Chemical biology studies on human and mouse secondary bile acids
Citation:Lu, Yin, Chemical biology studies on human and mouse secondary bile acids, Trinity College Dublin.School of Pharmacy & Pharma. Sciences, 2022
Thesis Yin Lu VIVA Corrections clean.pdf (Thesis) 9.260Mb
Bile acids are important regulators of multiple homeostatic mechanisms integrating cell proliferation, metabolism and inflammation. The overall objective of this thesis was to use chemical biology tools to understand problems in bile acid research including metabolism and mechanism of cytotoxicity and FXR activation with the purpose of informing development of new therapeutic agents. Chapters 1 and 2 review the general background of bile acids, including their classification, functions and biosynthesis in the liver and intestine. Chapter 2 goes on to describe investigations into synthesis of so-called isobile acids by epimerization of the 3α-hydroxyl group. We carried out biological evaluations on their cytotoxicity in vivo and found that isobile acids cause less cell death than their alpha isomer counterparts in general. Their effect on FXR activation in both reporter assay and coactivator assay was assessed. In Chapter 3 is described a novel and highly efficient process towards the synthesis of muribile acids (MCAs), a group of bile acids found in mice, that are of interest because of the position of the mouse in the study of bile acid function and metabolism and because selected bile acids may have therapeutic potential. We examined the ability of muribile acids to prevent cell death and identified ω-muricholic acid (ωMCA) with potential cytoprotective properties. The impact of ωMCA on DCA and tunicamycin-induced ER stress gene expression was assessed and the favourable cytoprotective and ER stress-reducing properties of ωMCA were identified. In Chapter 4 is described the synthesis and characterization of a panel of 3-sulfonamide-24-amides derived from UDCA based on SAR around potent cytotoxicity exhibited by 3-azido-24-amides and 3α-ethansulfonamide UDCA 29 (a cytotoxic compound causing entire cell death in the Caco-2 cell line) from previous studies from our lab. Toxicity was characterized in liver and colonic epithelial cells, showing some differences in sensitivity. 24-Amidation, which had been successful in generating highly toxic 3-azido analogues did not enhance further the toxicity of the 3α-sulfonamide series. It was shown that in the toxic sulfonamide series, 24-carboxylate was not necessary for activity since it could be replaced with primary alcohol or primary amide without loss in activity. Further studies on toxicity effects of 3α-trifluoromethyl derivatives were also carried out. In Chapter 5 is described a strategy for the design of bile acid carrier-based cytotoxic drugs by enhancing uptake of a cytotoxic payload. Bile acid analogues of chlorbambucil were designed and analysed in relation to their effect on cell viability and on their uptake and breakdown under cell proliferation assay conditions. It was shown that conjugation to bile acids can enhance uptake and increase cytotoxicity. A summary of the major findings drawn from the experimental data are articulated here. Firstly, isobile acids have less cytotoxicity activity compared with their 3α counterparts and this can be applied in the cancer treatment by altering the bile acid pool. Besides, muribile acids, especially ω-MCA is found to prevent cell death caused by toxic bile acids.
Author: Lu, Yin
Publisher:Trinity College Dublin. School of Pharmacy & Pharma. Sciences. Discipline of Pharmacy
Type of material:Thesis
Availability:Full text available