Methyl chenodeoxycholate

This acid has been detected in human feces (52). It has not been found in other sources. The acid may be prepared by Oppenauer oxidation of methyl chenodeoxycholate (87) followed by hydrolysis of the product. 

The answer is d, (Hardman, pp 934-935.) Chenodeoxycholic acid (chenodiol) and ursodiol have proved to he effective in some patients with cholesterol gallstones. Lovastatin lowers blood cholesterol levels but has no effect on gallstones. Methyl tertiary butyl ether and a new agent, monoctanoin, are infused directly into the common duct and will dissolve gallstones. 

Selective hydrolysis of the 3a-acetoxy-group of fully acetylated cholic acid derivatives has been achieved with methanolic HCl. The hydrolysis occurs more rapidly than the methylation of the side-chain carboxylic acid. The 3-monosulphates of cholic, chenodeoxycholic, and deoxycholic acids have been prepared using this selective hydrolysis on the fully acetylated methyl esters. The resultant 3a-hydroxy-compounds were then treated with chlorosulphonic acid and the... 

Fig. 5.4.4a Methyl ester-trimethylsilyl (TMS) ethers of BAs from a plasma sample, b n-Butyl ester-TMS ethers of BAs from a plasma sample (adapted from [15]). 1 Nor-cholic acid, 2 litho-cholic acid, 3 deoxycholic acid, 4 chenodeoxycholic acid, 5 cholic acid, 6 ursodeoxycholic acid, a cholesterol, b sitosterol)...

Plasma and urine samples from atherosclerotic and control rats were comparatively analyzed by ultrafast liquid chromatography coupled with ion trap-time-of-flight (IT-TOF) MS (UFLC-IT/TOF-MS) (16). They identified 12 metabolites in rat plasma and 8 metabolites in rat urine as potential biomarkers. Concentrations of leucine, phenylalanine, tryptophan, acetylcar-nitine, butyrylcamitine, propionylcamitine, and spermine in plasma and 3-0-methyl-dopa, ethyl /V2-acety I -1. -argininate, leucylproline, glucuronate, A(6)-(A-threonylcarbonyl)-adenosine, and methyl-hippuric acid in urine were decreased in atherosclerosis rats ursodeoxycholic acid, chenodeoxycholic acid, LPC (06 0), LPC (08 0), and LPC (08 1) in plasma and hippuric acid in urine were increased in atherosclerosis rats. The altered metabolites demonstrated abnormal metabolism of phenylalanine, tryptophan, bile acids, and amino acids. Lysophosphatidylcholine (LPC) plays an important role in inflammation and cell proliferation, which shows a relationship between LPC in the progress of atherosclerosis and other inflammatory diseases. 

The bile acids are produced in the liver by the metabolism of cholesterol. They are di- and trihydroxylated steroids with 24 C atoms. The structure of cholic acid was seen earlier (Sec. 6.6). Deoxycholic acid and chenodeoxycholic acid are two other bile acids. In the bile acids, all the hydroxyl groups have an a orientation, while the two methyl groups are /3. Thus, one side of the molecule is more polar than the other. However, the molecules are not planar but bent because of the cis conformation of the A and B rings. 

For the addition to C6o of two o-quinodimethane groups linked by tethers including methyl deoxycholate, hyodeoxycholate, and chenodeoxycholate units, we refer to Section IV.A.l.c.151... 

Momose, T, M Mure, T lida, J Goto and T Nambara (1998). Method for the separation of the unconjugates and conjugates of chenodeoxycholic acid and deoxycholic acid by two-dimensional reversed-phase thin-layer chromatography with methyl beta-cyclodextrin. Journal of Chromatography A, 811(1-2), 171-180. 

Chenodeoxycholate synthesis may possibly proceed along several pathways. As shown in Fig. 2, one route is similar to that for cholate, in which ring alterations are completed before side-chain oxidation. A second suggested route begins with the oxidation of a terminal methyl group of cholesterol, yielding 26-hydroxycholesterol (9,10), which is readily converted to chenodeoxycholate but not cholate in the rat. Such a route involving 26-hydroxy-cholesterol remains speculative in man, however, as this compound has not yet been identified as a metabolite of cholesterol in human bile and there is some recent evidence that 26-hydroxycholesterol is not an important intermediate in bile salt formation (11). 

