The synthesis of A-ring fluorinated bile acid analogues

Abstract

Bile acids are physiological detergent molecules with a function to absorb dietary lipids and hydrophobic molecules in the gastrointestinal tract. It has emerged that bile acids are also agonists for the FXR nuclear receptor and the TGR5 membrane-bound receptor, and are key in regulating metabolism via both genomic and non-genomic factors. It is also apparent that bile acids could play an important role in the treatment of Parkinson’s disease and some cancers. A number of pharmaceutical companies have developed selective BA receptor agonists, with some progressing through clinical trials for a variety of metabolic disorders.
Fluorine is used extensively in property optimisation due to its ability to modify a plethora of physicochemical effects. By selectively introducing fluorine into the bile acid skeleton, it is possible to modify hydrogen bonding properties, and thus improvements in receptor binding are conceivable. This thesis describes the synthesis of a number of fluorinated bile acid analogues, along with a discussion of some early biological results. Two interesting cases of an intramolecular C-F•••H-O hydrogen bond within the bile acid skeleton will also be presented

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ORCID for Bruno Linclau: orcid.org/0000-0001-8762-0170

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