UC Davis

Cholesterol, a major lipid component of animal plasma membranes (PM) and a small component in some plants, has been associated with the development of various diseases and infections, like Alzheimer’s disease (AD), Parkinson’s diseases (PD), H. pylori infection, etc., through an imbalance in cholesterol homeostasis or cholesterol modification. In addition to the bioactivity of lipids like cholesterol, glycolipids (glycosylceramides and sterol glycosides) have been reported to influence the release of T-helper 1 (TH1) and T-helper 2 (TH2) cytokines in mammals. Also, cholesterol has been reported to undergo a sugar exchange with glucosyl ceramides. In previous studies, cholesterol analogues with intrinsic or extrinsic fluorescent groups were used as probes to monitor biodistribution of cholesterol and the sugar exchange with glucosyl ceramides. However, problems arose with these cholesterol probes from disrupting plasma membranes to difficult extraction for metabolite characterization. Recently, a dehydroepiandrosterone (DHEA) probe with a primary alkoxyl-azido group mimicked cholesterol well while providing efficient extraction via copper(I)-catalyzed azide/alkyne cycloaddition (CuAAC) with 4-N-methylamino-1,8-napthalimidopropyne (MAN) for metabolite characterization and minimal disruption of plasma membranes. Currently, there are no azido-glycolipid probes available to monitor the metabolism of glycolipids during TH1 and TH2 cytokine release in addition to the sugar exchange with ceramides. In this project, two secondary C17 azido-DHEA (5 and 8) probes were prepared and six azido-glycolipid (14, 15, 16, 17, 22, and 24) probes were proposed to study the metabolism of lipids and glycolipids in various environments. Chapter 1 will focus on the bioactivity of sterols/sterol glycosides and previous sterol probes. Chapter 2 will discuss the total synthesis of the two secondary C17 azido-DHEA probes (5 and 8). Chapter 3 will cover the NMR characterization of various DHEA derivatives while Chapter 4 will describe previous glycosylceramide derivatives, the bioactivity of glycosylceramides, and the future synthesis of six azido-glycolipid probes (14, 15, 16, 17, 22, and 24).