Intramolecular cyclisation reactions of 5beta-cholan-24-amide, 3alpha-acetoxy-5beta-cholan-24-amide, and 3alpha-acetoxy-5beta-cholan-24-ol.
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Acetates↗
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Synthesis of new bile salt analogues, sodium 3 alpha, 7 alpha-dihydroxy-5 beta-cholane-24-sulfonate and sodium 3 alpha, 7 beta-dihydroxy-5 beta-cholane-24-sulfonate.
This report describes the chemical synthesis of two new bile salt analogues, namely sodium 3 alpha,7 alpha-dihydroxy-5 beta-cholane-24-sulfonate and sodium 3 alpha,7 beta-dihydroxy-5 beta-cholane-24-sulfonate from chenodeoxycholic acid and ursodeoxycholic acid, respectively. Each common bile acid was converted into the corresponding 5 beta-cholane-3,7,24-triol by treatment with ethyl chloroformate in the presence of triethylamine followed by sodium borohydride reduction. Reaction of the cholanetriol with p-toluenesulfonyl chloride at 4 degrees C afforded the partially tosylated product, 24-p-toluenesulfoxy-5 beta-cholane-3,7-diol, which was then treated with sodium iodide to produce 24-iodo-5 beta-cholane-3,7-diol. The 24-iodide was refluxed with sodium sulfite in aqueous ethanol to give the desired sulfonate analogue of the naturally occurring bile acid, chenodeoxycholic acid or ursodeoxycholic acid.
Bile Acids and Salts↗
Sulfonate analogues of chenodeoxycholic acid: metabolism of sodium 3 alpha, 7 alpha-dihydroxy-25-homo-5 beta-cholane-25-sulfonate and sodium 3 alpha, 7 alpha-dihydroxy-24-nor-5 beta-cholane-23-sulfonate in the hamster.
This report describes the chemical synthesis of a new bile acid analogue, namely, sodium 3 alpha, 7 alpha-dihydroxy-25-homo-5 beta-cholane-25-sulfonate from homochenodeoxycholic acid. The structure of the new compound was assigned by proton magnetic resonance and infrared spectrometry. Its metabolism was studied in the hamster in comparison with sodium 3 alpha, 7 alpha-dihydroxy-24-nor-5 beta-cholane-23-sulfonate and sodium taurochenodeoxycholate. After intraduodenal administration of the 3H-labeled analogues into bile fistula hamsters, both sulfonates were absorbed from the intestine and nearly 80% of the radioactivity was secreted into bile within 8 h. Intra-ileal administration revealed that these compounds resembled taurochenodeoxycholate in that they were much more rapidly absorbed from the ileum than from the proximal small intestine: more than 85% of the radioactivity was recovered in bile within 1 h. After intravenous infusion the sulfonates were efficiently extracted by the liver at rates similar to that of sodium taurochenodeoxycholate. Chromatographic analysis of the bile showed that, regardless of the route of administration, most (> 95%) of the sulfonates were not biotransformed and they became major biliary bile acids. Sodium 3 alpha, 7 alpha-dihydroxy-25-homo-5 beta-cholane-25-sulfonate and, to a lesser extent, sodium 3 alpha, 7 alpha-dihydroxy-24-nor-5 beta-cholane-23-sulfonate induced cholestasis at infusion rates at which sodium taurochenodeoxycholate produced choleresis.
Animals↗
Synthesis and absolute configuration at C-23 of [23R and 23S]-3 alpha, 7 alpha, 23-trihydroxy-5 beta-cholan-24-oic and [23R and 23S]-3 alpha, 7 alpha, 12 alpha, 23-tetrahydroxy-5 beta-cholan-24-oic acids.
