Synthesis of bioactive fluorinated bile acid analogues and investigating the influence of (deoxo)fluorination on alkanol and carbohydrate lipophilicity by a new logP determination method

Abstract

Since the identification of bile acids as natural ligands for FXR and TGR5 receptors, huge interest has arisen in this field, including the synthesis of semi-synthetic bile acid derivatives to increase binding potency and selectivity. Fluorine introduction is an attractive strategy in drug design and property optimization. This thesis describes the synthesis of fluorinated analogues of bile acids and the lead compound 6-ECDCA. Interesting observations of effects of fluorination on crystal packing modes will also be discussed.

Another important application of fluorination is lipophilicity (logP) modulation. However, logP measurement of non-UV active compounds is rather cumbersome and hampers research toward the understanding how aliphatic fluorination influences lipophilicity. Over the course of this thesis, a novel and straightforward method was developed for accurate measurement of lipophilicity of fluorinated compounds by using 19F NMR. Unlike many other methods, there is no requirement of UV activity for quantification, or the need for calibration curves for logP estimation. Using this method, logP values for a large number of fluorinated compounds were determined. Interesting effects and trends from different fluorination patterns were observed, along with the impact of stereochemistry on lipophilicity.

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Identifiers

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

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