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.
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.
Iida
Takashi
T
Department of Chemistry, College of Humanities and Sciences, Nihon University, Setagaya, Sakurajousui, Tokyo 156-8550, Japan. takaiida@chs.nihon-u.ac.jp
Kakiyama
Genta
G
Hibiya
Yohei
Y
Miyata
Shohei
S
Inoue
Takehiko
T
Ohno
Kohsaku
K
Goto
Takaaki
T
Mano
Nariyasu
N
Goto
Junichi
J
Nambara
Toshio
T
Hofmann
Alan F
AF
D001647:Bile Acids and Salts / Q000138:chemical synthesis* / Q000378:metabolism*; D002777:Cholestanols / Q000138:chemical synthesis* / Q000737:chemistry*; D002793:Cholic Acids / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D013058:Mass Spectrometry; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D012503:Saponins / Q000138:chemical synthesis*
D001647:Bile Acids and Salts; D002777:Cholestanols; D002793:Cholic Acids; D012503:Saponins