-Oxochenodeoxycholic Acid Using a 12α-Hydroxysteroid Dehydrogenase from Rhodococcus ruber
-
12α-Hydroxysteroid dehydrogenase (12α-HSDH) has the potential to convert cheap and readily available cholic acid (CA) to 12-oxochenodeoxycholic acid (12-oxo-CDCA), a key precursor for chemoenzymatic synthesis of the therapeutic bile acid ursodeoxycholic acid (UDCA). In this work, a native nicotinamide adenine dinucleotide (NAD+)-dependent 12α-hydroxysteroid dehydrogenase (Rr12α-HSDH) from Rhodococcus ruber was identified using a structure-guided genome mining (SSGM) approach, which is based on the structure of cofactor pocket and the conserved nicotinamide cofactor binding motif alignment. Rr12α-HSDH was heterologously overexpressed in Escherichia coli BL21 (DE3), purified and characterized. The purified Rr12α-HSDH showed a high oxidative activity of 290 U mg?1protein toward CA, with a catalytic efficiency (kcat/KM) of 5.10×103 mM?1 s?1. In a preparative biotransformation (100 mL), CA (200 mM, 80 g L?1) was efficiently converted to 12-oxo-CDCA in 1 h, with a 85% isolated yield and a space-time yield (STY) of up to 1632 g L?1 d?1. Furthermore, Rr12α-HSDH was shown to be able to catalyze the oxidation of other 12α-hydroxysteroids at high substrate loads (up to 200 mM), giving the corresponding 12-oxo-hydroxysteroids in 71%–85% yields, indicating the great potential of Rr12α-HSDH as a promising biocatalyst for the synthesis of various therapeutic bile acids. (Figure presented.).
- Shi, Shou-Cheng,You, Zhi-Neng,Zhou, Ke,Chen, Qi,Pan, Jiang,Qian, Xiao-Long,Xu, Jian-He,Li, Chun-Xiu
-
supporting information
p. 4661 - 4668
(2019/09/10)
-
- A facile synthesis of ursodeoxycholic acid and obeticholic acid from cholic acid
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A novel synthetic route of producing ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) was developed through multiple reactions from cheap and readily-available cholic acid. The reaction conditions of the key elimination reaction of mesylate ester group were also investigated and optimized, including solvent, base and reaction temperature. In the straightforward synthetic route for preparation of UDCA and OCA, most of the reaction steps have high conversions with average yields of 94% and 92%, and overall yield up to 65% (7 steps) and 36% (11 steps) from cholic acid, respectively. This promising route offers economical and efficient strategies for potential large-scale production of UDCA and OCA.
- He, Xiao-Long,Wang, Li-Ting,Gu, Xiang-Zhong,Xiao, Jie-Xin,Qiu, Wen-Wei
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p. 173 - 178
(2018/11/10)
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- Synthesis method of intermediate 7-ketolithocholic acid of ursodeoxycholic acid
-
The invention discloses a chemical synthesis method of intermediate 7-ketolithocholic acid (3alpha-hydroxy-7-one-5beta-cholestan-2-4-acid) of ursodeoxycholic acid, and belongs to the field of organic chemical synthesis. According to the method, cholic acid is adopted as a material, and is subjected to reactions including selective oxidation of 7alpha-hydroxy, benzyl esterification of a side chain carboxyl group, esterification of 3alpha-hydroxy, methanesulfonic acid esterification of 12alpha-hydroxy, elimination, hydrogenation and hydrolysis to synthesize the intermediate 7-ketolithocholic acid of the ursodeoxycholic acid; the cheap cholic acid is adopted as the material, the synthesis method has the advantages of being novel, low in cost, high in yield and environment-friendly and industrial production is facilitated.