This keto acid was detected in human feces (121) but is not known to occur elsewhere as a natural product. This acid and its esters have been valuable as intermediates in the preparation of chenodeoxycholic acid. The keto acid may be prepared by Cr03 oxidation of the methyl ester diacetate of cholic acid (163) followed by rigorous hydrolysis. Mild hydrolysis yields the 7-monoacetate (m.p. 239 °C) which may also be reduced by the Wolff-Kishner procedure to the 3,7-dihydroxy acid. 

In the original procedure described by Fieser and Rajagopalan (51) for the preparation of chenodeoxycholic acid, methyl esters were used throughout the sequence of reactions. Since methyl esters form hydrazides with hydrazine used in the Wolff-Kishner reduction, this side reaction is avoided by hydrolysis of the methyl ester (XXVII) to the free acid (XXVIII) before Wolff-Kishner reduction is attempted. 

With a purified enzyme preparation from Clostridium perfringens, Roovers et al. (36) cleave conjugated bile acids directly in plasma. Proteins are then precipitated with Ba(OH)2-saturated ethanol (123) and the supernatant is taken to near dryness. The residue is dissolved in a toluene-isopropanol-methanol-30 % aqueous NaOH (10 20 20 6, v/v) mixture, water is added, and neutral lipids removed by light petroleum extraction. Bile acids are then obtained by acidification and diethyl ether extraction. The bile acids are then methylated and analyzed as above except that the bile acid methyl esters are acetylated before chromatography on 1 % XE-60 columns at 250°C. With this column the following retention times relative to that of the diacetoxy derivative of methyl deoxycholate were found for the following acetate methyl ester derivatives lithocholic, 0.60 23-nor-deoxycholic acid (internal standard), 0.77 chenodeoxycholic acid, 1.24 and cholic acid, 1.88. The deoxycholic acid derivative was eluted after 9.0 min and methyl 5 3-cholanoate after 0.32 min. 

Fig. 8. The infrared spectra of the bile acids. (D) Chenodeoxycholic acid—Nujol mull—glassy amorphous melt. (E) Cholic acid—Nujol mull—glassy amorphous melt. (F) 5,3 Cholanic acid, 3,7,12-trione (dehydrocholic acid)—crystallized from a melt. Asterisks indicate Nujol bands, superimposed on methyl and methylene bands of chenodeoxycholic and cholic acids.

Fig. 9. Spectra of the common bile acids in C HaO H. (A) Cholanic acid. 18 and 19 refer to signals from protons of C 18 and C-19 angular methyl groups. The large peak between 7.5 and 9 ppm is due to the protons of the steroid nucleus. Protons of the C-23 Hz can be identified at about 7.8 ppm. Contaminating methanol protons are seen at 6.7 and 5.2 ppm in all spectra. (B) Lithocholic acid. The small broad peak at 6.5 is due to the proton at C-3. (C) Deoxycholic acid. Small peaks due to the protons attached to the rings at the C-12 and -3 position are noted at about 6,05 and 6.5 ppm. (D) Chenodeoxycholic acid. Small peaks due to the protons attached to the steroid nucleus at position C-7 and C-3 are noted at 6.23 and 6.6 ppm. (E) Cholic acid. Peaks are due to the protons attached to the nucleus at position C-3, -7, and -12 are noted at 6.6, 6.2, and about 6 ppm. All spectra were taken at 33.4 C (67).

Steroids.—Intramolecular Diels-Alder reactions of o-quinodimethanes, generated by thermolysis of the corresponding benzocyclobutanes, continue to form the basis of many steroid syntheses, " including estradiol derivatives, 18-hydroxyestrone, (+)-chenodeoxycholic acid, and des-A-ring steroids. Two alternative ways to obtain o-quinodimethanes, by photoenolization of o-methylphenyl ketones or by a fluoride-ion-induced elimination reaction [(191)- (192)1, have been utilized in syntheses of 19-nor-steroids and O-methyl estrone (193), respectively. 

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