Cholanic acids structure

Fig. 2. Chemical structures of monensin (a) and cholanic acid (b). (Cited from Ref.8))...

Cholanic acid also possesses the ability of transporting cations across a lipophilic membrane but the selectivity is not observed because it contains no recognition sites for specific cations. In the basic region, monensin forms a lipophilic complex with Na+, which is the counter ion of the carboxylate, by taking a pseudo-cyclic structure based on the effective coordination of the polyether moiety. The lipophilic complex taken up in the liquid membrane is transferred to the active region by diffusion. In the acidic region, the sodium cation is released by the neutralization reaction. The cycle is completed by the reverse transport of the free carboxylic ionophore. 

Cholanic acid C24H40O2, a monobasic saturated acid containing four hydroaromatic rings, is the parent substance of the two natural acids, which are its trihydroxy- and dihydroxy-derivatives. It is very highly probable that the following structural formula for cholic acid is correct ... 

The method was first applied in studies of a bacterial polysaccharide, cholanic acid, composed of hexasaccharide repeating-units having117 the structure 51. The hydroxypropyl ester of this polysac-... 

Bile acids synthesized in the liver are primarily derivatives of 5/S-cholanic acid however, bile acids of lower animals and some fishes may be predominantly of the 5 a or alio series. A significant feature of these two types of bile acids lies in the planar structure of the 5a-acids as opposed to the 5j8-acids where ring A is extended below the planes of rings B, C, and D (Fig. 1). As noted below small quantities of alio acids are now detected from mammalian sources. 

Fig. 1. Comparison of structures of 5a- and 5/8-bile acids. Allocholic acid (3a,7a,12a-trihydroxy-5a-cholanic acid) cholic acid (3a,7a,12a-trihydroxy-5 -cholanic acid).

Other precursors of the muricholates via 6)8-hydroxylation include 5)8-cholanic acid [78], lithocholic acid [84-86], 7-oxolithocholic acid [95,96], and ursodeoxycholic acid (3a,7j6-dihydroxy-5/3-cholanic acid) [97], The rat metabolized 12a-hydroxy-5/S-cholanic acid to 6/S,12a-dihydroxy-5)S-cholanic acid [83] and a small amount of 6)3,7a,12a-trihydroxy-5 -cholanic acid [98]. 3a,6)8,12a-Trihydroxy-5)8-cholanic acid was isolated from urine of surgically jaundiced rats after administration of de-oxycholate [99]. A series of bile acids from rat bile of unconfirmed structures but containing the 6/3,7/3-diol will be reviewed in Section II1.3. 

As noted earlier, bile acids were among the first steroids to be obtained in pure crystalline form. These compounds played an important role in the effort devoted to divining the structure of steroids. Bile acids as a result acquired a sizeable number of trivial names, most of which gave little information as to their chemical structure. One approach to systematic names is based on the hypothetical cholanoic acid 8-1 (Scheme 8). Bile acids are then named as derivatives of this structure using the mles used for other classes of steroids. Note the cis A-B ring fusion in this series. The systematic name for 8-2, lithocholic acid, is then simply 3a-hydroxy-5/3-cholanic acid. Chenodeoxycholic acid, 8-3, becomes 3a,7a-dihydroxy-5/3-cholanic acid. The predominant acid in bile, 8-3, is cholic acid itself, or, 3a,7a,12a-trihydroxy-5 )8-cholanic acid. 

The sequence that established the structure of the pregnan nucleus starts with the chain length probing sequence depicted in Scheme 1.12. The carboxylic acid derivative 12-1, which can, in concept, be prepared from cholanic acid by initial exhaustive reduction to remove the hydroxyl groups followed by two rounds of sequence depicted in Scheme... 

The most abundant naturally occurring bile acids in higher vertebrates are derivatives of cholanic acid (1) (Fig. 1), a 24-carbon-atom steroid possessing the characteristic cyclopentanophenanthrene nucleus. The structure and nomenclature of this class of compounds have been described in detail by Fieser and Fieser (25), Kritchevsky (26), and Van Belle (27). 

The elucidation of the structure of bile acids stems from the early observations of Adolf Windaus and of Heinrich Wieland that cholanic acid could be obtained from either cholesterol or cholic acid they inferred from this that bile acids are steroidal in nature. Wieland and his group showed... 

The dehydration of desoxycholic acid (33) yielded a diene mixture that could be hydrogenated to cholanic acid (34). Wieland and his co-workers also showed that both lithocholic and chenodesoxycholic acids were related to cholanic acid (35, 36). The positions and configurations of the hydroxyl groups were determined in the course of a series of oxidative cleavage studies, which actually bore upon the question of the ring structure. 