A synthesis of /23R and 23S/-3 alpha, 7 alpha, 23-trihydroxy-5 beta-cholan-24-oic acids is described. Lithium enolate of completely protected starting chenodeoxycholic acid was directly hydroxylated at C-23 by the oxidoperoxymolybdenum /hexamethylphosphoric triamide/ /pyridine/ complex. The resulting derivatives containing hydroxyl group at C-23 were separated by liquid column chromatography and their configurations at C-23 were assigned by molecular rotation as well as circular dichroism measurements. In a similar way /23R and 23S/-3 alpha, 7 alpha, 12 alpha, 23-tetrahydroxy-5 beta-cholan-24-oic acids were prepared and their structures identified. Synthetic compounds of the 23R configuration proved to be identical with the bile acids previously isolated from seal bile.
Cholic Acids↗
Antimicrobial activity of basic cholane derivatives. X. Synthesis of 3 alpha- and 3 beta-amino-5 beta-cholan-24-oic acids.
A simple and convenient route to 3 alpha- and 3 beta-amino-5 beta-cholan-24-oic acids was developed via Leuckart-Wallach amination reduction and subsequent acid hydrolysis. Two epimeric formylamino derivatives were produced (alpha and beta), 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.
Lithocholic Acid↗
Ganglion-blocking activity of bisquaternary ammonium salts derived from 3 ,12 -diamino-5 -cholane and 3 ,12 -diamino-24-nor-5 -cholane.
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Amines↗
Novel derivatives of 3 alpha,7 alpha-dihydroxy-5 beta-cholan-24-oic acid (chenodeoxycholic acid) and 3 alpha,7 beta-dihydroxy-5 beta-cholan-24-oic acid (ursodeoxycholic acid).
Several 7-acyl cheno- and ursodeoxycholic acids were obtained in good yields starting from the corresponding cheno- and ursodeoxycholic acids, by a diacylation-selective hydrolysis procedure. A superior method for the synthesis of the 7-oleyl derivatives, by a selective acylation procedure, is also presented.
Chemical Phenomena↗
Synthesis of (22R and 22S)-3 alpha, 7 alpha, 22-trihydroxy-5 beta-cholan-24-oic acids and structure of haemulcholic acid, a unique bile acid isolated from fish bile.
(22R and 22S)-3 alpha, 7 alpha, 22-trihydroxy-5 beta-cholan-24-oic acids were synthesized, starting from chenodeoxycholic acid, in order to establish the chemical structure of haemulcholic acid, which has been found in certain fish as the major bile component. Oxidative decarboxylation of diformoxylated chenodeoxycholic acid with lead tetraacetate yielded 24-nor-5 beta-chol-22-ene-3 alpha, 7 alpha-diol, which was hydroxylated to form a mixture of (22R and 22S)-24-nor-5 beta-cholane-3 alpha, 7 alpha, 22,23-tetrols. Lead tetraacetate oxidation of the mixture yielded 3 alpha, 7 alpha-dihydroxy-23,24-dinor-5 beta-cholan-22-a1. A Reformatsky reaction of the dihydroxydinorcholanal with bromoacetate resulted in the formation of a mixture of (22R and 22S)-3 alpha, 7 alpha, 22-trihydroxy-5 beta-cholan-24-oic acids. The bile acids epimeric at C-22 were resolved by silica gel column chromatography, and their configurations of C-22 were assigned by a modification of Horeau's method and 13C-nuclear magnetic resonance spectroscopy. By direct comparison with synthetic bile acids, the naturally occurring haemulcholic acid was shown to be (22S)-3 alpha, 7 alpha, 22-trihydroxy-5 beta-cholan-24-oic acid.
Animals↗
Transformation of cholanic acid derivatives into pharmacologically active esters of phenolic acids by heterogeneous Wittig reaction.
Steroid esters of cynnamic acid derivatives have been synthesized by a heterogeneous Wittig reaction under sonochemical conditions from the corresponding triphenylphosphonium bromides and unprotected phenolic aldehyds using K2CO3 as a base. 5 beta-Cholan-3 alpha, 7 alpha, 12 alpha, 24-E-ferulate (11') exhibited a marked inhibitory effect on influenza virus A. The synthetic 3 alpha, 24-E-diferulates of 5 beta-cholan-3 alpha, 24- diol, 5 beta-cholan-3 alpha, 12 alpha, 24-triol and 5 beta-cholan-3 alpha, 7 alpha, 12 alpha, 24-tetrol (8, 9 and 12) showed antitumor activity on leukemia P-388 in mice.
