Chemical synthesis of (22E)-3α,6β,7β-trihydroxy-5β-chol-22-en-24-oic acid and its taurine and glycine conjugates: a major bile acid in the rat

Genta Kakiyama,Takashi Iida,Atsushi Yoshimoto,Takaaki Goto,Nariyasu Mano,Junichi Goto,Toshio Nambara,Lee R Hagey,Alan F Hofmann

doi:10.1194/jlr.d300027-jlr200

Genta Kakiyama, Takashi Iida + Show 7 more

Open Access

https://doi.org/10.1194/jlr.d300027-jlr200

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Abstract

A method for the synthesis of Delta(22)-beta-muricholic acid (Delta(22)-beta-MCA), (22E)-3 alpha,6 beta,7 beta-trihydroxy-5 beta-chol-22-en-24-oic acid, and its taurine and glycine conjugates (Delta(22)-beta-muricholyltaurine and Delta(22)-beta-muricholylglycine) is described. The key intermediate, 3 alpha,6 beta,7 beta-triformyloxy-23,24-dinor-5 beta-cholan-22-al, was prepared from beta-muricholic acid (beta-MCA) via the 24-nor-22-ene and 24-nor-22,23-diol derivatives. Wittig reaction of the aldehyde with (carbomethoxymethylene) triphenylphosphorane and subsequent hydrolysis gave (unconjugated) Delta(22)-beta-MCA. Condensation reaction of the unconjugated acid with taurine or glycine methyl ester using diethylphosphorocyanide yielded the naturally occurring taurine or glycine conjugate (N-acylamidate) of Delta(22)-beta-MCA. These synthetic reference compounds are now available for investigation of the metabolism of beta-MCA by bacterial and hepatic enzymes in the rat and should also be useful as substrates for reductive deuteration or tritiation to give the 22,23-(2)H or (3)H-beta-MCA.

Highlights

A method for the synthesis of ⌬22-␤-muricholic acid (⌬22-␤-MCA), (22E)-3␣,6␤,7␤-trihydroxy-5␤-chol-22-en24-oic acid, and its taurine and glycine conjugates (⌬22-␤-muricholyltaurine and ⌬22-␤-muricholylglycine) is described
In 1993, Davis and Thompson (4) used 1H- and 13C-NMR to establish the chemical structure of the unsaturated bile acids as ⌬22␤-muricholic acid [⌬22-␤-MCA; (22E)-3␣,6␤,7␤-trihydroxy5␤-chol-22-en-24-oic acid], and Thompson, Davis, and Morris (5) reported that its plasma concentration in female Fischer rats exceeded that of ␤-MCA
We report the chemical synthesis of ⌬22-␤-MCA [1a] and its taurine [1b] and glycine [1c] conjugates (⌬22␤-muricholyltaurine and ⌬22-␤-muricholylglycine)

Summary

Introduction

A method for the synthesis of ⌬22-␤-muricholic acid (⌬22-␤-MCA), (22E)-3␣,6␤,7␤-trihydroxy-5␤-chol-22-en24-oic acid, and its taurine and glycine conjugates (⌬22-␤-muricholyltaurine and ⌬22-␤-muricholylglycine) is described. In 1993, Davis and Thompson (4) used 1H- and 13C-NMR to establish the chemical structure of the unsaturated bile acids as ⌬22␤-muricholic acid [⌬22-␤-MCA; (22E)-3␣,6␤,7␤-trihydroxy5␤-chol-22-en-24-oic acid], and Thompson, Davis, and Morris (5) reported that its plasma concentration in female Fischer rats exceeded that of ␤-MCA.

Results

Conclusion