From 53 Bile Acids

The aggregation behavior of C21-DA salt in dilute electrolyte medium appears to resemble that of certain polyhydroxy bile salts (25,16). That C21-DA, with a structure quite different from bile acids, should possess solution properties similar to, e.g., cholic acid is not entirely surprising in light of recent conductivity and surface tension measurements on purified (i.e., essentially monocarboxylate free) disodium salt aqueous solutions, and of film balance studies on acidic substrates (IX) The data in Figure 3 suggest that C21-DA salt micelles Incorporate detergents - up to an approximate weight fraction of 0.5 -much like cholate Incorporates lecithin or soluble... 

Erlejman AG, Fraga CG, Oteiza PI. 2006. Procyanidins protect Caco-2 cells from bile acid- and oxidant-induced damage. Free Radic Biol Med 41 1247-1256. 

Merck and Co. had produced the cortisone used by Hench in research quantities using a 36-step synthesis from bile acids. Hench s revelation rapidly escalated interest in steroidal anti-inflammatories. A brief outline of ongoing developments in each of these fields follows. 

For a detailed account of the many years of work taken to achieve a working process to produce cortisone from bile acids, see Fieser, L. F., and Fieser, M. Steroids, Reinhold Publishing Co., New York, 1959, Chapter 19. 

Photooxygenations in the presence of Cu(I) were also applied with good yields in the chemistry of natural products. Under mild conditions a pyrrolidino dienamine derived from bile acids underwent cleavage at the y,<5-double bond to give the corresponding 5/ -pregnan-20-one29 (Scheme 15). 

In 1948 cortisone was made from bile acids in quantity sufficient for clinical trial, and the dramatic demonstration of its power to induce remission of rheumatoid arthritis was published the following year. In 1950 it was realised that cortisone was biologically inert and that the active natural hormone is hydrocortisone (cortisol). Since then an embarrassingly large number of synthetic steroids has been made and offered to the clinician. They are derived from natural substances (chiefly plant sterols), the constitutions of which approach most nearly to that of the steroids themselves. A principal aim in research is to produce steroids with more selective action than hydrocortisone, which induces a greater variety of effects than desired in any patient who is not suffering from adrenal insufficiency. 

Derivation From adrenal gland extract (usually from cattle) (historical method), syntheticahy from bile acids, from other steroids or sapogenins. 

The most successful therapy for cholestasis of pregnancy has been ursodeoxycholic acid (Figure 33-1). Ursodeoxycholic acid is a naturally occurring bile acid, which, when administered, relieves both pruritus and liver function abnormalities. Experimental evidence suggests that it protects hepa-tocytes and cholangiocytes from bile acid-induced cytotoxicity and improves hepatobiliary excretion. Additionally, it decreases bile salt transfer to the fetus and improves the secretory function of placental trophoblast cells. Ursodeoxycholic acid is recycled through the enterohepatic circulation. 

Chemical hydrolysis or solvolysis is the only method available at present to remove sulfate groups from bile acids. It is known that some colonic bacteria possess a sulfatase which can utilize sulfated bile acids as substrate (H24), but this enzyme has not yet been purified. The position of the sulfate moiety in monosulfated bile acids is nearly always at C-3 and this group is easily removed by acid hydrolysis in ethereal solution after removal of glycine or taurine (VI). This method, however, does not remove sulfate groups from C-7 or C-12 (PI). For complete removal, other methods have been described, including solvolysis in acidified methanol-acetone for 18 hours at 37°C (P6), acidified ethyl acetate-ethanol for 16 hours at 39 C (A6), or acidified 2,2-dimethoxypropane for 12 hours at room temperature (C3). 

Bile salts (made from bile acids) are secreted from the liver, stored in the gallbladder, and passed through the bile duct and into the intestine (Figure 18.3). They are involved in emulsification of fats in the intestine, aid digestion and absorption of fats and fat-soluble vitamins (Figure 18.4). 