Animals↗
Enzymes involved in the formation of 3 beta, 7 beta-dihydroxy-12-oxo-5 beta-cholanic acid from dehydrocholic acid by Ruminococcus sp. obtained from human intestine.
Ruminococcus sp. PO1-3 from human intestinal flora reduced dehydrocholic acid to 3 beta-hydroxy-7,12-dioxo-5 beta-cholanic acid by means of the enzyme 3 beta-hydroxysteroid dehydrogenase (Akao, T., Akao, T., Hattori, M., Namba, T. and Kobashi, K. (1986) J. Biochem. (Tokyo) 99, 1425-1431). This bacterium and its crude extract gave rise to another product, showing a lower RF value on TLC, from dehydrocholic acid. The product was identified as 3 beta, 7 beta-dihydroxy-12-oxo-5 beta-cholanic acid. The crude extract reduced 7-ketolithocholic acid and its methyl ester, but not 6-ketolithocholic acid and 12-ketochenodeoxycholic acid, in the presence of NADPH, and oxidized ursodeoxycholic acid and beta-muricholic acid, but not cholic acid, chenodeoxycholic acid, deoxycholic acid and hydrocholic acid, in the presence of NADP+. Therefore, besides 3 beta-hydroxysteroid dehydrogenase, 7 beta-hydroxysteroid dehydrogenase was shown to be present in this bacterium. The two dehydrogenases were clearly separated from each other by butyl-Toyopearl 650 M column chromatography. From dehydrocholic acid, 7 beta-hydroxy-3,12-dioxo-5 beta-cholanic acid was produced by 7 beta-hydroxysteroid dehydrogenase and 3 beta, 7 beta-dihydroxy-12-oxo-5 beta-cholanic acid was produced by combination of two enzymes, 7 beta- and 3 beta-hydroxysteroid dehydrogenase.
3-Hydroxysteroid Dehydrogenases↗
3 alpha, 7 alpha, 12 alpha-trihydroxy-24-nor-5 beta-cholan-23-sulfonate: synthesis and suitability for the study of cholate transport.
In order to facilitate the study of transport processes of unconjugated C-24 bile salts, simple syntheses of 3 alpha, 7 alpha, 12 alpha-trihydroxy-24-nor-5 beta-cholan-23-sulfonate (norcholansulfonate) and 3 alpha, 7 alpha, 12 alpha-trihydroxy-24-nor-5 beta-[7 beta 5H] cholan-23-sulfonate were devised. The hydrophilic-hydrophobic properties of norcholansulfonate, as determined by its chromatographic behavior as well as by its partition between l-octanol and water, are more similar to those of cholyltaurine than to those of cholate. Self-association of norcholansulfonate in phosphate buffer, pH 7.4, with an ionic strength of 150 mM begins at a concentration of about 1 mM, comparable to that of cholyltaurine and cholate, as determined by spectral changes in fluorescence emissions of {N-[7-(4-nitrobenzo-2-oxa-1, 3-diazol)]-7b-amino-3a, 12a-dihydroxy-5b-cholan-24 - oyl}-2'-aminoethanesulfonate (7 beta-NBD-NCT). The apparent CMC value obtained from solubilization of the dye Orange OT, 8.5 mM, is comparable to that of cholytaurine. 7.5 mM, and lower than that of cholate, 9.5 mM. Norcholansulfonate is readily taken up by rat liver and completely excreted unmetabolized into bile with about the same secretion maximum (Tm) as cholyltaurine. Biliary excretion of norcholansulfonate is inhibited by cholyltaurine, and, vice versa, norcholansulfonate inhibits cholyltaurine secretion. Concerning metabolism and excretion, norcholansulfonate with the sulfonate group in the position where cholate has the carboxylate group should behave as an appropriate cholate analogue in mediated transport processes.
Animals↗
Toxicity order of cholanic acids using an immobilised cell biosensor.
