- Preparation method of lithocholic acid and intermediates thereof
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The invention discloses a synthesis method of lithocholic acid and an intermediates thereof. According to the preparation method of the lithocholic acid intermediate, a compound I reacts with hydrogento generate a compound II in a mixed solvent by taking palladium on carbon as a catalyst and adding specific alkali; a low-price botanical bulk fermentation product BA is used as a raw material, andlithocholic acid is synthesized through side chain construction, hydrogenation, reduction, hydrolysis and other reactions; and the selectivity of 5beta hydrogen in the hydrogenation reaction is improved, high-toxicity reagents such as hydrazine hydrate are prevented from being used for hydroxyl due to removal of other animal-derived cholic acids, and the method is environmentally friendly, high insafety, simple in route, mild in reaction condition and suitable for industrial mass production.
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- STEROID COMPOUNDS AS TREG MODULATORS AND USES THEREOF
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Steroid compounds are disclosed that have a formula represented by the following: (I) and wherein R1, R2, R3a, R3b, R4a, R4b, R5, R6a, R6b, R7, R
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Paragraph 0315
(2020/05/19)
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- Vitamin E analogues differentially inhibit human cytochrome P450 3A (CYP3A)-mediated oxidative metabolism of lithocholic acid: Impact of δ-tocotrienol on lithocholic acid cytotoxicity
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Lithocholic acid is a cytotoxic bile acid oxidized at the C-3 position by human cytochrome P450 3A (CYP3A) to form 3-ketocholanoic acid, but it is not known whether this metabolite is cytotoxic. Tocotrienols, in their various isomeric forms, are vitamin E analogues. In the present study, the hypothesis to be tested is that tocotrienols inhibit CYP3A-catalyzed lithocholic acid 3-oxidation, thereby influencing lithocholic acid cytotoxicity. Our enzyme catalysis experiments indicated that human recombinant CYP3A5 in addition to CYP3A4, liver microsomes, and intestinal microsomes catalyzed lithocholic acid 3-oxidation to form 3-ketocholanoic acid. Liver microsomes with the CYP3A5*1/*3 and CYP3A5*3/*3 genotypes were associated with decreased lithocholic acid 3-oxidation. α-Tocotrienol, γ-tocotrienol, δ-tocotrienol, and a tocotrienol-rich vitamin E mixture, but not α-tocopherol (a vitamin E analogue), differentially inhibited lithocholic acid 3-oxidation catalyzed by liver and intestinal microsomes and recombinant CYP3A4 and CYP3A5. Compared to lithocholic acid 3-oxidation, CYP3A-catalyzed testosterone 6β-hydroxylation was inhibited to a lesser extent by α-tocotrienol, γ-tocotrienol, δ-tocotrienol, and a tocotrienol-rich vitamin E mixture. δ-Tocotrienol inhibited lithocholic acid 3-oxidation by a mixed mode. Like lithocholic acid, 3-ketocholanoic acid was also cytotoxic in human intestinal and liver cell models. δ-Tocotrienol decreased the extent of lithocholic acid 3-oxidation and this inhibition was associated with enhanced cytotoxicity in LS180 cells treated with δ-tocotrienol and lithocholic acid. Overall, vitamin E analogues inhibited in vitro lithocholic acid 3-oxidation in an isomer-dependent manner, with inhibition occurring with tocotrienols, but not α-tocopherol. The enhanced lithocholic acid toxicity by δ-tocotrienol in a human intestinal cell model warrants future investigations in vivo.
- Wong, Siew Ying,Teo, Josephine Si Min,Chai, Swee Fen,Yeap, Szu Ling,Lau, Aik Jiang
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- Method for preparing acid through oxidating alcohols or aldehydes by oxygen
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The invention provides a method for preparing acid through oxidating alcohols or aldehydes by using oxygen or oxygen in air as an oxidant. The method comprises the steps: oxidating the alcohols or aldehydes to produce the acid at room temperature in an organic solvent in a manner of taking ferric nitrate (Fe(NO3)3.9H2O), 2,2,6,6-tetramethylpiperidyl nitrogen oxide (TEMPO) and an inorganic halide as catalysts and taking the oxygen or air as an oxidant, and oxidating diols to produce lactone; or, carrying out a reaction on the aldehydes, which serve as a raw material, under neutral conditions by taking ferric nitrate as a catalyst, and oxidating the aldehydes to produce the acid and peroxy acid. The method has the advantages that the method is environmentally friendly, the cost is low, the yield is high, the atomic economical efficiency is high, the compatibility of substrate functional groups is good, the reaction conditions are mild, a reaction scale can be enlarged, and the like, so that the method is suitable for being applied to industrial production.
