- Synthesis of deuterium-labeled 17-hydroxyprogesterone suitable as an internal standard for isotope dilution mass spectrometry
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A synthesis is reported of 17-hydroxyprogesterone, labeled with four atoms of deuterium at ring C and suitable for use as an internal standard for isotope dilution mass spectrometry. Base-catalyzed equilibration of methyl 3α-acetoxy-12-oxo-cholanate (III) with 2H2O, followed by reduction of the 12-oxo group by the modified Wolff-Kisher method using [2H]diethylene glycol and [2H]hydrazine hydrate afforded [11, 11, 12, 12, 23, 23-2H]lithocholic acid (V). The Meystre-Miescher degradation of the side chain of V yielded 3α-hydroxy-5β-[11, 11, 12, 12-2H]pregnan-20-one (X). Oxidation of the 3,20-enol-diacetate of X with perbenzoic acid followed by saponification afforded 3α,17-dihydroxy-5β-[11, 11, 12, 12-2H]pregnan-20-one (XI). Oxidation of XI with N-bromoacetamide yielded 17-hydroxy-5β-[11, 11, 12, 12-2H]pregnane-3,20-dione (XII). Bromination of XII followed by dehydrobromination yielded 17-hydroxy-[11, 11, 12, 12-2H] progesterone (XIV) consisting of 0.3% 2H0-, 1.1% 2H1-, 8.6% 2H2-, 37.1% 2H3-, 52.1% 2H4-, and 0.8% 2H5-species.
- Shimizu,Yamaga,Kohara
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- Synthesis and biological activity of novel deoxycholic acid derivatives
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We report the synthesis and biological activity of new semi-synthetic derivatives of naturally occurring deoxycholic acid (DCA) bearing 2-cyano-3-oxo-1-ene, 3-oxo-1(2)-ene or 3-oxo-4(5)-ene moieties in ring A and 12-oxo or 12-oxo-9(11)-ene moieties in ring C. Bioassays using murine macrophage-like cells and tumour cells show that the presence of the 9(11)-double bond associated with the increased polarity of ring A or with isoxazole ring joined to ring A, improves the ability of the compounds to inhibit cancer cell growth.
- Popadyuk, Irina I.,Markov, Andrey V.,Salomatina, Oksana V.,Logashenko, Evgeniya B.,Shernyukov, Andrey V.,Zenkova, Marina A.,Salakhutdinov, Nariman F.
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- Bile acid-derived molecular tweezers: Study of solvent effects in binding, and determination of thermodynamic parameters by an extraction-based protocol
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A family of bile acid-based molecular tweezers (1-3) were synthesized, and their binding affinities with picric acid in different solvents were evaluated using a simple extraction-based protocol. The binding affinities increased in nonpolar solvents. The size of the solvent molecule did not affect the binding constant. Thermodynamic parameters for the binding of picric acid in CCl4 were also determined by this method. Binding constants of these tweezers with trinitrofluorenone in CDCl3 were determined by NMR titration.
- Potluri,Maitra
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- Chemical Synthesis of Rare Natural Bile Acids: 11α-Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids
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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.
- Namegawa, Kazunari,Iida, Kyoko,Omura, Kaoru,Ogawa, Shoujiro,Hofmann, Alan F.,Iida, Takashi
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p. 403 - 411
(2018/06/08)
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- The synthesis and antitumor activity of lithocholic acid and its derivatives
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In this paper, a new and concise synthetic route of lithocholic acid (LCA) using commercially available steroid source deoxycholic acid is reported. A series of amide derivatives of LCA were also synthesized and investigated for their activity against the growth of MCF-7 and MCF-7/ADR cells using the sulforhodamine B assay. For MCF-7, the most potent compound 20 showed a 20-fold higher antitumor activity than LCA. For MCF-7/ADR, the most potent compound 24 showed a 22-fold higher antitumor activity than LCA. The transwell migration assay of 20 was evaluated on MDA-MB-231 cells. The colony formation and apoptosis assays of 20 were performed on MCF-7 and MCF-7/ADR cell lines.
- He, Xiao-Long,Xing, Yajing,Gu, Xiang-Zhong,Xiao, Jie-Xin,Wang, Ying-Ying,Yi, Zhengfang,Qiu, Wen-Wei
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- Chemical synthesis of uncommon natural bile acids: The 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids
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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.
- Iida, Takashi,Namegawa, Kazunari,Nakane, Naoya,Iida, Kyoko,Hofmann, Alan Frederick,Omura, Kaoru
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p. 1397 - 1402
(2016/10/03)
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- Synthesizing method of lithocholic acid
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The invention discloses a synthesizing method of lithocholic acid. The synthesizing method is characterized in that deoxycholic acid is used as the raw material, and the deoxycholic acid is subjected to reactions such as methyl esterification protection, acetic anhydride protection of 3 hydroxyl groups, dewatering, hydrogenation and hydrolysis to synthesize the lithocholic acid. The synthesizing method is simple in step, few in side reaction, high in yield, easy in raw material obtaining, suitable for industrial production, and capable of solving the problems that the prior art is excessively high in synthesizing cost, low in yield and not suitable for large-scale industrial production.
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- METHODS FOR THE PURIFICATION OF DEOXYCHOLIC ACID
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Synthetic methods for preparing deoxycholic acid and intermediates thereof, high purity synthetic deoxycholic acid, compositions and methods of use are provided. Also, provided are processes for the synthesis of 12-keto or 12-α-hydroxy-steroids from Δ-9,11-ene, 11-keto or 11-hydroxy-β-steroids. This invention is also directed to novel compounds prepared during the synthesis. This invention is also directed to the synthesis of deoxycholic acid starting from hydrocortisone.