Little further was substantiated about cholic acid (or about bile acids generally) for nearly five decades. The name, cholic acid, had become well established, but trivial names based partly on imperfect characterization were common, so that consideration of nomenclature was a part of Wieland s first report on the bile acids in 1912 (56). A review of the evidence then available included that cholic acid was a trihydroxy, monocarboxylic acid and that two of the alcohols were secondary. The final presentation of the structure of cholic acid awaited the correct steroid formulation in 1932 (113, 114). By that time the structural relationship between the sterols and bile acids was well established. The preparation of cholanic acid from cholic acid had been reported in the paper by Wieland and Weil in 1912 (56). The preparation of cholanic acid from cholesterol (through coprostane) was reported in 1919 by Windaus and Neukirchen (55). 

The occurrence of a species-specific bile acid in pig bile [Haslewood (1) Haslewood and Sjovall (2)] and of two such acids in rat bile [Bergstrom and Sjovall (3) Hsia et al. (4) Matschiner et al. (5)] was observed almost simultaneously. After their isolation and characterization, these acids were found to be isomeric 3a,6,7-trihydroxy-5/5-cholanic acids. The acid from pig bile was named hyocholic acid [Haslewood (6) Ziegler (7)], and the two acids from rat bile were named a- and /3-muricholic acids [Hsia et al. (8)]. The fourth isomer of these glycols was identified as a metabolite of hyodeoxycholic acid (3rt,6a-dihydroxy-5 9-cholanic acid) in the rat [Matschiner et al. (9, 10)], and was named ry-muricholic acid [Hsia et al. (8)]. The vicinal glycol structures in ring B of these acids are unique features, but even more unique are their species-specific characteristics which are particularly demonstrated in the metabolic pathways that lead to their formation. 

This chapter brings together the information concerning the isolation, the elucidation of structures, and the methods of chemical synthesis of the four 3a,6,7-trihydroxy-5/3-cholanic acids. Recent findings of taurochenode-oxycholate 6/3-hydroxylase are also discussed since the enzyme system directly concerns the formation of a-muricholic acid. 

The structure of hyocholic acid was proposed by Haslewood (24) and by Ziegler (7) to be 3a,6a,7 -trihydroxy-5 -cholanic acid (I, Fig. 1). Since it was known that pig bile contains hyodeoxycholic acid (3a,6a-dihydroxy) and chenodeoxycholic acid (3a,7a-dihydroxy) the bile was assumed to contain possibly also an acid with both 6a- and 7a-hydroxyl groups. Chemical evidence for the vicinal glycol structure in hyocholic acid was found after chromic oxidation. The product, 3-keto-6,7-secocholanic acid-6,7-dioic... 

Hyocholic acid forms an acetonide (IV). Although it could not be crystallized [Ziegler (7) Haslewood (24)], its formation was substantiated by chromatographic mobility and data of quantitative acetylation. Formation of the acetonide gave evidence for the m-glycol structure in hyocholic acid. The a-orientation of this 6,7-glycol was deduced from data of molecular rotations. Based on values from Barton and Klyne (34), the calculated molecular rotation of 3a,6a,7a-trihydroxy-5/3-cholanic acid would be —13 and that of the 3a,6a,7 -isomer, +249. The observed molecular rotation of hyocholic acid was +19. It was therefore concluded that hyocholic acid is the 3a,6a,7a rather than the 3a,6/3,7/3-isomer [Ziegler (7)]. 

Confirmative evidence of the proposed structure was obtained from partial synthesis of hyocholic acid [Hsia et al. (30)]. An important intermediate in the synthesis was 3a,6a-dihydroxy-7-keto-5 -cholanic acid (VII, Fig. 2), first prepared by Takeda et al. (35). The 3 - and 6a-hydroxyl groups in VII were established by the formation of hyodeoxycholic acid (IX) after hydrogenolysis of the ethylenedithioketal derivative (VIII) with Raney nickel. Hyocholic acid was obtained from VII either by reduction with sodium borohydride or by hydrogenation in the presence of platinum both methods were known to produce the axially oriented 7a-hydroxy from 7-keto bile acids [Mosbach et al. (36) Iwasaki (37)]. More direct evidence for the la-hydroxyl group in hyocholic acid was found in a later study [Hsia et al. (8)], when hyocholic acid was derived from bromohydrin acetate XII (Fig. 3),... 

The diaxial trans-g yco structure in a-muricholic acid was substantiated by partial synthesis. a-Muricholic acid could be derived from either the 6a, 7a-epoxide XVI [Hsia et al. (39)] or the 6,9,7/9-epoxide XV [Hsia et al. (41)] (Fig. 4) by scission of the epoxide rings and hydrolysis of the acetates thus formed. In accordance to the Fiirst and Plattner rule [Fiirst and Plattner (42)], ionic opening of an ethylene oxide results in the diaxial trans-g yco. The structure of a-muricholic acid therefore should be 3a,6,9,7a-tri-hydroxy-5/9-cholanic acid (XVII). The orientation of the epoxide ring in XV and that... 