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Paragraph 0051; 0052; 0053; 0054; 0103; 0104; 0105
(2017/09/29)
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- Iron Catalysis for Room-Temperature Aerobic Oxidation of Alcohols to Carboxylic Acids
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Oxidation from alcohols to carboxylic acids, a class of essential chemicals in daily life, academic laboratories, and industry, is a fundamental reaction, usually using at least a stoichiometric amount of an expensive and toxic oxidant. Here, an efficient and practical sustainable oxidation technology of alcohols to carboxylic acids using pure O2 or even O2 in air as the oxidant has been developed: utilizing a catalytic amount each of Fe(NO3)3·9H2O/TEMPO/MCl, a series of carboxylic acids were obtained from alcohols (also aldehydes) in high yields at room temperature. A 55 g-scale reaction was demonstrated using air. As a synthetic application, the first total synthesis of a naturally occurring allene, i.e., phlomic acid, was accomplished.
- Jiang, Xingguo,Zhang, Jiasheng,Ma, Shengming
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supporting information
p. 8344 - 8347
(2016/07/26)
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- Lithocholic acid and derivatives: Antibacterial activity
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In order to develop bioactive lithocholic acid derivatives, we prepared fifteen semi-synthetic compounds through modification at C-3 and/or C-24. The reactions showed yields ranging from 37% to 100%. The structures of all compounds obtained were identified on the basis of their spectral data (IR, MS, 1D- and 2D-NMR). The activity of lithocholic acid and derivatives was evaluated against the growth of Escherichia coli, Staphylococcus aureus, Bacillus cereus and Pseudomonas aeruginosa. The derivative 3α-formyloxy-5β-cholan-24-oic acid (LA-06) showed the best activity, with MIC values of 0.0790 mM against E. coli (Ec 27) and B. cereus in both cases, and 0.0395 mM against S. aureus (ATCC 12692). Lithocholic acid and the derivatives with MIC ≤ 1.2 mM were evaluated on the susceptibility of some bacterial pathogens to the aminoglycoside antibiotics neomycin, amikacin and gentamicin was evaluated. There are no previously reported studies about these compounds as modifiers of the action of antibiotics or any other drugs.
- Do Nascimento, Patrícia G.G.,Lemos, Telma L.G.,Almeida, Macia C.S.,De Souza, Juliana M.O.,Bizerra, Ayla M.C.,Santiago, Gilvandete M.P.,Da Costa, José G.M.,Coutinho, Henrique D.M.
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- BILE ACID ANALOG TGR5 AGONISTS
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Provided herein are bile acid analogues and derivatives, methods of synthesizing bile acid analogues and derivatives and their use in treating diabetes and liver disease.
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Paragraph 0252
(2014/08/06)
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- Novel self-assembled lithocholic acid nanoparticles for drug delivery in cancer
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Novel versatile self-assembled nanoparticles were developed from biocompatible, biodegradable lithocholic acid derivatives. These nanoparticles can incorporate different cytotoxic drugs (paclitaxel and doxorubicin) and PI3K signalling inhibitor (PI103). D
- Patil, Sumersing,Patil, Sohan,Gawali, Suhas,Shende, Shrikant,Jadhav, Shraddha,Basu, Sudipta
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p. 19760 - 19764
(2013/11/06)
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- Characterization of rabbit aldose reductase-like protein with 3β-hydroxysteroid dehydrogenase activity
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In this study, we isolated the cDNA for a rabbit aldose reductase-like protein that shared an 86% sequence identity to human aldo-keto reductase (AKR)1 1B10 and has been assigned as AKR1B19 in the AKR superfamily. The purified recombinant AKR1B19 was similar to AKR1B10 and rabbit aldose reductase (AKR1B2) in the substrate specificity for various aldehydes and α-dicarbonyl compounds. In contrast to AKR1B10 and AKR1B2, AKR1B19 efficiently reduced 3-keto-5α/β-dihydro-C19/C21/C24-steroids into the corresponding 3β-hydroxysteroids, showing Km of 1.3-9.1 μM and kcat of 1.1-7.6 min-1. The stereospecific reduction was also observed in the metabolism of 5α- and 5β- dihydrotestosterones in AKR1B19-overexpressing cells. The mRNA for AKR1B19 was ubiquitously expressed in rabbit tissues, and the enzyme was co-purified with 3β-hydroxysteroid dehydrogenase activity from the lung. Thus, AKR1B19 may function as a 3-ketoreductase, as well as a defense system against cytotoxic carbonyl compounds in rabbit tissues. The molecular determinants for the unique 3-ketoreductase activity were investigated by replacement of Phe303 and Met304 in AKR1B19 with Gln and Ser, respectively, in AKR1B10. Single and double mutations (F303Q, M304S and F303Q/M304S) significantly impaired this activity, suggesting the two residues play critical roles in recognition of the steroidal substrate.