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Paragraph 0104-0105
(2017/08/31)
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- Synthesis method for obeticholic acid intermediate 7-ketolithocholic acid
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The invention discloses a chemical synthesis method for an obeticholic acid intermediate 7-ketolithocholic acid (3alpha-hydroxy-7-keto-5beta-cholestane-24-acid), and belongs to the field of organic chemical synthesis. The method adopts cholic acid as a raw material, and through 7alpha-hydroxyl selective oxidation, side chain carboxyl esterification, 3alpha-hydroxyl etherification, 12alpha-hydroxyl methanesulfonic acid esterification, elimination, hydrogenation, hydrolysis and other reactions, the obeticholic acid intermediate 7-ketolithocholic acid is synthesized. The synthesis method for 7-ketolithocholic acid adopts cheap cholic acid as the raw material, and has the advantages of novel synthesis method, low cost, high yield, environmental friendliness and convenience in industrialized production.
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Paragraph 0111-0113
(2017/08/31)
-
- Synthetic method of 7-keto-lithocholic acid
-
The invention discloses a chemical synthetic method of an intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, and belongs to the field of organic chemical synthesis. According to the chemical synthetic method of the intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, cholic acid is adopted as a raw material, and through reactions of selective oxidization of 7alpha-hydroxyl, esterification of side chain carboxyl groups, esterification of 3alpha-hydroxyl, methanesulfonic acid esterification, elimination, hydrogenation, and hydrolysis of 12alpha-hydroxyl, the intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid is synthesized. According to the chemical synthetic method of the intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, cheap cholic acid is adopted as the raw material, the synthesis method is novel, low in cost, high in yield and environmentally friendly, which facilitates industrialized production.
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-
Paragraph 0111; 0112; 0128; 0129
(2017/09/02)
-
- [...] synthetic method and intermediate (by machine translation)
-
The invention discloses a method for synthesizing [...], the cholic acid as the raw material, after 7 α - hydroxy selective oxidation, side chain carboxyl ester, 3 α - hydroxy ester, 12 α - hydroxy methanesulfonic acid esterification, eliminate, selective hydrolysis of 3 bit ester group, with the three-a chlorosilane reaction to produce the silicon ether, with acetaldehyde to aldol condensation, and the hydrolysis, catalytic hydrogenation reduction olefinic bond, carbonyl reduction reaction such as, to synthesize states the aobeiaobei cholic acid. The method of the invention uses cheap cholic acid as raw materials, synthetic method is novel, low cost, high yield, mild reaction conditions, easy post treatment, environmental friendly, convenient to industrial production. (by machine translation)
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Paragraph 0134-0136
(2017/11/16)
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- Chenodeoxycholic acid synthesis method
-
The invention discloses a chenodeoxycholic acid synthesis method, wherein cholic acid is used as a raw material, and 7[alpha]-hydroxyl selective oxidation, side-chain carboxyl esterification, 3[alpha]-hydroxyl esterification, 12[alpha]-hydroxymethanesulfonic acid esterification, elimination, hydrolysis, reduction and other reactions are performed to prepare the chenodeoxycholic acid. According to the present invention, the chenodeoxycholic acid synthesis method has advantages of simple step, less side reaction, high yield and easily available raw materials, is suitable for industrial production, can solve the problems of high synthesis cost, low yield and the like in the prior art, and is suitable for industrial mass-production.
- -
-
Paragraph 0130; 0131
(2017/12/27)
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- A synthesis method of ursodeoxycholic acid (by machine translation)
-
The invention discloses a method for synthesizing of ursodeoxycholic acid, the cholic acid as the raw material, after 7 α - hydroxy selective oxidation, side chain carboxyl ester, 3 α - hydroxy ester, 12 α - hydroxy methanesulfonic acid esterification, elimination, hydrolysis, reduction of synthesis of ursodeoxycholic acid. The invention of ursodeoxycholic acid synthesis method, simple steps, less side reaction, high yield, raw materials are easy, is suitable for industrial production, solved in the prior art synthesis cost high, the yield is low and the like, and has a wide application. (by machine translation)
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Paragraph 0090-0092
(2018/03/01)
-
- METHODS FOR PREPARATION OF BILE ACIDS AND DERIVATIVES THEREOF
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The present application relates to a method of preparing compounds of Formula (A) or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof.