Therefore, I shall concentrate on only those bile acids that have been reasonably well studied from a physicochemical point of view and which have some relation to physiology and biochemistry of living things. Because the specific physical characteristics of the bile acids and their alkaline metal salts vary considerably with the number of hydroxyl groups present on the steroid nucleus, I will present a fairly detailed description of the physicochemical properties of cholanic acid (no hydroxyl groups), monohydroxy, dihydroxy, and trihydroxy bile acids. Since the triketo bile acid (dehydrocholic acid) has been used widely as a choleretic, its properties will also be discussed. Unfortunately, many interesting bile acids and bile alcohols isolated from a variety of vertebrates (29-32) have not been studied physicochemical ly. However, knowing their molecular structure, many of the properties of these compounds can be deduced by comparison with the known properties of bile acids discussed in this chapter. 

The crystalline structure of cholanic acids and their alkaline metal salts has unfortunately been neglected. The major crystallographic work was carried oUt by Kratky, Giacomello, and co-workers (76-79) 30 years ago and was oriented toward solving the structure of the choleic acids. These substances, isolated by Wieland and Sorge (80), are mixed crystals of deoxy-cholic acids (or certain other bile acids such as a and apocholic acids) obtained on crystallization from organic solvents. A summary of the work on choleic acid appears in Sobotka (28). 

The most important end products in mammalian cholesterol metabolism are the bile acids. The parent C24-acid is cholanic acid with a ring structure identical to that of coprostanol (A/B cis). The bile acids are hydroxylated cholanic acids, all hydroxyl-groups have a-orientation. Consequently, they do not form digi-tonides. The principal acids are cholic acid (3a, 7a, 12a-trihydroxy-cholanic acid), chenodeoxycholic acid (3a, 7a-dihydroxycholanic acid) and deoxy-cholic acid (3a, 12a-dihydroxycholanic acid). Lithocholic acid (3a-hydroxycholanic acid) also occurs in human bile, but only in small amounts. 

The cmc of bile salts is strongly influenced by its structure the trihydroxy cholanic acids have a higher cmc than the less hydrophilic dihydroxy derivatives. As expected, the pH of solutions of these carboxylic acid salts has an influence on micelle formation. At sufficiently low pH, bile acids which are sparingly soluble will be precipitated from solution, initially being incorporated or solubilized in the existing micelles. The pH at which precipitation occurs, on saturation of the micellar system, is generally about one pH unit higher than the pK of the bile acid. 

The taurine residue can also be found as an amide derivative of the 26-carboxylic acid function in the 3p,5a,6p,15a-polyhydroxylated steroids 328 and 329, which were obtained from the starfish Myxoderma platyacanthum [245]. The structures of both compounds were determined from spectral data and chemical correlations. The bile of the sunfish Mola mola has been shown to contain a new bile acid conjugated with taurine (330) together with sodium taurocholate. Compound 330 was identified as sodium 2-[3a,7a, 11 a-trihydroxy-24-oxo-5P-cholan-24-yl]amino]ethane-sulfonate on the basis of its physicochemical data and chemical transformations [246]. 

Fig. 1. Chemical structures of SP-cholestane (A), Sp-cholan-24-oic acid (B), and bile acids found in human gallbladder bile (C-G).

Bile acids contain hydroxyl groups, which are usually substituted at positions, C-3, C-7, or C-12 of the steroid nucleus. The three major bile acids found in man are 3a,7a,12a-trihydroxy-5P-cholan-24-oic acid 3a,7a-dihydroxy-5p-cholan-24-oic add and 3a,12a-dihydroxy-5p-cholan-24-oic acid. Because of the complexities of steroid nomenclature, bile acids are nearly always referred to by trivial names. 11108, the three major human bile acids are named cholic acid, chenodeoxycholic acid, and deoxycholic acid, respectively, and their chemical structures are shown in Fig. 1. Human bile does, however, contain small amounts of other bile acids, such as lithocholic acid (3a-hydroxy-5P-cholan-24-oic add) and ursodeoxycholic add (3a,7p-dihydroxy-5p-cholan-24-oic acid) (see Fig. 1). 

There is a wide variety in the types of bile acids found in different animal species. Some species have unique bile acids, such as a-muricholic acid (3a,6p,7a-trihydroxy-5p-cholan-24-oic add) and -muridiolic add (3a,6, 7 -trihydroxy- -cholan 24-oic acid) in rats and mice, and hyodeoxycholic acid (3a,6a-dihydroxy-Sp-cholan>24-oic acid) in pigs. Haslewood (H9) has studied the distribution of bile acids in the animal kingdom and has suggested that the C-24 adds, which are common to most advanced animal forms, can be regarded as the present endpoints in the evolution of the chemical structure of bile adds. 

---