Effect of the presence of a free hydroxyl group on the enantiodiscrimination properties of cholic acid based CSPs bearing 2-naphthylcarbamate and 3,5-dinitrophenylcarbamate moieties in the HPLC resolution of racemic compounds

Two new chiral selectors, obtained by derivatizing two of the three hydroxyl groups of cholic acid with 2-naphthylisocyanate and 3,5-dinitrophenylisocyanate, have been prepared and linked to silica gel to obtain chiral stationary phases (CSPs) for the HPLC separation of enantiomers. The enantiodiscriminating capability of the two CSPs has been compared to that of the analogous CSP obtained from an exhaustively derivatized cholic acid based selector, in order to establish the effect of the presence of a free hydroxyl group on the enantiodiscrimination properties of this kind of selector. The chromatographic results demonstrate that the enantioselectivity of these selectors strongly depends on the position of the hydroxyl group on the cholestanic backbone.     

Cholic acid-based fluorescent probes for enantioselective recognition of trifunctional amino acids

The ditopic fluorescent photoinduced electron transfer (PET) amino acid sensory probes and were designed and synthesized from cholic acid. To confer the probes with specific binding ability, an amidothiourea moiety and a cyclic diamino-chiral receptive site were introduced on the C17 side chain and the C7 and C12 hydroxyl pendants, respectively. In acetonitrile, the probes demonstrated differential binding toward trifunctional amino acids like serine, lysine, threonine and tyrosine against other simple amino acids. Enantioselectivities (KD/KL) of up to 8.9 and sensitivities in the micromolar range with the probes were observed for trifunctional amino acids.     

Oligomeric cholates: amphiphilic foldamers with nanometer-sized hydrophilic cavities

The hydroxyl at the C-3 of cholic acid was converted to an amino group, and the resulting amino-functionalized cholic acid was used as a monomer to prepare amide-linked oligomeric cholates. These cholate oligomers fold into helical structures with nanometer-sized hydrophilic internal cavities in solvent mixtures consisting of mostly nonpolar solvents such as carbon tetrachloride or ethyl acetate/hexane and 2-5% of a polar solvent such as methanol or DMSO. The conformations of the foldamers were studied by UV, fluorescence, fluorescence quenching, and fluorescence resonance energy transfer. The nature of the polar/nonpolar solvents and their miscibility strongly influenced the folding reaction. Folding was cooperative, as evidenced by the sigmoidal curves in solvent denaturation experiments. The folded conformers became more stable with an increase in the chain length. The folding/unfolding equilibrium was highly sensitive toward the amount of polar solvent. One percent variation in the solvent composition could change the folding free energies by 0.5-1.4 kcal/mol.     

Methyl 12-[d-prolinoylamino]cholate as a versatile organocatalyst for the asymmetric aldol reaction of cyclic ketones

The use of cholic acid derivative 1, bearing a d-prolinamide moiety linked at the 12-position of cholic acid methylester, as an organocatalyst in the asymmetric aldol reaction of cyclic ketones and aromatic aldehydes, gave the corresponding aldol products in good yield and ee up to 98%. This organocatalyst has proven to be efficient both in water and in organic solvent, where it has been used with a 1% loading.     

Intramolecular Coaggregation Behavior in Novel Cyclotriveratrylenes with Cholic Acid Podants

Two molecules la and 1b consisting of one cyclotriveratrylene (CTV) and three cholic acid podants have been designed and synthesized. Fluorescent studies in water/dimethoxyethane mixtures reveal an intramolecular coaggregation between the CTV and the attached cholic acid moieties. Their fluorescent emission intensity increases and then decreases with the increase of water content, whereas under the same measuring conditions the intensity of CTV derivative 2a, which possesses no similar cholic acid moiety, increases and then reaches a maximum value. The intensity decrease in la and 1b has been attributed to the decrease of the microenvironmental polarity in media of increasing polarity because of the shielding effect of the hydrophobic face of the cholic acid moiety.     