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-
Page/Page column 77
(2017/03/08)
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- Search and discovery of actinobacteria capable of transforming deoxycholic and cholic acids
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The capability of 54 selected actinobacteria strains of different phyla to convert deoxycholic (DCA) and cholic (CA) acids under aerobic conditions was studied. Except for the two species, the strains did not grow on DCA (1 g/l) as a sole carbon source, but some of them effectively converted DCA performing 7β- and 9α- hydroxylation, 3α- and 12α-dehydrogenation, partial cleavage of the isoprenoic side chain and Δ4-dehydrogenation. Ursocholic acid, 9α-hydroxy-3,12-dioxo-23,24-bisnorchol-4-ene-22-oic acid, 3-keto-DCA and other end metabolites had been firstly identified in the actinobacteria strains. The total yield of 12α-hydroxy-3-oxo-chol-4-ene-24-oic and 3,12-dioxochol-4-ene-24-oic acids from DCA with Rhodococcus erythropolis VKM Ac-1152 reached 95%. Almost 80% DCA were converted to 9α-hydroxy-3,12-dioxo-23,24-bisnorchol-4-en-22-oic acid by Rhodococcus sp. MTS-77. Unlike DCA, cholic acid (CA) was confirmed to be a growth substrate for majority of the examined strains, but only three Rhodococcus strains exhibited 7α- and/or 12α-HSDH activities thus forming 7-keto-DCA and 12-keto-chenodeoxycholic acid as major products from CA. Steroid metabolites were identified by TLC, GC, MS, 1H- and 13C NMR analyses. The results may contribute to the knowledge of biocatalytic potential of diverse soil-dwelling actinobacteria towards bile acids, and could be applied at the development of novel bioprocesses for production of the valuable cholanic acids.
- Deshcherevskaya, N. O.,Lobastova, T. G.,Kollerov, V. V.,Donova, M. V.,Kazantsev, A. V.
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p. S157 - S165
(2018/04/03)
-
- Radical-mediated dehydrogenation of bile acids by means of hydrogen atom transfer to triplet carbonyls
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The aim of the present paper is to explore the potential of radical-mediated dehydrogenation of bile salts (BSs), which is reminiscent of the enzymatic action of hydroxysteroid dehydrogenase enzymes (HSDH). The concept has been demonstrated using triplet carbonyls that can be efficiently generated upon selective UVA-excitation. Hydrogen atom transfer (HAT) from BSs to triplet benzophenone (BP) derivatives gave rise to radicals, ultimately leading to reduction of the BP chromophore with concomitant formation of the oxo-analogs of the corresponding BSs. The direct reactivity of triplet BP with BSs in the initial step was evaluated by determining the kinetic rate constants using laser flash photolysis (LFP). The BP triplet decay was monitored (λmax = 520 nm) upon addition of increasing BS concentrations, and the obtained rate constant values indicated a reactivity of the methine hydrogen atoms in the order of C-3 2 than under O2, also supporting the role of the oxygen-quenchable triplet in the dehydrogenation process. Furthermore, irradiation of deaerated aqueous solutions of sodium cholate in the presence of KPMe provided the oxo-analogs, 3[O],7[O]-CA, 3[O]-CA and 7[O]-CA, arising from the HAT process.
- Miro,Marin,Miranda
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p. 2679 - 2683
(2016/03/05)
-
- Hydroxylation of lithocholic acid by selected actinobacteria and filamentous fungi
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Selected actinobacteria and filamentous fungi of different taxonomy were screened for the ability to carry out regio- and stereospecific hydroxylation of lithocholic acid (LCA) at position 7β. The production of ursodeoxycholic acid (UDCA) was for the first time shown for the fungal strains of Bipolaris, Gibberella, Cunninghamella and Curvularia, as well as for isolated actinobacterial strains of Pseudonocardia, Saccharothrix, Amycolatopsis, Lentzea, Saccharopolyspora and Nocardia genera. Along with UDCA, chenodeoxycholic (CDCA), deoxycholic (DCA), cholic (CA), 7-ketodeoxycholic and 3-ketodeoxycholic acids were detected amongst the metabolites by some strains. A strain of Gibberella zeae VKM F-2600 expressed high level of 7β-hydroxylating activity towards LCA. Under optimized conditions, the yield of UDCA reached 90% at 1 g/L of LCA and up to 60% at a 8-fold increased substrate loading. The accumulation of the major by-product, 3-keto UDCA, was limited by using selected biotransformation media.