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Paragraph 0444
(2013/06/05)
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- METHODS FOR THE SYNTHESIS AND PURIFICATION OF DEOXYCHOLIC ACID
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Synthesis and purification of deoxycholic acid and its salts are provided.
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Page/Page column 17
(2013/02/28)
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- METHODS FOR THE PURIFICATION OF DEOXYCHOLIC ACID
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Synthetic methods for preparing deoxycholic acid and intermediates thereof, high purity synthetic deoxycholic acid, compositions and methods of use are provided. Also, provided are processes for the synthesis of 12-keto or 12-α-hydroxysteroids from Δ-9,11-ene, 11-keto or 11-hydroxy-β-steroids. This invention is also directed to novel compounds prepared during the synthesis. This invention is also directed to the synthesis of deoxycholic acid starting from hydrocortisone.
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Page/Page column 85-86
(2011/07/07)
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- Synthesis of deoxycholic-derived chiral stationary phases possessing both arylcarbamate and arylamide moieties: Evaluation of their chiral discrimination properties in the HPLC resolution of racemic compounds
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Two families of chiral selectors derived from deoxycholic acid, possessing both an arylamide and an arylcarbamate group on the cholestanic backbone were synthesized and covalently bonded to silica gel to afford new chiral stationary phases (CSPs A1-D1 and A2-D2) for the HPLC resolution of racemic compounds. The chromatographic data concerning the resolution of selected racemic compounds on CSPs A1-D1 and A2-D2 were compared with those obtained using analogous CSPs possessing only arylcarbamate groups on the cholestanic system (CSPs A-D). This has allowed us to establish that the resolution capability of CSPs A1-D1 and A2-D2 depends not only on the position of the arylamide group on the cholestanic backbone, but also on the electronic characteristics of the aromatic substituents.
- Iuliano,Masini,Felix,Salvadori
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p. 2811 - 2825
(2007/10/03)
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- Solvent effect in molecular recognition: Determining binding constants in different solvents following an extraction based protocol
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Semi-rigid molecular tweezers 1, 3 and 4 bind picric acid with more than tenfold increment in tetrachloromethane as compared to chloroform.
- Maitra, Uday,Rao, Photon,Vijay Kumar,Balasubramanian,Mathew, Lizamma
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p. 3255 - 3258
(2007/10/03)
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- Substituted Methyl 5β-Cholan-24-oates. I - 17O NMR Spectral Characterization
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Methyl esters of four common bile acids, 3α-hydroxy-5β-cholan-24-oic (lithocholic) acid, 3α,7α-dihydroxy-5β-cholan-24-oic (chenodeoxycholic) acid, 3α,12α-dihydroxy-5β-cholan-24-oic (deoxycholic) acid and 3α,7α,12α-trihydroxy-5β-cholan-24-oic (cholic) acid, and 14 acetylated, trifluoroacetylated, mesylated and oxo derivatives of methyl 5β-cholan-24-oates were prepared and their 17O NMR spectra recorded.In spite of their relatively high molecular masses and the rigid molecular structure of the steroid skeleton, most of the oxygens included in these structures gave well resolved 17O NMR resonance lines at natural abundance in 0.25-0.5 M acetonitrile solutions at 75 deg C.In agreement with the present 17O NMR results, molecular mechanics calculations revealed that a hydroxy substituent located at the 3α-position clearly differs from the hydroxyls at the 7α- and 12α-positions.This is due to the fact that the 3α-hydroxyl possesing only two γ-carbons at antiperiplanar positions is less shielded than the other hydroxyls influenced also by the shielding effects of γ-gauche carbons.The spectral deconvolution of the overlapping signals of the 7α- and 12α-hydroxyls is based on a computer-aided method or on chemical substitutions.The oxo groups located at the longitudinal (3-oxo) vs. transversal (7- and 12-oxo) axes of the steroid framework show very different quadrupolar relaxation properties and 17O NMR linewidths owing to the strong anisotropy of overall molecular motion.In contrast, the 17O NMR linewidths of all 3α-, 7α- and 12α-hydroxyls are very similar and clearly smaller than those of the corresponding oxo groups, revealing that their quadrupolar relaxtion is merely determined by their internal rotation rather than by the overall molecular motion. - Keywords: NMR 17O NMR 17O chemical shifts 17O relaxation Methyl 5β-cholan-24-oates Methyl esters of bile acids
- Kolehmainen, Erkki,Kaartinen, Mari,Kauppinen, Reijo,Kotoneva, Jari,Lappalainen, Kari,et al.
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p. 441 - 445
(2007/10/02)
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- REDUCTION OF 12-OXO DERIVATIVES OF SOME BILE ACIDS
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Methyl ester of 3α-acetoxy-12-oxo-9 (11)-cholenic acid and some other analogous compounds were reduced to the corresponding 9(11)-unsaturated 12-hydroxy derivatives by the action of sodium borohydride in the presence of cerium(III) chloride.A part of our work, viz. preparation of steroid hormones from bile acids, was the reduction of 9(11)-unsaturated 12-oxo derivatives of some bile acids, with the view of obtaining the corresponding 9(11)-unsaturated 12-hydroxy derivatives.Hitherto, the only safe route has been hydrogenation of starting 9(11)-unsaturated 12-oxo derivatives on platinum at elevated pressures, which, preserving the allyl double bond, yields a mixture of the two isomeric 12-hydroxy derivatives.
- Mickova, Ruzena
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p. 1239 - 1243
(2007/10/02)
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