Determination of critical micellar concentrations of cholic acid and its keto derivatives

The critical micellar concentration (CMC) values of keto derivatives of cholic acid (3,12-dihydroxy-7-oxo-5β-cholanoic acid, 3,7-dihydroxy-12-oxo-5β-cholanoic acid, 12-hydroxy-3,7-dioxo-5β-cholanoic acid, 3-hydroxy-7,12-dioxo-5β-cholanoic acid, 3,7,12-triketo-5β-cholanoic acid) and cholic acid itself, were determined. Replacement of hydroxyl groups in cholic acid molecule with keto groups yields the derivatives whose CMC values increase with increase in the number of keto groups introduced. The CMCs of derivatives with the same number of keto groups but at different positions do not differ significantly. The relationship between the number of keto groups in the molecule of cholic acid keto derivatives and CMC value can be described by the following equation: CMC = 43 number of keto groups + 14.667. The effect of NaCl concentration on CMC increases with increase in the number of keto groups.     

Highly enantioselective and efficient organocatalytic aldol reaction of acetone and β,γ-unsaturated α-keto ester

An effective organocatalytic asymmetric aldol reaction of acetone to β,γ-unsaturated α-keto ester has been developed. In the presence of 5 mol % of 9-amino (9-deoxy)-epicinchona alkaloid and 10 mol % of 4-nitrobenzoic acid, the aldol adducts containing a chiral tertiary alcohol moiety were obtained in excellent yields and enantioselectivities.     

A catalytic one-step process for the chemo- and regioselective acylation of monosaccharides

An organocatalytic method for the chemo- and regioselective acylation of monosaccharides has been developed. Treatment of octyl beta-D-glucopyranoside with isobutyric anhydride in the presence of 10 mol % of a C2-symmetric chiral 4-pyrrolidinopyridine catalyst (1) at -50 degrees C gave the 4-O-isobutyryl derivative as the sole product in 98% yield. Thus, chemoselective acylation, favoring a secondary hydroxyl group in the presence of a free primary hydroxyl group, and regioselective acylation, favoring one of three secondary hydroxyl groups, took place with perfect selectivity. A competitive acylation between octyl beta-D-glucopyranoside and a primary alcohol (2-phenylethanol) with 1.1 equiv of isobutyric anhydride in the presence of 1 gave the 4-O-isobutyrate of octyl beta-D-glucopyranoside with 99% regioselectivity in 98% yield, which indicates that acylation of the secondary hydroxyl group at C(4) of the carbohydrate proceeds in an accelerative manner. A possible mechanism, involving multiple hydrogen-bonding between 1 and the monosaccharide, is proposed for the chemo- and regioselective acylation.     

Synthesis of new bio‐based hydrogels derived from bile acids by free‐radical photo‐polymerization

In this article, the study on the swelling and thermal behaviors of a new series of bile acid‐based polymeric hydrogels is reported. For this purpose, in the first step, the reduction of carboxyl acid groups of some common bile acids including cholic acid (CA), chenodeoxy cholic acid (CDCA), and lithocholic acid (LCA) to the corresponding alcohols by lithium aluminum hydride (LiAlH₄) in THF solution is performed. Then, hydroxyl functionalities of the obtained products are reacted with the acryloyl chloride in the presence of triethylamine (TEA). Finally, the cross‐linking reactions between acryloyl functionalized bile acids and methoxy poly(ethylene glycol) monomethacrylate (MPEGMA) are conducted by free‐radical photo‐polymerization technique at λ = 350 nm in the presence of 2,2‐Dimethoxy‐2‐phenylacetophenone (DMPA) as an initiator to achieve the desired bile acid‐based polymeric hydrogels. The resulting hydrogels and their intermediates are characterized by Fourier transform infrared (FT‐IR) and Proton nuclear magnetic resonance (¹H‐NMR) spectroscopies. The swelling and thermal behavior of the obtained hydrogels indicates that the hydrogel starting from cholic acid is more swellable and has enhanced thermostability compared to others. Thus, the results of this study offer beneficial insights to researchers working in particularly bio‐medical industry.     

含胆酸高分子化合物的制备和特性*

胆酸是哺乳动物体内合成的一种天然化合物,具有特殊的分子结构和优良的生物适应性。由胆酸合成的高分子化合物保持了胆酸的部分性质,如双亲性、手性、侧基反应活性和自组装性能等。在化学和药学领域,含胆酸高分子材料具有重要的应用价值。本文从自由基聚合形成的含胆酸高分子化合物、胆酸修饰的高分子化合物和胆酸聚合物等几个方面综述了含胆酸高分子化合物的制备和特性,并对胆酸在高分子材料方面的新用途作了展望。     

Hydrophilic polymethacrylates containing cholic acid‐ethylene glycol derivatives as pendant groups

In an effort to improve the hydrophilicity of bile acid containing polymers, we have synthesized new methacrylate monomers by incorporating ethylene glycol and oligo(ethylene glycol) spacers of different lengths between cholic acid and methacrylate residues. The monomers were subsequently polymerized by free radical reaction in solution. The methyl ester protecting groups on the cholic acid residue were selectively hydrolyzed to restore the carboxylic acid group of cholic acid. Water absorption tests showed that the hydrophilicity of the polymers was improved with increasing length of oligo(ethylene glycol) spacers and upon restoration of the carboxylic acid group of the cholic acid residue.     