- Kollerov,Monti,Deshcherevskaya,Lobastova,Ferrandi,Larovere,Gulevskaya,Riva,Donova
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p. 370 - 378
(2013/03/28)
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- Synthesis of various secosteroidal macrocycles by ring-closing metathesis
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We set out to describe an efficient and versatile method for preparing secosteroidal macrocycles from cholic acid, via an oxidative ring-expansion/ring-opening sequence and a ring-closing metathesis reaction as the key steps. The characteristic 1H and 13C NMR spectroscopic features of the synthesized compounds are reported.
- Ibrahim-Ouali, Malika,Romero, Eugénie
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p. 651 - 661
(2013/07/11)
-
- Exploitation of a laccase/meldola's blue system for NAD+ regeneration in preparative scale hydroxysteroid dehydrogenase-catalyzed oxidations
-
An enzymatic regeneration system consisting of laccase and the 2H +/2e- redox mediator Meldola's blue (MB) was developed for the efficient oxidation of reduced nicotinamide adenine dinucleotide (NADH) cofactor and employed in the gram-scale oxidation of cholic acid (1) to its 7-keto derivative (1a) by 7a-hydroxysteroid dehydrogenase (7a- HSDH) in an aqueous, buffered reaction system. The regenerating enzyme, laccase, reduces molecular oxygen as terminal 4H+/4e- acceptor to water and concomitantly reoxidizes NADH via MB at high turnover rates. The regeneration system was successfully applied to quantitatively convert 1 (50 mM, 20.4 g) into 1a with a space-time yield of 5.8 mmolL-1h-1. High total turnover numbers were achieved for 7a-HSDH (4.2×105) and laccase (1.1× 10.6). Alternatively, the regeneration system was employed on the conversion of the methyl ester derivative of cholic acid (2, 200 mM, 5.9 g) dissolved in isopropyl acetate as organic solvent in a biphasic system. Due to the high concentration of 2 and the excellent performance of the enzymatic cascade reaction even under the harsh process conditions, space-time yields of up to 20 mmolL-1h-1(8.5 gL-1h -1) of the produced 7-keto derivative 2a were obtained. The irreversibility and high driving force of the regenerating reaction allowed quantitative conversions and easy product recovery.
- Ferrandi, Erica Elisa,Monti, Daniela,Patel, Ilabahen,Kittl, Roman,Haltrich, Dietmar,Riva, Sergio,Ludwig, Roland
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p. 2821 - 2828
(2013/01/15)
-
- Regioselective oxidation of cholic acid and its 7β epimer by using o-iodoxybenzoic acid
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Rational exploration directed by DFT (density functional theory) based atomic Fukui indices, lead to development of regioselective oxidation of cholic acid and its 7β epimer by o-iodoxybenzoic acid. In case of cholic acid only, 7α-hydroxyl underwent oxidation, where as in its 7β epimer the selectivity was towards 12α-hydroxy group. Since these oxidations are the key steps in synthesis of ursodeoxycholic acid starting from cholic acid these findings may be useful in devising a protection free synthetic route.
- Dangate, Prasad S.,Salunke, Chetan L.,Akamanchi, Krishnacharya G.
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experimental part
p. 1397 - 1399
(2011/11/06)
-
- POLYHYDROXYLATED BILE ACIDS FOR TREATMENT OF BILIARY DISORDERS
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The invention provides, in part, polyhydroxylated bile acids for treating biliary disorders, for example, biliary disorders arising out of cholestasis or portal hypertesion. The invention also provides, in part, polyhydroxylated bile acids for stimulating bile flow. New compounds 2α,3α,7α,12α-tetrahydroxy-5β-cholanoic acid and 3α,4α,7α,12α-tetrahydroxy-5β-cholanoic acid are disclosed, uses thereof and synthesis thereof.
