Abstract
The objective of our research was to develop ursodiol analogs that are structurally modified to modulate hepatic side-chain amidation and prevent 7-dehydroxylation by intestinal bacteria while at the same time maintaining the critical micellar concentration (CMC) and hydrophilicity of ursodiol. More than 20 naturally occurring bile acids were screened for physicochemical properties. Then, two generations of analogs were studied, and those with physicochemical properties similar to ursodiol's were analyzed for physiologic properties. The first generation of analogs included molecules with steric and/or electronic hindrance on the side chain; the second group consisted of the same molecules conjugated with glycine or taurine and also “pseudoconjugated” analogs (23-hydroxylated, esterified, and amidated with other amino acids). Of the first-generation analogs, only cyclopropane D derivative and trans-olefin were useful to our purposes, being conjugated by the liver and almost completely recovered in bile. These two analogs were deconjugated and 7-dehydroxylated but with slower kinetics. The hydrophilicity of the molecules could be augmented by increasing the polarity of the steroid ring. Among the pseudoconjugated analogs, the CMC values were similar to those of the natural analogs, although hydrophobicity differed among the group. The analogs that were not deconjugated were not 7-dehydroxylated either. All of the pseudoconjugated bile acids were efficiently taken up by the liver, and their recovery in bile was similar to that of glycine and taurine ursodiol. From these studies we now know that side chain configuration and conformation are important in the conjugation and deconjugation processes. Mild modification of the side chain can prevent 7-dehydroxylation and thus yield a bile acid more resistant to intestinal bacteria and more bioavailable. Prevention of hepatic conjugation improves biliary secretion and recovery of many analogs.
Similar content being viewed by others
References
Danzinger RG, Hofmann AF, Schoenfield LJ, Thistle JL: Dissolution of cholesterol gallstones by chenodeoxycholic acid. N Engl J Med 268:1–8, 1972
Schoenfield LJ, Lachin JM, The Steering Committee: Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: The National Cooperative Gallstone Study. A controlled trial of efficacy and safety. Ann Intern Med 95:257–282, 1981
Nakagawa S, Makino I, Ishizaki T, Dohi I: Dissolution of cholesterol gallstones by ursodeoxycholic acid. Lancet 2:367–369, 1977
Roda E, Bazzoli F, Morselli Labate AM, Mazzella G, Roda A, Sama C, Festi D, Aldini R, Barbara L: Ursodeoxycholic acid vs chenodeoxycholic acid as cholesterol gallstone-dissolving agents: A comparative randomized study. Hepatology 2:804–810, 1982
Bachrach WH, Hofmann AF: Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Dig Dis Sci 27:737–856, 1982
Frigerio G: Ursodeoxycholic acid (UDCA) in the treatment of dyspepsia: Report of a multicenter controlled trial. Curr Ther Res 26:214–224, 1979
Stefaniwsky AB, Tint GS, Speck J, Shefer S, Salen G: Ursodeoxycholic acid treatment of bile reflux gastritis. Gastroenterology 89:1000–1004, 1985
Podda M, Ghezzi C, Battezzati PM, Bertolini E, Crosiniani A, Petroni ML, Zuin M: Ursodeoxycholic acid for chronic liver disease. J Clin Gastroenterol 10(Suppl 2):S25-S31, 1988
Leuschner U, Leuschner M, Sieratzki J, Kurtz W, Hubner K: Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow up. A pilot study. Dig Dis Sci 30:642–649, 1985
David R, Kurtz W, Strohm WD, Leuschner U. Die wirkung von ursodesoxycholsaure bei chronischnen leberkrankungen: Eine pilot Studie. Z Gastroenterol 23:420, 1985 (abstract)
Fisher MM, Paradine ME: Influence of ursodeoxycholic acid on biochemical parameters in cholestatic liver disease. Gastroenterology 90:1725, 1986; (abstract)
Poupon R, Chretien Y, Pupon RE, Pallet F, Calmus Y, Darms F: Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet 1:834–836, 1987
Ghezzi C, Zuin M, Battezzati PM, Podda M: Effect of ursodeoxycholate taurine and ursodeoxycholate plus taurine on serum enzyme levels in patients with chronic hepatitis. Hepatology 7:1110, 1987 (abstract)
Carey MC, Small DM: The physical chemistry of cholesterol solubility in bile: Relationship to gallstone formation and dissolution in man. J Clin Invest 61:998–1026, 1978
Holzbach RT, Marsh M, Olszewski M, Holan K: Cholesterol solubility in bile: Evidence that supersaturated bile is frequent in healthy man. J Clin Invest 52:1467–1479, 1973
Roda E, Mazella G, Roda A, Aldini R, Festi D, Bazzoli F, Messale E, Morselli AM, Barbara L: Effect of chenodeoxycholic and ursodeoxycholic acid administration on biliary lipid secretion in normal weight and obese gallstone patients.In Bile Acids and Lipids. G Paumgartner, A Stiehl, W Gerok, (eds). Lancaster, England: MTP Press, 1980
Loria P, Carulli N, Medici G, Menozzi D, Salvioli G, Bertolotti M, Montanari M: Effect of ursocholic acid on bile lipid secretion and composition. Gastroenterology 90:865–874, 1986