There is considerable published evidence of the use of cells of various species to evaluate the toxicity of numerous compounds, many of pharmaceutical interest. The coupling of cell colonies with a suitable transduction device has led to the development in recent years of toxicity biosensors based on the alteration of a process or a cell metabolic function by the toxic substance under examination. A biosensor based on immobilised yeast cells (Saccharomyces cerevisiae) has been developed recently in this department for the purpose of performing a rapid toxicity test in aqueous environmental matrices. This biosensor has now been used in the toxicity screening of a number of sodium salts of conjugated and free cholanic acids. The "toxicity degree" scale, which was found by placing in decreasing order the values of the slopes of the straight lines obtained by quantifying changes in the behaviour of the respirometric curve, plotted before and after incubation, using known concentrations of cholanic acid sodium salts, was: deoxycholic acid > chenodeoxycholic acid > ursodeoxycholic acid > cholic acid, for free cholanic acids; and glycodeoxycholic acid > glycochenodeoxycholic acid > glycocholic acid, for glycocholanic acids. These values are in good agreement with published toxicity data obtained in vitro. This sensor can thus be considered to provide a valid instrument for the preliminary evaluation of the toxicity of organic compounds or drugs.
Biosensing Techniques↗
Synthesis of 24-nor-5 beta-cholan-23-oic acid derivatives: a convenient and efficient one-carbon degradation of the side chain of natural bile acids.
An efficient procedure for obtaining nor-bile acids from natural (C24) bile acids is described. Treatment of formylated bile acids with sodium nitrite in a mixture of trifluoroacetic anhydride with trifluoroacetic acid gives, through a "second order" Beckmann rearrangement, 24-nor-23-nitriles. These compounds, on alkaline hydrolysis, afford the corresponding nor-bile acids in high yields. The sequence was successfully applied to the synthesis of 3 alpha-hydroxy-24-nor-5 beta-cholan-23-oic (norlithocholic) acid, 3 alpha,6 alpha- (norhyodeoxycholic), 3 alpha,7 alpha- (norchenodeoxycholic), 3 alpha,7 beta- (norursodeoxycholic), and 3 alpha,12 alpha-dihydroxy-24-nor-5 beta-cholan-23-oic (nordeoxycholic) acids, as well as 3 alpha,7 alpha,12 alpha-trihydroxy-24-nor-5 beta-cholan-23-oic (norcholic) acid. 13C-NMR spectra of their methyl esters are reported. The procedure provides a more rapid alternative to the Barbier-Wieland degradation for shortening by one methylene group the side chain of natural (C24) bile acids.
Bile Acids and Salts↗
Vulpecholic acid (1 alpha, 3 alpha, 7 alpha-trihydroxy-5 beta-cholan-24-oic acid): a novel bile acid of a marsupial, Trichosurus vulpecula (Lesson).
A novel trihydroxylated C24 bile acid was isolated from the gallbladder bile of the Australian opossum, Trichosurus vulpecula (Lesson). This acid, for which the name vulpecholic acid is proposed, was identified as 1 alpha, 3 alpha, 7 alpha-trihydroxy-5 beta-cholan-24-oic. The structure proof included mass spectral and 1H and 13C nuclear magnetic resonance characterization of all crucial derivatives obtained by: oxidation of the methyl ester to a triketone with the enolizable 1,3-diketone function; methylation of this triketone to two isomeric methyl enol ethers; and reductive removal of oxygen functions from this triketone to give 5 beta-cholan-24-oic and 7-oxo-5 beta-cholan-24-oic acids. Vulpecholic acid was found in the bile in the unconjugated form; it accounted for more than 60% of the solid bile material. The marsupial T. vulpecula is the first example of a mammal secreting a 1 alpha-hydroxylated bile acid as well as the first example of a mammal secreting the major bile acid in a free form.
Animals↗
Identification of 3 beta, 7 beta-dihydroxy-5 beta-cholan-24-oic acid in serum from patients treated with ursodeoxycholic acid.
