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Chemical Synthesis of the 3-sulfooxy-7-N-acetylglucosaminyl-24-amidated Conjugates of 3beta,7beta-dihydroxy-5-cholen-24-oic Acid, and Related Compounds: Unusual, Major Metabolites of Bile Acid in a Patient With Niemann-Pick Disease Type C1

Chemical Synthesis of the 3-sulfooxy-7-N-acetylglucosaminyl-24-amidated Conjugates of 3beta,7beta-dihydroxy-5-cholen-24-oic Acid, and Related Compounds: Unusual, Major Metabolites of Bile Acid in a Patient With Niemann-Pick Disease Type C1

Takashi Iida, Genta Kakiyama, Yohei Hibiya, Shohei Miyata, Takehiko Inoue, Kohsaku Ohno, Takaaki Goto, Nariyasu Mano, Junichi Goto, Toshio Nambara, Alan F Hofmann

Steroids. 2006 Jan;71(1):18-29.

PMID: 16197972

Abstract:

The chemical synthesis of 3beta,7beta-dihydroxy-5-cholen-24-oic acid, triply conjugated by sulfuric acid at C-3, by N-acetylglucosamine (GlcNAc) at C-7, and by glycine or taurine at C-24, is described. These are unusual, major metabolites of bile acid found to be excreted in the urine of a patient with Niemann-Pick disease type C1. Analogous double-conjugates of 3beta-hydroxy-7-oxo-5-cholen-24-oic acid were also prepared. The principal reactions involved were: (1) beta-d-N-acetylglucosaminidation at C-7 of methyl 3beta-tert-butyldimethylsilyloxy (TBDMSi)-7beta-hydroxy-5-cholen-24-oate with 2-acetamido-1alpha-chloro-1,2-dideoxy-3,4,6-tri-O-acetyl-d-glucopyranose in the presence of CdCO(3) in boiling toluene; (2) sulfation at C-3 of the resulting 3beta-TBDMSi-7beta-GlcNAc with sulfur trioxide-trimethylamine complex in pyridine; and (3) direct amidation at C-24 of the 3beta-sulfooxy-7beta-GlcNAc conjugate with glycine methyl ester hydrochloride (or taurine) using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride as a coupling agent in DMF. The structures of the multi-conjugated bile acids were characterized by liquid chromatography-mass spectrometry with an electrospray ionization probe under the positive and negative ionization modes.

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