Synthesis, characterization, and receptor interaction profiles of enantiomeric bile acids.

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Katona BW, Cummins CL, Ferguson AD, Li T, Schmidt DR, Mangelsdorf DJ, Covey DF

Synthesis, characterization, and receptor interaction profiles of enantiomeric bile acids.

J Med Chem. 2007 Nov 29;50(24):6048-58. Epub 2007 Oct 27.

PubMed ID
17963371 [ View in PubMed
]
Abstract

Bile acids are endogenous steroid detergents with receptor-mediated physiologic actions including activation of the G-protein coupled receptor TGR5 and gene regulation mediated by nuclear receptors. In this study, we report the first synthesis of enantiomeric lithocholic acid (ent-LCA, ent-1) and chenodeoxycholic acid (ent-CDCA, ent-2) via ent-testosterone (3). ent-1 was synthesized in 21 total steps in 4.2% yield, whereas ent-2 was obtained in 23 total steps in 0.8% yield. Critical micelle concentrations of the enantiomeric bile acids were found to be identical to their natural counterparts. Furthermore, enantiomeric bile acids were also tested for their ability to modulate bile acid activated proteins: farnesoid X receptor, vitamin D receptor, pregnane X receptor, and TGR5. Interestingly, ent-1 and ent-2 showed differential interactions with these proteins as compared to their corresponding natural bile acids. These data highlight the potential for using enantioselectivity as a way to distinguish between receptor and nonreceptor-mediated functions of natural bile acids.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Chenodeoxycholic acidG-protein coupled bile acid receptor 1ProteinHumans
Unknown
Not AvailableDetails
Chenodeoxycholic acidNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Not AvailableDetails
Pharmaco-transcriptomics
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
Chenodeoxycholic acidApprovedABCB118647
upregulated		[Chenodeoxycholic Acid binds to and results in increased activity of NR1H4 protein] which results in increased expression of ABCB11 mRNA2q31.1
Chenodeoxycholic acidApprovedCYP7A11581
downregulated		[Chenodeoxycholic Acid analog binds to and results in increased activity of NR1H4 protein] which results in decreased expression of CYP7A1 mRNA8q12.1
Chenodeoxycholic acidApprovedCYP7A11581
downregulated		[Chenodeoxycholic Acid binds to and results in increased activity of NR1H4 protein] which results in decreased expression of CYP7A1 mRNA8q12.1
Chenodeoxycholic acidApprovedFABP62172
upregulated		[Chenodeoxycholic Acid binds to and results in increased activity of NR1H4 protein] which results in increased expression of FABP6 mRNA5q33.3
Chenodeoxycholic acidApprovedNR0B28431
upregulated		[Chenodeoxycholic Acid binds to and results in increased activity of NR1H4 protein] which results in increased expression of NR0B2 mRNA1p36.11