An unknown bile acid was found by gas-liquid chromatography in the serum of patients who were administered ursodeoxycholic acid for the treatment of cholesterol gallstones. Identification of the chemical structure of the unknown bile acid was performed by the use of gas-liquid chromatography-mass spectrometry. Mass spectrum analysis of the methyl ester trimethylsilyl ether of the bile acid showed explicitly that this is dihydroxy-5 beta-cholanoic acid, since peaks at m/e 460 and 370 characteristic of methyl ester trimethylsilyl ether of dihydroxy bile acid were clearly exhibited. Sites of the two hydroxyl groups on the steroid nucleus were determined to be at the 3- and 7-positions by conversion of the bile acid to the corresponding dioxo-cholanoic acid and by comparison of the gas-liquid chromatographic behavior with those of authentic dioxo bile acids. Four authentic 3,7-dihydroxy-5 beta-cholan-24-oic acids were chemically synthesized and retention times and mass spectra of their methyl ester trimethylsilyl ether derivatives compared precisely with that of the unknown bile acid. The results indicate that the unknown bile acid is 3 beta, 7 beta-dihydroxy-5 beta-cholan-24-oic acid. Preliminary experiments suggest that 3 beta, 7 beta-dihydroxy-5 beta-cholan-24-oic acid is absent as amino acid-conjugated forms in serum. It is also suggested that the bile acid is excreted into urine but not into bile.
Bile Acids and Salts↗
The synthesis of methyl 3 alpha, 7 alpha-diacetoxy-11-oxo-5 beta-cholan-24-oate.
Reaction of methyl-3 alpha-7 alpha-diacetoxy-11 alpha-bromo-12-oxo-5 beta-cholan-24-oate with sodium borohydride in pyridine solution containing sodium acetate gave the corresponding 11 beta, 12 beta-epoxide in 65% yield. The epoxy-ring was opened with hydrobromic or hydroiodic acid to give the corresponding 12 alpha-halo-11 beta-alcohols, which were converted to the halo-ketones and finally to methyl 3 alpha,7 alpha-diacetoxy-11-oxo-5 beta-cholan-24-oate.
Borohydrides↗
Potential tissue-imaging agents: 23-(trimethyl [117mSn]stannyl)-24-nor-5 alpha-cholan-3 beta-ol.
Tin-117m-labeled 23-(trimethylstannyl)-24-nor-5 alpha-cholan-3 beta-ol (2) has been prepared by reaction of trimethyl [117mSn]tin lithium with 3 beta-acetoxy-23-bromo-24-nor-5 alpha-cholane (1). Tin-117m (2) shows pronounced adrenal uptake (2.5% injected dose) in female rats 1 day after injection. Furthermore, the adrenal to liver (9.1:1) and adrenal to blood (33.7:1) ratios are high after this period. The absorbed radiation dose values from [117mSn]2 to human organs have also been estimated by using rat tissue distribution and excretion data. [117mSn]2 is the first reported tissue-specific organic radiopharmaceutical labeled with this nuclide and may have potential as an adrenal imaging agent.
Adrenal Glands↗
Synthesis of 6-hydroxylated bile acids and identification of 3 alpha,6 alpha,7 alpha,12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid in human meconium and neonatal urine.
Three 6-hydroxylated bile acids, 3 alpha,6 alpha,7 alpha,12 alpha-, 3 alpha,6 beta,7 alpha,12 alpha- and 3 alpha,6 beta,7 beta,12 alpha-tetrahydroxy-5 beta-cholan-24-oic acids, were synthesized from methyl cholate, and a sensitive method was developed for analyzing them by gas chromatography-mass spectrometry for the stoichiometric study of fetal bile acids. 3 alpha,6 alpha,7 alpha,12 alpha-Tetrahydroxy-5 beta-cholan-24-oic acid (6 alpha-hydroxylated cholic acid) was identified from human meconium and healthy neonatal urine by comparison with the mass spectrum of the reference compound. In human meconium, 6 alpha-hydroxylated cholic and chenodeoxycholic acids were determined in 1.2% and 29.0% of the total bile acids, respectively. We discuss the significance of hydroxylation at the C-1 beta and C-6 alpha positions of bile acids and their elimination in fetal and neonatal periods.
Bile Acids and Salts↗