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Page/Page column 38; Sheet 10
(2011/04/14)
-
- A ring-closing metathesis approach to secosteroidal macrocycles
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An efficient synthesis of secosteroidal macrocycles has been achieved via an oxidative ring-expansion/ring-opening sequence and a ring-closing metathesis reaction as the key steps.
- Ibrahim-Ouali, Malika,Zoubir, Jamel,Romero, Eugénie
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scheme or table
p. 7128 - 7131
(2012/01/04)
-
- Synthesis of new, UV-photoactive dansyl derivatives for flow cytometric studies on bile acid uptake
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Four new fluorescent derivatives of cholic acid have been synthesized; they incorporate a dansyl moiety at 3α-, 3β-, 7α- or 7β- positions. These cholic acid analogs are UV photoactive and also exhibit green fluorescence. In addition, they have been demonstrated to be suitable for studying the kinetics of bile acid transport by flow cytometry. The Royal Society of Chemistry 2009.
- Rohacova, Jana,Marin, M. Luisa,Martinez-Romero, Alicia,O'Connor, Jose-Enrique,Gomez-Lechon, M. Jose,Donato, M. Teresa,Castell, Jose V.,Miranda, Miguel A.
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experimental part
p. 4973 - 4980
(2010/02/16)
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- 7α- and 12α-Hydroxysteroid dehydrogenases from Acinetobacter calcoaceticus lwoffii: a new integrated chemo-enzymatic route to ursodeoxycholic acid
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We report the very efficient biotransformation of cholic acid to 7-keto- and 7,12-diketocholic acids with Acinetobacter calcoaceticus lwoffii. The enzymes responsible of the biotransformation (i.e. 7α- and 12α-hydroxysteroid dehydrogenases) are partially purified and employed in a new chemo-enzymatic synthesis of ursodeoxycholic acid starting from cholic acid. The first step is the 12α-HSDH-mediated total oxidation of sodium cholate followed by the Wolf-Kishner reduction of the carbonyl group to chenodeoxycholic acid. This acid is then quantitatively oxidized with 7α-HSDH to 7-ketochenodeoxycholic acid, that was chemically reduced to ursodeoxycholic acid (70% overall yield).
- Giovannini, Pier Paolo,Grandini, Alessandro,Perrone, Daniela,Pedrini, Paola,Fantin, Giancarlo,Fogagnolo, Marco
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experimental part
p. 1385 - 1390
(2009/04/06)
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- Xanthomonas maltophilia CBS 897.97 as a source of new 7β- and 7α-hydroxysteroid dehydrogenases and cholylglycine hydrolase: Improved biotransformations of bile acids
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The paper reports the partial purification and characterization of the 7β- and 7α-hydroxysteroid dehydrogenases (HSDH) and cholylglycine hydrolase (CGH), isolated from Xanthomonas maltophilia CBS 897.97. The activity of 7β-HSDH and 7α-HSDH in the reduction of the 7-keto bile acids is determined. The affinity of 7β-HSDH for bile acids is confirmed by the reduction, on analytical scale, to the corresponding 7β-OH derivatives. A crude mixture of 7α- and 7β-HSDH, in soluble or immobilized form, is employed in the synthesis, on preparative scale, of ursocholic and ursodeoxycholic acids starting from the corresponding 7α-derivatives. On the other hand, a partially purified 7β-HSDH in a double enzyme system, where the couple formate/formate dehydrogenase allows the cofactor recycle, affords 6α-fluoro-3α, 7β-dihydroxy-5β-cholan-24-oic acid (6-FUDCA) by reduction of the corresponding 7-keto derivative. This compound is not obtainable by microbiological route. The efficient and mild hydrolysis of glycinates and taurinates of bile acids with CGH is also reported. Very promising results are also obtained with bile acid containing raw materials.
