Display options
Cite
Roda A, Grigolo B, Pellicciari R, et al. Structure-activity relationship studies on natural and synthetic bile acid analogs. Dig Dis Sci. 1989;34(12):24S-35Sdoi: 10.1007/BF01536659.
Roda, A., Grigolo, B., Pellicciari, R., & Natalini, B. (1989). Structure-activity relationship studies on natural and synthetic bile acid analogs. Digestive diseases and sciences, 34(12), 24S-35S. https://doi.org/10.1007/BF01536659
Roda, A, et al. "Structure-activity relationship studies on natural and synthetic bile acid analogs." Digestive diseases and sciences vol. 34,12 (1989): 24S-35S. doi: https://doi.org/10.1007/BF01536659
Roda A, Grigolo B, Pellicciari R, Natalini B. Structure-activity relationship studies on natural and synthetic bile acid analogs. Dig Dis Sci. 1989 Dec;34(12):24S-35S. doi: 10.1007/BF01536659. PMID: 2598765.
Copy Download .nbib Format: NLM
Share it on

Dig Dis Sci. 1989 Dec;34(12):24S-35S. doi: 10.1007/BF01536659.

Structure-activity relationship studies on natural and synthetic bile acid analogs.

Digestive diseases and sciences

A Roda, B Grigolo, R Pellicciari, B Natalini

Affiliations

  1. Istituto di Chimica Analitica, Universitá di Messina, Italy.

PMID: 2598765 DOI: 10.1007/BF01536659

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.

Cited by

References

  1. Lancet. 1987 Apr 11;1(8537):834-6 - PubMed
  2. J Clin Gastroenterol. 1988;10 Suppl 2:S25-31 - PubMed
  3. J Pharm Sci. 1988 Jul;77(7):596-605 - PubMed
  4. Hepatology. 1988 Nov-Dec;8(6):1571-6 - PubMed
  5. J Med Chem. 1988 Apr;31(4):730-6 - PubMed
  6. J Lipid Res. 1987 Dec;28(12):1384-97 - PubMed
  7. Clin Sci (Lond). 1987 Jan;72(1):11-7 - PubMed
  8. Gastroenterology. 1986 Apr;90(4):837-52 - PubMed
  9. Gastroenterology. 1986 Apr;90(4):865-74 - PubMed
  10. J Med Chem. 1985 Feb;28(2):239-42 - PubMed
  11. Dig Dis Sci. 1985 Jul;30(7):642-9 - PubMed
  12. Gastroenterology. 1985 Nov;89(5):1000-4 - PubMed
  13. Am J Dig Dis. 1974 Oct;19(10):877-86 - PubMed
  14. J Clin Invest. 1973 Jun;52(6):1467-79 - PubMed
  15. N Engl J Med. 1972 Jan 6;286(1):1-8 - PubMed
  16. J Lipid Res. 1984 Dec 15;25(13):1477-89 - PubMed
  17. Hepatology. 1984 Sep-Oct;4(5 Suppl):72S-76S - PubMed
  18. J Lipid Res. 1984 Apr;25(4):407-10 - PubMed
  19. J Clin Invest. 1978 Apr;61(4):998-1026 - PubMed
  20. J Med Chem. 1984 Jun;27(6):746-9 - PubMed
  21. J Biol Chem. 1983 May 25;258(10):6362-70 - PubMed
  22. Ann Intern Med. 1981 Sep;95(3):257-82 - PubMed
  23. J Lipid Res. 1982 Jan;23(1):70-80 - PubMed
  24. Lancet. 1977 Aug 20;2(8034):367-9 - PubMed
  25. Dig Dis Sci. 1982 Aug;27(8):737-61 - PubMed
  26. Am J Physiol. 1982 Sep;243(3):G208-13 - PubMed
  27. Hepatology. 1982 Nov-Dec;2(6):804-10 - PubMed
  28. J Lipid Res. 1982 Nov;23(8):1167-73 - PubMed
  29. Gut. 1975 Jan;16(1):1-11 - PubMed
  30. Gastroenterology. 1977 Nov;73(5):1131-7 - PubMed

Substances

MeSH terms

Publication Types

LinkOut - more resources