- Endo, Satoshi,Matsunaga, Toshiyuki,Kumada, Sho,Fujimoto, Airi,Hara, Akira,Ohno, Satoshi,El-Kabbani, Ossama,Hu, Dawei,Toyooka, Naoki,Mano, Jun'Ichi,Tajima, Kazuo
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p. 23 - 30,8
(2020/08/20)
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- Synthesis of lithocholic acid derivatives as proteasome regulators
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Accumulation of aberrant protein aggregates, such as amyloid β peptide (Aβ), due to decreased proteasome activities, might contribute to the neurodegeneration in Alzheimer's disease. In this study, lithocholic acid derivatives 3α-O-pimeloyl-lithocholic acid methyl ester (2) and its isosteric isomer (6) were found to activate the chymotrypsin-like activity of the proteasome at an EC50 of 7.8 and 4.3 μM, respectively. Replacing the C24 methyl ester in 2 with methylamide resulted in a complete devoid of proteasome activating activity. Epimerizing the C3 substituent from an α to β orientation transformed the activator into a proteasome inhibitor. Unlike the cellular proteasome activator PA28, proteasome activated by 2 was not inhibited by Aβ. Furthermore, 2 potently antagonized the inhibitory effect of Aβ on the proteasome. In summary, compound 2 represents a novel class of small molecules that not only activates the proteasome but also antagonizes the inhibitory effect of Aβ on the proteasome.
- Dang, Zhao,Jung, Kathy,Qian, Keduo,Lee, Kuo-Hsiung,Huang, Li,Chen, Chin-Ho
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supporting information
p. 925 - 930
(2013/01/15)
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- Lithocholic acid analogues, new and potent α-2,3-sialyltransferase inhibitors
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A new type of noncompetitive α-2,3-sialyltransferase inhibitor has been synthesized; we report the discovery, preparation and inhibitory activity of sixteen lithocholic acid analogues. The Royal Society of Chemistry 2006.
- Chang, Kai-Hsuan,Lee, Lenselot,Chen, Jessica,Li, Wen-Shan
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p. 629 - 631
(2008/02/10)
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- Diversity oriented one-pot synthesis of complex macrocycles: Very large steroid-peptoid hybrids from multiple multicomponent reactions including bifunctional building blocks
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Sixteen in one go: Up to 16 new bonds connect 12 building blocks to form 54-membered macrocycles (46-membered example shown) in a one-pot procedure combining bifunctional components with multicomponent reactions. The large rings are not made of repetitive subunits and form an ideal basis for the fast construction of libraries of chiral host molecules. (Chemical Equation Presented)
- Wessjohann, Ludger A.,Voigt, Brunhilde,Rivera, Daniel G.
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p. 4785 - 4790
(2007/10/03)
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- Synthesis of dinorcholane and 5β-cholane derivatives
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The convenient synthesis of seven dinorcholane and 5β-cholane derivatives, 3β-acetoxy-23,24-dinorchol-5-en-22-oyl methoxy anhydride (2), 3β-acetoxy-23,24-dinorchol-5-en-22-oyl chloride (3), 3β-acetoxy-23,24- dinorchol-5-en-22-ol (4), 3α-acetoxy-5β-cholan-24-oic acid (6), 3α-acetoxy-5β-cholan-24-oic acid ethyl ester (7), 3-oxo-5β-cholan-24-oic acid (8) and 3-oxo-5β-cholan-24-oic acid ethyl ester (9) have been described. Full spectroscopic data for these compounds are presented.
- Nahar, Lutfun,Turner, Alan B.
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p. 329 - 332
(2007/10/03)
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- Synthesis and characterization of lithocholic acid derived dipyrromethanes: Precursors for pyrrole-steroidal macrocycles
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Three steroidal dipyrromethanes, 3,3,24,24-tetrakis(pyrrol-2-yl)-5β- cholane 1, 3,3-bis(pyrrol-2-yl)-5β-cholan-24-oic acid 2, and methyl 3,3-bis(pyrrol-2-yl)-5β-cholan-24-oate 3, have been prepared from 3α-hydroxy-5β-cholan-24-oic acid (lithocholic acid) 4 in good overall yields. The structures of 1-3 have been fully characterized by 1H, 13C, PFG DQF 1H-1H COSY, 1H- 1H ROESY, 13C DEPT-135, PFG 1H-13C HMQC, PFG 1H-13C HMBC, and PFG 1H- 15N HMBC NMR spectra. Their molecular weights and compositions have been determined by ESI-TOF and EI mass spectra, and elemental analyses. The energetically optimised geometry and isotropic 13C NMR chemical shifts of 3,3,24,24-tetrakis(pyrrol-2-yl)-5β-cholane 1 have been calculated by ab initio HF/6-31G* and DFT B3PW91/6-311G* methods.
