SYNTHESIS OF NEMATODE SIGNALING MOLECULES

Abstract

Because of the high homology of signaling pathways to higher animals, C. elegans has become a preferred model organism to study animal development and human diseases, including Alzheimer’s diseases (AD) and obesity. C. elegans produce a family of small molecules called ascarosides, which are based on glycosides of the dideoxysugar ascarylose. This family of small molecules function as signaling molecules that regulate many aspects of their life history, including development, lifespan, social communication, as well as interactions with other species. Ascarosides not only regulate many aspects of worm biology, they can also be perceived by plant and even mammals: with a history of hundreds of million years, plants and animals have evolved to recognize ascarosides as an ancient molecular signature of nematodes. For example, ascr#18 can trigger the defense response of almost all plants and increase their resistance to multiple plants diseases, while ascr#7 can suppress the development of autoimmune diseases on mouse models. Given the significance of ascaroside-based signaling molecules, there exists a need to develop approaches to synthesize ascarosides efficiently, elucidate perception mechanisms, and determine how they are metabolized in vivo. Deeveloping appropriate chemical strategies to address these challenges forms the central goal of this thesis. In Chapter 1, I will present a versatile approach to ascaroside synthesis I developed. Compared to previous methods, this new approach enables regioselective modification and thus greatly facilitates structure activity relationship (SAR) studies. In Chapter 2, I will present a thiol-catalyzed redox rearrangement approach to synthesize ascarosides that further simplifies ascaroside synthesis, reducing the number of steps required to synthesize protected ascarylose from commercially available starting material from seven to three. Chapter 3 describes development, synthesis, and biological evaluation of trifunctional probes to identify the receptors of ascarosides. Specifically, the synthesis of four ascr#8 probes will be reported, two of which retained biological activity comparable to that of the natural, unmodified ascaroside. Chapter 4 describes the innovative application of isotope labeling to detect and identify new ascaroside metabolites and related metabolic pathways. In Chapter 5, applications of the synthetic strategies developed in chapter 1 and 2 to the syntheses of several peroxisomal β-oxidation-dependent ascaroside derivatives are described. In chapter 6, the identification and assignment of absolute configuration of a peroxisomal α-oxidation shunt metabolite ameth#11 are described, in addition to a synthesis of enantiomerically pure ameth#11 biological evaluation.