- Pedrini, Paola,Andreotti, Elisa,Guerrini, Alessandra,Dean, Mariangela,Fantin, Giancarlo,Giovannini, Pier Paolo
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p. 189 - 198
(2007/10/03)
-
- 7α-OH epimerisation of bile acids via oxido-reduction with Xanthomonas maltophilia
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The microbial 7α-OH epimerisation of cholic, chenodeoxycholic, and 12-ketochenodeoxycholic acids (7α-OH bile acids) with Xanthomonas maltophilia CBS 827.97 to corresponding 7β-OH derivatives with scarcity of oxygen is described. With normal pressure of oxygen the 7-OH oxidation products are obtained. No biotransformations are achieved in anaerobic conditions. The microbial 7α-OH epimerisation is achieved by oxidation of 7-OH function and subsequent reduction. Partial purification, in fact, of the enzymatic fraction revealed the presence of two hydroxysteroid dehydrogenases (HSDH) α- and β-stereospecific together with a glycocholate hydrolase. On the basis of these results a further application is the microbial reduction of 6α-fluoro and 6β-fluoro-3α-hydroxy-7-oxo-5β-cholan-24-oic acid methyl esters to the corresponding 7α-OH and 7β-OH derivatives.
- Medici, Alessandro,Pedrini, Paola,Bianchini, Ercolina,Fantin, Giancarlo,Guerrini, Alessandra,Natalini, Benedetto,Pellicciari, Roberto
-
-
- Synthesis of four cholic acid-based CSPs containing 2-naphthoyl carbamate and 3,5-dinitrophenylcarbamate moieties and their evaluation in the HPLC resolution of racemic compounds
-
Four new chiral selectors, obtained by derivatising the hydroxy groups of cholic acid with 2-naphthylisocyanate and 3,5-dinitrophenylisocyanate have been prepared and linked to silica gel to obtain new chiral stationary phases (CSPs) for the HPLC separation of enantiomers. The CSP containing only 2-naphthylcarbamate groups is able to separate the enantiomers of π-acidic substrates, whereas the CSPs containing one 3,5-dinitrophenylcarbamate group and two 2-naphthyl carbamate moieties resolve π-acidic racemic compounds as well as π-basic substrates, with the observed enantiodiscriminating capabilities depending on the arrangement of the different carbamoyl units on the cholestanic backbone.
- Iuliano,Pieraccini,Felix,Salvadori
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p. 1265 - 1275
(2007/10/03)
-
- Anodic electrochemical oxidation of cholic acid
-
Regioselectivity in the anodic electrochemical oxidation of cholic acid with different anodes is described. The oxidation with PbO2 anode affords the dehydrocholic acid in quantitative yield after 22 h. 3α,12α-Dihydroxy-7-oxo-5β-cholan-24-oic acid (59%) and 3α-hydroxy-7,12-dioxo-5β-cholan-24-oic acid (51%) are obtained stopping the reaction at lower time. The rate of the OH-oxidation is C7 > C12 > C3. The electro-oxidation with platinum foil anode gives selectively the 7-ketocholic acid in 40% yield. On the other hand, the graphite plate anode, varying the reaction conditions, produces selectively the dehydrocholic acid in quantitative yield or the 3α,12α-dihydroxy-7-oxo-5β-cholan-24-oic acid (96%) while the 3α,7α-dihydroxy-12-oxo-5β-cholan-24-oic acid (34%) is obtained together with the other oxo acids. Copyright
- Medici, Alessandro,Pedrini, Paola,De Battisti, Achille,Fantin, Giancarlo,Fogagnolo, Marco,Guerrini, Alessandra
-
-
- Regiospecific oxidoreductions catalyzed by a new Pseudomonas paucimobilis hydroxysteroid dehydrogenase
-
The preparative-scale regio- and stereo-specific oxidation of hydroxy groups and reduction of keto functions at C(3) of several C21 bile acids, catalyzed by a new 3α-hydroxysteroid dehydrogenase (3α-HSDH) is reported. The crude enzyme, isolated from the cells of Pseudomonas paucimobilis, revealed the presence of a further enzymatic fraction containing a secondary alcohol dehydrogenase (SADH), that has been used to recycle the cofactor.