- Koivukorpi, Juha,Valkonen, Arto,Kolehmainen, Erkki
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- Synthesis of ester-linked lithocholic acid dimers
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Four lithocholic acid dimers were synthesised via esterification. The ester-linked dimer, 3-oxo-5β-cholan-24-oic acid (cholan-24-oic acid methyl ester)-3-yl ester, (3α,5β), was obtained by condensation of methyl lithocholate with 3-oxo-5β-cholan-24-oic acid. Borohydride reduction of this ester-linked dimer gave 3α-hydroxy-5β-cholan-24-oic acid (cholan-24-oic acid methyl ester)-3-yl ester, (3α,5β), which was acetylated to 3α-acetoxy-5β-cholan-24-oic acid (cholan-24-oic acid methyl ester)-3-yl ester, (3α,5β). Reaction of methyl lithocholate with oxalyl chloride yielded the oxalate dimer, bis(5β-cholan-24-oic acid methyl ester)-3α-yl oxalate.
- Nahar, Lutfun,Turner, Alan B.
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p. 1157 - 1161
(2007/10/03)
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- Preparation of bile acids
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Certain bile acids find use in the pharmaceutical industry. In view of the wide distribution of serious diseases such as HIV, AIDS and Bovine Spongiform Encephalopathy (BSE) it is desirable to avoid—as far as practicable—to have any components of animal origin in medicaments in order to eliminate any danger of infection. The present invention relates to a method of providing bile acids from non-animal starting materials.
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- Catalytic oxidations of steroid substrates by artificial cytochrome p-450 enzymes.
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Catalysts comprising manganese-porphyrins carrying cyclodextrin binding groups are able to perform hydroxylations with substrate selectivity and regio- and stereoselectivity and high catalytic turnovers. The geometries of the catalyst/substrate complexes override intrinsic substrate reactivities, permitting attack on geometrically accessible saturated carbons of steroids in the presence of secondary carbinol groups and carbon-carbon double bonds, as in enzymatic reactions. Selective hydroxylations of steroid carbon 9 positions are of particular practical interest.
- Yang, Jerry,Gabriele, Bartolo,Belvedere, Sandro,Huang, Ying,Breslow, Ronald
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p. 5057 - 5067
(2007/10/03)
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- Improved enantioselectivity in the epoxidation of cinnamic acid derivatives with dioxiranes from keto bile acids
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The asymmetric epoxidation of substituted cinnamic acids has been obtained in the presence of different keto bile acid derivatives as optically active carbonyl inducers and Oxone as oxygen source. Predominant or almost exclusive formation of both enantiomeric epoxides is obtained (ee up to 95%) depending on the specific substitution at carbons C(7) and C(12) of the bile acid.
- Bortolini, Olga,Fantin, Giancarlo,Fogagnolo, Marco,Forlani, Roberto,Maietti, Silvia,Pedrini, Paola
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p. 5802 - 5806
(2007/10/03)
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- Regiospecific oxidoreductions catalyzed by a new Pseudomonas paucimobilis hydroxysteroid dehydrogenase
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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)
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- Antimicrobial activity of basic cholane derivatives. X. Synthesis of 3α- and 3β-amino-5β-cholan-24-oic acids
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A simple and convenient route to 3α- and 3β-amino-5β-cholan-24-oic acids was developed via Leuckart-Wallach amination reduction and subsequent acid hydrolysis.Two epimeric formylamino derivatives were produced (α and β), approximately in a 1:1 ratio, as determined by 13C nuclear magnetic resonance spectroscopy.The two isomers were separated by making use of their different solubilities in ethyl ether.The absolute configuration of the two amino acids was assigned by comparison with authentic reference samples.Keywords: Leuckart-Wallach reaction; 3-amino-5β-cholan-24-oic acids; epimers; separation; absolute configuration; steroids; synthesis, 3α- and 3β-amino-5β-cholan-24-oic acids
- Bellini, Anna M.,Mencini, Elena,Quaglio, Maria P.,Guarneri, Mario,Fini, Adamo
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p. 395 - 398
(2007/10/02)
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