Ion-selective electrodes based on molecular tweezer-type neutral carriers

Potentiometric properties of cholic and deoxycholic acid derivatives substituted with various ion-recognizing moieties, such as dithiocarbamate, bipyridyl, glycolic and malonic diamides, urea and thiourea, and trifluoroacetophenons (TFAP), have been studied using solvent polymeric membranes. The dithiocarbamate and bipyridyl group containing ionophores exhibit high silver ion selectivity. The cholic acid derivatized with glycolic diamides exhibited high calcium selectivity, but its complex formulation constant was 10⁵ times smaller than that of ETH 1001. The reduced calcium binding ability of the glycolic diamide-substituted ionophore was advantageous for eliminating anionic interference. The bi- or tripodal malonic diamide-substituted ionophores exhibited substantially increased magnesium selectivity. Anion-selective ionophores have been designed by substituting urea and thiourea group containing chains to the hydroxyl linkers of chenodeoxycholic acid frames; their selectivity closely followed the sequence of Hoffmeister series, except the unusually large response of the thiourea-substituted ionophore to sulfate. The most successful examples of cholic or deoxycholic acid frame-based ionophores are those functionalized with two carbonate-selective TFAP groups: bipodal TFAP groups behaves like a tweezers for the incoming carbonate, and exhibit analytically interference free and quantitative responses to the carbonate in serum and seawater samples.     

New Acyclic Dimers of Cholic Acid with Oxamide and Hydrazide Spacers

Summary. Three new acyclic dimers of cholic acid with oxamide and isomeric hydrazide (N,N′-diacylhydrazine) spacers were obtained. The oxamide spacers bind two identical steroidal subunits through position 3 (head-to-head dimer) or position 23 (tail-to-tail dimer). In the case of a third dimer the hydrazine moiety binds two molecules of cholic acid through position 24 (tail-to-tail dimer).     

Synthesis and reaction of β‐hydroxyaspartic acid‐based polymethacrylate

O‐Methacryloyl‐N‐(tert‐butoxycarbonyl)‐β‐hydroxyaspartic acid dimethyl ester was synthesized by methyl esterification of β‐hydroxyaspartic acid, followed by protection of the amino group with the tert‐butoxycarbonyl group and then the reaction of the hydroxyl group with methacryloyl chloride. The monomer efficiently underwent radical polymerization to afford the corresponding polymer with a number‐average molecular weight of 42,000 in good yields. The alkaline hydrolysis of the polymer occurred not only at the methyl ester but also at the ester moiety between the main and side chains of the polymer. The methyl ester‐free polymer gradually released β‐hydroxyaspartic acid moiety in a phosphate buffer solution with pH = 7.3 and 7.8. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 2782–2788, 2002     

New Acyclic Dimers of Cholic Acid with Oxamide and Hydrazide Spacers

Three new acyclic dimers of cholic acid with oxamide and isomeric hydrazide (N,N′-diacylhydrazine) spacers were obtained. The oxamide spacers bind two identical steroidal subunits through position 3 (head-to-head dimer) or position 23 (tail-to-tail dimer). In the case of a third dimer the hydrazine moiety binds two molecules of cholic acid through position 24 (tail-to-tail dimer).     