- Bianchini, Ercolina,Chinaglia, Nicola,Dean, Mariangela,Giovannini, Pier Paolo,Medici, Alessandro,Pedrini, Paola,Poli, Silvia
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p. 1391 - 1398
(2007/10/03)
-
- Microbial 7-OH epimerisation of bile acids
-
The microbial 7-OH epimerisation of cholic and chenodeoxycholic acids with Xanthomonas maltophilia CBS 827.97 to ursocholic and ursodeoxycholic acids with scarsity of oxygen is described. With normal pressure of oxygen the 7-ketocholic and the 7-ketochenodeoxycholic acids are obtained. No biotransformation is achieved in anaerobic conditions.
- Dean, Mariangela,Fantin, Giancarlo,Fogagnolo, Marco,Medici, Alessandro,Pedrini, Paola,Poli, Silvia
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p. 693 - 694
(2007/10/03)
-
- Regioselective microbial oxidation of bile acids
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High regioselectivity in the microbial oxidation of C7, C3 and C12 hydroxyl groups of cholic, chenodeoxycholic, deoxycholic and hyocholic acids 1-4 is reported. The tested microrganisms have been isolated from 50 environmental samples withdrawed from an industry that extracts and purify bile acids.
- Fantin, Giancarlo,Ferrarini, Sabina,Medici, Alessandro,Pedrini, Paola,Poli, Silvia
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p. 1937 - 1942
(2007/10/03)
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- A new non-enzymatic route to chenodeoxycholic acid
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A novel route for the production of the chenodeoxycholic acid is described, based on the selective non-enzymatic reduction of dehydrocholic acid. The relative reactivity scale was established to be in the order: 12-keto (1), 7-keto (2), 3-keto (17.5).
- Bortolini, Olga,Cova, Umberto,Fantin, Giancarlo,Medici, Alessandro
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p. 335 - 336
(2007/10/03)
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- Design, Synthesis, and Evaluation of Bile Acid-Based Molecular Tweezers
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A family of bile acid-based molecular tweezers (7-9) has been constructed readily from simple precursors.Binding experiments with various electron deficient aromatic compounds showed that tweezer 8 binds trinitrofluorenone 10e with an association constant of 220 M-1 in CDCl3.Single-crystal X-ray analysis of compound 8 shows aromatic-aromatic interactions producing a two-dimensional lattice of pyrene units.Tweezer 8 was immobilized on Merrifield resin, and binding studies have shown that these data compare well with those of the solution state studies.
- D'Souza, Lawrence J.,Maitra, Uday
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p. 9494 - 9502
(2007/10/03)
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- Preparative-Scale Regio- and Stereospecific Oxidoreduction of Cholic Acid and Dehydrocholic Acid Catalyzed by Hydroxysteroid Dehydrogenases
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NAD(P)-dependent hydroxysteroid dehydrogenases were used as catalysts for the oxidoreduction of the hydroxyl-keto groups of cholic acid (3α,7α,12α-trihydroxy-5β-cholan-24-oic acid) and dehydrocholic acid (3,7,12-trioxo-5β-cholan-24-oic acid).Cholic acid was regiospecifically oxidized, on a preparative scale, at each of the three possible positions, and dehydrocholic acid regio- and stereospecifically reduced at each of the three positions.The compounds were quantitatively transformed and the products were 97-99percent pure.The assignment of product structure was made by NMR.The nicotinamide cofactors were enzymatically regenerated, in situ, with the α-ketoglutarate/glutamate dehydrogenase, formate/formate dehydrogenase or glucose/glucose dehydrogenase systems.The enzymes were employed in the free form or immobilized on Sepharose CL-4B.
- Riva, Sergio,Bovara, Roberto,Pasta, Piero,Carrea, Giacomo
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p. 2902 - 2906
(2007/10/02)
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