Synthesis of 3.ALPHA.,7.ALPHA.,14.ALPHA.-Trihydroxy-5.BETA.-cholan-24-oic Acid: A Potential Primary Bile Acid in Vertebrates

Abstract

Chenodeoxycholic acid (CDCA, 3a,7a-dihydroxy-5b-cholan-24-oic acid) and cholic acid (CA, 3a,7a,12a-trihydroxy-5b-cholan-24-oic acid) are formed from cholesterol in the liver and are the dominant primary bile acids in many vertebrate species. CDCA may be considered the building block of all trihydroxy-bile acids and in many vertebrates one additional hydroxy group is added, either to the steroid nucleus or to the isopentanoic acid side chain.2) Such additional hydroxylation may occur either at any stage of an intermediate during bile acid biosynthesis or after the mature molecule has been synthesized. 6a-Hydroxylation of CDCA in the pig to give a 3a,6a,7a-trihydroxy acid (hyocholic acid) was reported by Haslewood and Sjövall.3) In the rat and mouse, 6b-hydroxylation results in the formation of 3a,6b,7a-trihydroxy bile acid (a-muricholic acid). 4) In more recent work, 1a-hydroxylation (vulpecholic acid) of CDCA was identified in the Australian opossum.5) The 1b-epimer 6) of this bile acid has been reported to be present in the bile of fruit pigeons and doves (Columbiformes) and in the human biological fluids from newborns and from adult patients with cholestatic liver diseases.7) The 4b-hydroxy derivative 8) of CDCA occurs in the biliary bile acids of patients with hepatobiliary diseases and in neonates and newborn infants. Hydroxylation at the C-5 (b-OH) position has been reported to occur in the biliary bile acids of the pheasant, 1) and 5b-hydroxylation of analogous nor-CDCA was demonstrated in hamster liver.9) The presence of the 3a,7a,15a-trihydroxy acid noted in the biliary bile acids of the marsupial and of the swan.1) In the most recent work, Hagey et al. 10) have reported the existence of the 3a,7a,16a-trihydroxy acid as a primary bile acid in many species of birds such as herons (Ardeidae), pelicans (Pelecanidae) and owls (Tytonidae).Hydroxylation on the side-chain of CDCA has also been reported. Haemulcholic [(22S)-3a,7a,22-trihydroxy] acid occurs in the bile of bony fish 11) whereas b-phocacholic [(23R)-3a,7a-23-trihydroxy] acid is present in the biliary bile acid of marine mammals, 12) ducks 13) and flamingos.14)The above findings of the species differences in the bile acid metabolism of vertebrates are, therefore, of interest from the viewpoint of their metabolism and physiological functions, as well as phylogenetic significance. For these reasons, new sites of "third" hydroxylation of CDCA are of considerable interest.As mentioned above, "third site" hydroxylation at C-1, -4, -5, -6, -12, -15, -16, -22 and -23 in CDCA has now been known and/or characterized in the literature. However, the occurrence of 14a-hydroxylated CDCA has not yet been reported, though it is a logical compound to be formed in vertebrates, as the 3a,5b,7a-trihydroxy compound having a tert-hydroxy group at C-5 does occur in some species. In a survey of the biliary bile acids of some 900 vertebrate species, unidentified C 24 trihydroxy bile acids were often present as major components. 15) Our labolatory has had a program aimed ...

Structural verification of petromyzestrosterol by total syntheses of both C14-epimers of its 3-O-methyl derivative

“…Dehydration of the hydroxy group at C14 in 2b was carried out with TsOH·H 2 O in hot toluene, giving trisubstituted alkene 16 in 89% yield. 9 Epoxidation of 16 with mCPBA took place from the α-face to provide 17a in 78% yield along with its diastereomer 17b (structure not shown) in 4% yield. Reductive cleavage of 17a with LiAlH 4 furnished 3- O -methyl-14α-petromyzestrosterol ( 1b ) in 83% yield, the stereochemistry of which was determined by comparison of its 1 H and 13 C NMR spectra with those of 14β-isomer 2b .…”

Relative inhibitory activity of bile acids against 12-<I>O</I>-tetradecanoylphorbol-13-acetate-induced inflammation, and chenodeoxycholic acid inhibition of tumour promotion in mouse skin two-stage carcinogenesis

“…The following bile acid derivatives used in this study were synthesized in our laboratory: 4, 26, 34, 35 and 44; [9] 5 and 8; [10] 6; [11] 7, 23, 28, 36, 40, 41, 45, 46 and 48; [12] 14 and 37; [13] 15,16,17,18,19,20,21,22,38,39,49 and 50; [14] and 47. [15] The other compounds (12,13,29,30 and 31) were from our laboratory collection.…”

Steroids: partial synthesis in medicinal chemistry

“…The partial synthesis of 3a,7a,14a-trihydroxy-5b-cholan-24-oic acid has been described. 76 The C-14a hydroxyl group was introduced by oxidation with dimethyldioxirane. The farnesol X receptor is activated by endogenous bile acids and plays a variety of physiological roles related to the modulation of gene transcription.…”