Northfield TC, Hofmann AF: Biliary lipid output during three meals and an overnight fast: I. Relationship to bile acid pool and cholesterol saturation of bile in gallstone and control subjects. Gut 16:1–11, 1975
Mosbach EH: Approaches to the development of new cholelitholytic agents.In Bile Acids and Cholesterol in Health and Disease. G Paumgartner, A Steihl, W Gerok, (eds). Lancaster, England, MTP Presss, 1983, pp 11–20
Mizuho U, Bertram IC, Mosbach EH: New bile acid analogs: 3α,7α-dihydroxy-7β-methyl-5β-cholanoic acid, 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid, and 3α-hydroxy-7-methyl-5β-cholanoic acid. J Lipid Res 25:407–410, 1984
Pellicciari R, Cecchetti S, Natalini B, Roda A, Grigolo B, Fini A: Bile acids with a cyclopropyl containing side chain. 1. Preparation and properties of 3α,7β-dihydroxy-22,23-methylene-5β-cholan-24-oic acid. J Med Chem 27:746–749, 1984
Pellicciari R, Cecchetti S, Natalini B, Roda A, Grigolo B, Fini A: Bile acid with cyclopropane containing side chain. 2. Synthesis and properties of 3α, 7β-dihydroxy-22,23-methylene-5β-cholan-24-oic acid-N-(2-sulfo-ethyl)amide. J Med Chem 28:239–242, 1985
Roda A, Grigolo B, Aldini R, Simoni P, Pellicciari R, Natalini B, Balducci R: Bile acids with a cyclopropyl-containing side chain. IV. Physicochemical and biological properties of the four diasteroisomers of 3α,7β-dihydroxy-22,23-methylene-5β-cholan-24-oic acid. J Lipid Res 28:1384–1397, 1987
Roda A, Aldini R, Grigolo B, Simoni P, Roda E, Pellicciari R, Lenzi PL, Natalini B: 23-Methyl-3α,7β-dihydroxy-5β-cholan-24-oic acid. Dose-response study of biliary secretion in rat. Hepatology 8:1571–1576, 1988
Roda A, Hofmann AF, Mysels KJ: The influence of bile salt structure on self-association in aqueous solution. J Biol Chem 258:6362–6370, 1983
Hofmann AF, Roda A: Physicochemical properties of bile acid and their relationship to biological properties: an overview of the problem. J Lipid Res 25:1477–1489, 1984
Roda A, Fini A: Effect of nuclear hydroxy substituents on aqueous solubility and acidic strength of bile acids. Hepatology 4(Suppl):72S-76S, 1984
Zouboulis Vafiadis I, Dumont M, Erlinger S: Conjugation is rate limiting in hepatic transport of ursodeoxycholate in the rat. Am J Physiol 243:G208-G213, 1982
Fedorowsky T, Salen G, Colallilo A, Tint GS, Mosbach EH, Hall JC: Metabolism of ursodeoxycholic acid in man. Gastroenterology 73:1131–1137, 1977
Fisher CD, Cooper NS, Rothschild MA, Mosbach EH: Effect of dietary chenodeoxycholic acid and lithocholic acid in the rabbit. Am J Dig Dis 19:877–886, 1974
Roda A, Fini A, Grigolo B, Simoni P, Rusticali GA, Natalini B: Factor analysis of physico-chemical properties of bile acids. Ann Chim 78:15–23, 1988
Fini A, Roda A, De Maria P: Chemical properties of bile acids. Part 2. pKa values in water and aqueous methanol of some hydroxy bile acids. Eur J Med Chem 17:467–470, 1982
Fini A, Roda A, Fugazza R, Grigolo B: Chemical properties of bile acids. III. Acid structure and solubility in water. J Solution Chem 14:595–603, 1985
Aldini R, Roda A, Morselli Labate AM, Cappelleri G, Roda E, Barbara L: Hepatic bile acid uptake: Effect of conjugation, hydroxyl and keto groups, and albumin binding. J Lipid Res 23:1167–1173, 1982
Aldini R, Roda A, Morselli AM, Simoni P, Roda E, Barbara L: Effect of albumin on taurocholate uptake kinetics in rat liver. Clin Sci 72:11–17, 1987
Aldini R, Roda A, Morselli AM, Grigolo B, Simoni P, Roda E, Barbara L: Species differences of the hepatic uptake of bile acids. Ital J Gastroeterol 19:1–4, 1986
Roda A, Grigolo B, Roda E, Simoni P, Pellicciari R, Natalini B, Fini A, Morselli Labate AM: Quantitative relationship between bile acid structure and biliary lipid secretion in rats. J Pharm Sci 77:596–605, 1988
Pellicciari R, Natalini B, Cecchetti S, Porter B, Roda A, Grigolo B, Balducci R: Bile acids with a cyclopropyl-containing side chain. 3. Separation, identification and properties of all four stereoisomers of 3α, 7β-dihydroxy-22,23-methylene-5β-cholan-24-oic acid (CUDCA). J Med Chem 31:730–736, 1988
Pellicciari R, Natalini B, Marinozzi M, Ursini A, Roda A, Grigolo B: Reazioni di ossidazione di alchilsililcheteneacetali e loro applicazioni nella sintesi di acidi biliari naturali 23-ossidrilati. Atti del VI Congresso Nazionale della Divisione di Chimica Farmaceutica della SCI, Alghero, 1986
Armstrong MJ, Carey MC: The hydrophobic-hydrophilic balance of bile salts. Inverse correlation between reverse-phase high performance liquid chromatographic mobilities and micellar cholesterol solubilizing capacities. J Lipid Res 23:70–80, 1982
Yoon YB, Hagey LR, Hofmann AF, Gurantz D, Michelotti EL, Steinbach JH: Effect of side-chain shortening on the physiologic properties of bile acids: Hepatic transport and effect on biliary secretion of 24-nor-ursodeoxycholate in rodents. Gastroenterology 90:837–852, 1986
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Roda, A., Grigolo, B., Pellicciari, R. et al. Structure-activity relationship studies on natural and synthetic bile acid analogs. Digest Dis Sci 34 (Suppl 12), S24–S35 (1989). https://doi.org/10.1007/BF01536659
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01536659