Gas chromatography-mass spectrometry of the trimethylsilyl (oxime) ether/ester derivatives of cholic acids: their presence in the aquatic environment

This paper presents a derivatization, mass fragmentation study relating to the most common six cholic acids, such as cholic, lithocholic, chenodeoxycholic, ursodeoxycholic, 3-hydroxy,7-ketocholanic and dehydrocholic acids, identified and quantified as pollutants in the aquatic environment at the first time. Derivatizations have been performed with the two-step process (1: oximation, 2: silylation) varying the time and temperature of both reactions. Optimum responses have been obtained after 30 min oximation with hydroxylamine.HCl and 90 min silylation with hexamethyldisilazane and trifluoroacetic acid at 70 degrees C. Fragmentation patterns of the trimethylsilyl (oxime) ether/ester derivatives of all six cholic acids provided the theoretically expected, fully derivatized compounds. Reproducibility/linearity of derivatives calculated on the basis of the corresponding selective fragment ions, characterized by the relative standard deviation percentages of measurements, proved to be < or =4.9 (RSD%). The practical utility of the method was shown by the identification and quantification of cholic acids as pollutants in the aquatic environment. Subsequently to a solid phase extraction study varying the pH of extractions (pH 2, pH 4 and pH 7), applying the OASIS cartridges, it has been confirmed that the recoveries for all six cholic acids are acceptable, varying between 77% and 104%, and are independent on the pH. The total cholic acid content of a Hungarian wastewater plants' influent wastewater varied between 184 microg/L and 356 microg/L, while the Danube rivers' cholic acid content was 4.1 microg/L, only.     

The Effect of the Side Chain on Gelation Properties of Bile Acid Alkyl Amides

Six bile acid alkyl amide derivatives were studied with respect to their gelation properties. The derivatives were composed of three different bile acids with hexyl or cyclohexyl side chains. The gelation behaviour of all six compounds were studied for 36 solvents with varying polarities. Gelation was observed mainly in aromatic solvents, which is characteristic for bile-acid-based low molecular weight gelators. Out of 108 bile acid-solvent combinations, a total of 44 gel systems were formed, 28 of which from lithocholic acid derivatives, only two from deoxycholic acid derivatives, and 14 from cholic acid derivatives. The majority of the gel systems were formed from bile acids with hexyl side chains, contrary to the cyclohexyl group, which seems to be a poor gelation moiety. These results indicate that the spatial demand of the side chain is the key feature for the gelation properties of the bile acid amides.     

Effects of aminotriazole treatment on biosyntheses of primary bile acids in vivo.

The influence of aminotriazole treatment on primary bile acid biosynthesis was studied in detail. After administration of aminotriazole to rats, bile was collected for 8 h. The content of chenodeoxycholic acid in the bile was increased to 144% of the control by aminotriazole treatment, but that of cholic acid was decreased to 48.4%. In another experiment, [4-14C]cholesterol was injected into rats immediately after aminotriazole treatment, and then bile was collected. The content of radioactive chenodeoxycholic acid in the bile was significantly increased to 130% of the control, but that of radioactive cholic acid was unchanged. In a similar experiment with [2-14C]mevalonate, the content of radioactive chenodeoxycholic acid in the bile was hardly changed by aminotriazole treatment, but that of radioactive cholic acid was greatly decreased to 41.2% of the control. Aminotriazole treatment did not affect the ratios of tauroconjugate to glycoconjugate of the two bile acids. Thus, aminotriazole treatment affects the syntheses of not only cholesterol (F. Hashimoto, C. Sugimoto and H. Hayashi, Chem. Pharm. Bull., 38, 2532 (1990); F. Hashimoto and H. Hayashi, Biochim. Biophys. Acta, 1086, 115 (1991)) but also primary bile acids in vivo. Namely, aminotriazole treatment activated biosynthesis of chenodeoxycholic acid from exogenous cholesterol, but did not affect that of cholic acid. Aminotriazole hardly affected the synthesis of chenodeoxycholic acid through endogenous cholesterol (from mevalonate), but inhibited that of cholic acid.     

Synthesis and conformational studies of a new host system based on cholic acid

New synthetic hosts have been designed incorporating two molecules of cholic acid linked by a rigid diamine. Proton NMR studies indicate that the compounds exist in a rigid conformation with the steroid hydroxyl groups intramolecularly hydrogen-bonded. Heat or addition of methanol leads to conformational isomerism due to insertion of methanol into the cavity.A preliminary report of this work was presented at the 4th International Symposium on Inclusion Phenomena, July 20–25, 1986, Lancaster, U.K.     

Organocatalytic asymmetric 5-hydroxyisoxazolidine synthesis: a highly enantioselective route to beta-amino acids

The highly chemo- and enantioselective organocatalytic tandem reaction between N-protected hydroxyl amines and alpha,beta-unsaturated aldehydes is presented; the reaction provides access to 5-hydroxyisoxazolidines and beta-amino acids in high yields and with 90-99% ee.