The synthesis of bioactive fluorinated bile acid analogues

Abstract

Bile acids are naturally occurring steroidal compounds found within the bile of humans and other mammals. They have key physiological functions including the absorption of dietary lipids and hydrophobic drug molecules and they also are responsible for the regulation of cholesterol levels.

Bile acids have recently emerged also as signalling molecules and are agonists at the FXR nuclear receptor and TGR5 membrane-bound receptor, both of which are found in a multitude of human tissue types. Because of this, natural and semi-synthetic bile acids have steadily been gaining traction over recent decades as drug candidates. Pharmaceutical companies are investigating selective bile acid receptor agonists for a broad range of diseases including cancer, Parkinson’s disease, diabetes, metabolic disorder and liver disease, with some progressing well through clinical trials.

Fluorine is widely used during drug discovery to selectively modify a myriad of physiochemical properties including acidity, lipophilicity and hydrogen bond donating capacity. Therefore, the introduction of fluorine to potential bile acid drug candidates is of great interest. This thesis describes the synthesis of a number of fluorinated bile acid analogues, with a particular focus on targeting non-alcoholic steatohepatitis (NASH), a prominent condition underlying liver disease. A brief summary of preliminary biological data is also presented.

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

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