The synthesis of fluorinated bile acid analogues

Abstract

Bile acids are a type of acidic steroid found in the bile of mammals and other vertebrates. They are key in the digestion of food but also play a role as signalling molecules, regulating their own synthesis and transport, as well as being involved in the homeostasis of energy and glucose. Because of this role, naturally-occurring and semi-synthetic bile acids have been used to treat a range of liver diseases and disorders for many years. Additionally, bile acids and their derivatives have been investigated for their roles in the treatment of cancer and, more recently, various life-changing neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease.

In drug discovery, fluorine is widely used to modulate the properties of potential drug candidates, including pKa, hydrogen-bond donating capacity and logP/D. Because of this, introduction of fluorine atoms to the polycyclic ring system of a bile acid is of high interest, to investigate the biological effects compared to those of the non-fluorinated analogues. This thesis describes the synthesis of a number of fluorinated bile acid analogues, along with the discussion of the biological activities of selected compounds in liver and neurodegenerative diseases. The crystal packing of a number of the analogues and intermediates in their synthesis is also discussed.

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

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