Formation of suitable derivatives from bile acids has also been a subject of numerous studies. Since the earlier procedures have been reviewed [314-316], a continuous interest in the subject of derivatization appears to indicate that there is still a need for improvement. The initial derivatization of the acidic function to form methyl esters seems to be almost universally employed, while the remaining functional groups (hydroxy and keto) can be converted to a number of derivatives. A number of earlier and more recent studies have endorsed silylation, although various types of acylation are also common [219]. Permethylation has also been advocated recently [22S], but no biological separations were demonstrated using this approach. 

McKenzie BF, Marttox VR, Engel LL, et al. Steroids derived from bile acids. VI. An improved synthesis... 

Samples of lignin, wood, or cellulose were suspended in phosphate buffer (pH 7.0, y = 0.5) containing varying concentrations of sodium cholate, sodium deoxycholate or sodium taurocholate. The concentration remaining in the supernatant after equilibration for 20-24 h was determined by measuring the absorption spectra of polyenylic carbocations formed from bile acids in 72% sulfuric acid ( ). ... 

However, more active and selective eatalysts are adamantyl-L-prolinamide 36, and camphor-lO-sulfonamide-based prolinamides 37, which contain additional stereocentres. Prolinamides derived from bile acids such as epiandrosterone 38, or cholic acid 39 ° exert good enantiocontrol, probably because the cholestanic structure that forms a functionalised chiral cavity with the appended prolinamide groups that were able to exert a good stereocontrol on the orientation of the substrate. 

In vertebrates higher on the phylogenetic scale than amphibians, the side chain is shortened to five C-atoms (Fig. 127). The reaction starts with the formation of CoA esters from bile acids and resembles the / -oxidation of fatty acids (D 3.2). Propionyl CoA is liberated and C24-bile acids are formed, which may then be oxidized, reduced, dehydroxylated, and coupled with glycine or taurine. These reactions are carried out at least in part by the microorganisms of the intestine. 

Sodium borohydride reduction is carried out with 1 mg reagent in 0.5 ml isopropanol. The rates of reduction differ with the position of the keto group (108). Treatment with lithium aluminum hydride in diethyl ether results in formation of C-24-ols from bile acid methyl esters. This may be valuable in chromatographic identification work, especially if combined with mass spectrometry. 

Denike JK, Zhu XX. Preparation of new polymers from bile acid derivatives. Macromol Rapid Commun. 1994 15 459-65. 

The single pulse NMR spectra of bile are dominated by broad resonances that arise from bile acids that... 

Besides the functionalization of alkanes and cycloalkanes, from an early stage on enzymatic steroid hydroxylation with wild-t) e whole cells was a broadly studied research field, leading to a range of industrial processes [131]. An early example is the production of hydrocortisone by microbial lla-hydroxylation starting from bile acid. Further examples are microbial hydroxylations running at a scale of up to 200m at the company Schering AG. 

CJH4O5, H02CCH(0H)C02H. Colourless crystals with IH O lost at 60 C. M.p. IhO C (decomp.). Prepared by heating dinitrotartaric acid in aqueous alcohol, taurine, aminoethylsulpbonic acid, C2H7NO3S, NHj CHj CH SOjH. Crystallizes in columns, decomposing at 317 C. In combination with cholic acid it forms one of the bile acids. It is formed in the liver from cysteine. 

Steroids are another class of natural products with multiple chirality centers One such compound is cholic acid which can be obtained from bile Its structural formula IS given m Figure 7 12 Cholic acid has 11 chirality centers and so a total (including cholic acid) of 2" or 2048 stereoisomers have this constitution Of these 2048 stereoiso mers how many are diastereomers of cholic acid s Remember Diastereomers are stereoisomers that are not enantiomers and any object can have only one mirror image Therefore of the 2048 stereoisomers one is cholic acid one is its enantiomer and the other 2046 are diastereomers of cholic acid Only a small fraction of these compounds are known and (+) cholic acid is the only one ever isolated from natural sources... 

The outer layer or cortex of the adrenal gland is the source of a large group of sub stances known as corticosteroids Like the bile acids they are derived from cholesterol by oxidation with cleavage of a portion of the alkyl substituent on the D ring Cortisol IS the most abundant of the corticosteroids but cortisone is probably the best known Cortisone is commonly prescribed as an antiinflammatory drug especially m the treat ment of rheumatoid arthritis... 

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