Lithocholic acid, synthesis

Lithocholic acid, structure of, 1082 Locant, IUPAC naming and, 87 Lone-pair electrons, 9 Loratadine, structure of, 206 Lotaustralin. structure of. 766 Low -density polyethylene, synthesis of, 1210... 

Fatty acids have also been converted to difunctional monomers for polyanhydride synthesis by dimerizing the unsaturated erucic or oleic acid to form branched monomers. These monomers are collectively referred to as fatty acid dimers and the polymers are referred to as poly(fatty acid dimer) (PFAD). PFAD (erucic acid dimer) was synthesized by Domb and Maniar (1993) via melt polycondensation and was a liquid at room temperature. Desiring to increase the hydrophobicity of aliphatic polyanhydrides such as PSA without adding aromaticity to the monomers (and thereby increasing the melting point), Teomim and Domb (1999) and Krasko et al. (2002) have synthesized fatty acid terminated PSA. Octanoic, lauric, myristic, stearic, ricinoleic, oleic, linoleic, and lithocholic acid acetate anhydrides were added to the melt polycondensation reactions to obtain the desired terminations. As desired, a dramatic reduction in the erosion rate was obtained (Krasko et al., 2002 Teomim and Domb, 1999). 

The second approach was applied in the synthesis of fatty acid terminated polyanhydrides. Polyanhydrides based on sebacic acid, and terminated with oleic, stearic, linoleic or lithocholic acid, or combinations of several fatty acids were synthesized 21). The general structure of fatty acid terminated polyanhydrides is shown in Figure 1. 

The incorporation of fatty acids into a polyanhydride chain was investigated using two fatty acids lithocholic acid and ricinoleic acid. Lithocholic acid containing polyanhydrides (Figure 2) were prepared by two step synthesis. Polyanhydrides reached molecular weights of 21000-115000 Da, depending on the polymer composition. Release of model drugs from these polymers showed sustained release of 5FU for almost 3 weeks and triamcinolone for 4 weeks (22). 

Synthesis and characterization of lithocholic acid derived dipyrromethanes. Koivukorpi et aO in early 2004 reported the synthesis of a series of steroidal dipyrromethane analogues that can be exploited for the synthesis of pyrrole-steroidal macrocycles. The authors used long-range HMBC data to confirm the structure. 

Coenzyme A (CoA) derivatives of bile acids were prepared [33,34] by a modification of the mixed anhydride procedure for the synthesis of palmityl CoA. A yield of 70% was calculated from the quantity of cholylhydroxamate formed after treatment of the CoA derivative with hydroxylamine. By modification of this procedure and purification of the products by chromatography on Sephadex LH-20, aqueous solutions of CoA derivatives of cholic, chenodeoxycholic, deoxycholic, and lithocholic acids were pbtained, frozen at - 70°C, and shown to be free from hydrolysis for several months [35]. 

I. P. Beletskaya s group has extensively examined the synthesis of macrocycles via the Buchwald-Hartwig amination by the reaction of long chain diamines with di-halo arenes.87 High dilution is often required as dimers and other oligiomers are major side products. Yields are moderate at best (20-60% yield of 45 or 46), but this methodology allows access to aza-crown ethers and modified macrocycles of lithocholic acid (47).88... 

The situation in the decompensated patients is less well understood. These patients, in the author s experience, have greater than 100 cm resection and often have an ileal transverse colostomy. The bile acid synthesis rate is quite similar to that in the compensated patients, but in an occasional patient it seems to be lower. The bile acids of bile contain a normal or high proportion of deoxycholic acid, and fecal bile acids are predominantly lithocholic acid and deoxycholic acid. Jejunal concentrations of bile acids are markedly reduced, and up to one-half of the bile acids which are present may have... 

The bile acid derivative, 3P-acetoxychol-5-en-24-oic acid (32), has been converted in two steps in high yield to 25-hydroxycholesterol (80). The homocholenic acid derivative (33) prepared by a photochemical Wolff rearrangement in this transformation served as a key early intermediate in the first chemical synthesis of la,25-dihydroxycholecalciferol (171). Lithocholic acid, likewise, has been converted to an intermediate (16) used for the preparation of the dihydroxyvitamin (35). Hyodeoxy-cholic acid (34) also shows promise of being a desirable starting material for 25-hydroxycholesterol (132). 

Scheme 11 (a) Structures of bile acids and (b) synthesis of polyanhydiide liom dimers of lithocholic acid [110] (reproduced with permission fixjm American Chemical Society)... 

The bile acid pool normally consists of about 2-4 g of conjugated and unconjugated primary and secondary bile acids. Daily loss of bile acids in feces, mostly as lithocholate, is about 0.2-0.4 g. Hepatic synthesis of bile acids equals this amount, so that the size of the bile acid pool is maintained at a constant level. 

Bile acids in meconium also reflect atypical synthesis. Back and Walter [209] reported on the presence of 14 bile acids obtained from meconium of 6 healthy infants (Table 2B). On the average 21% of chenodeoxycholate and of hyocholate and 8% of cholate were sulfated. Deoxycholate was the major bile acid of the sulfate fraction lithocholate, 3/8-hydroxy-5-cholenate [175] and 3, 12a-dihydroxy-5-cholenate were found only in the sulfate fraction, but quantities of lithocholate (range 0.3-1.4%) and 3i8,12a-dihydroxy-5-cholenate were small. The amount of l, 3tt,7a,12a-tetrahydroxy acid (79% as the taurine conjugate and 21% unconjugated) ranged from 3.6 to 11.1% of the total bile acids [209]. The feta bile adds of a number of animals, normal, adrenalectomized, thyroidectomized, or diabetic, are reviewed by Subbiah and Hassan ]210]. 

Synthesis of sulphate esters of14COOH-lithocholic and taurolithocholic acids... 

The quantities of lithocholate required to produce cirrhosis when/ed to rats (about 625 mg/kg) exceed by approximately 100 times the amounts found in man. The concentration of lithocholate in human gallbladder bile ranges from 0.2 to 5 mg/ml (mean 1.5 mg/ml), while that in human blood serum rarely exceeds 1 //g/ml (1). Rats, however, readily convert lithocholate to other less toxic bile salts, mainly 3a, 6) -dihydroxy-5 -cholanoic acid, in feeding experiments (71). The human liver does not readily convert lithocholate to other compounds to any significant extent (2). It thus may be possible that on a mg/kg basis lithocholate may be more toxic to man than to rats. Rabbits, like man, are unable to convert lithocholate to other compounds (73), and cirrhosis develops in these animals when lithocholate is fed at the 0.25% dietary level (about 0.17 mg/kg/day). An estimate of lithocholate synthesis in a healthy adult would be about 3-4 mg/kg/day. 

B.a. are biosynthesized from cholesterol by 7a-hy-droxylation, reduction of the double bond at podtion S, and epimerization at position 3. The side chain is shortened by -oxidation. Free B.a. can be prepared by alkaline hydrolysis of animal bile. They are used as starting materials for the partial laboratory synthesis of important steroid hormones. See Cholic acid, Deoxychohc acid, Lithocholic add. 

---