Synthesis of fluorinated bile acids and investigation of their hydrogen bond properties

Abstract

Bile acids are naturally occurring steroidal compounds present in the bile of mammals. They are involved in the absorption and digestion of ingested fats, lipophilic vitamins and drugs. In addition, they also control secretion and regulation of cholesterol metabolism.
Bile acids have recently emerged as signalling molecules of receptors such as FXR and TGR5. Ursodeoxycholic acid (UDCA) and its taurine conjugate TUDCA were shown to inhibit the expression of angiotensin converting enzyme 2, a membrane receptor which facilitates entry of different coronaviruses into the human body. In addition, TUDCA was also shown to have a neuroprotective function over mitochondria and endoplasmic reticulum, whose malfunctions are critical in the progression of neurodegenerative diseases such as Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis.
Fluorine is widely used in drug discovery to selectively modify physiochemical properties such as acidity and hydrogen bond donating capacity. Therefore, the introduction of fluorine to potential bile acid drug candidates is of interest. This thesis describes syntheses of several fluorinated bile acid derivatives with the aim to evaluate how strategic incorporation of fluorine influences the hydrogen bond donating capacity of vicinal hydroxy groups. Strategies that enable fluorination of non-standard bile acid positions, namely the D-ring, are also investigated herein.

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Identifiers

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

ORCID for Sam Thompson: orcid.org/0000-0001-6267-5693

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