TOTAL SYNTHESIS OF A SURUGATOXIN PROGENITOR AND THE DEVELOPMENT OF A METABOLIC REPORTER FOR IMAGING GLYCOSYLATION IN VIVO
Organic synthesis represents perhaps the most versatile and powerful approach in the molecular sciences to construct functional molecules. Among the many applications of modern organic synthetic methods are the achievement of total syntheses of biologically important natural products and the invention of small molecule probes for interrogating cell biology. This dissertation begins in Chapter 1 by providing two introductory vignettes exemplifying the power and potential of organic synthesis toward challenges in natural product total synthesis and chemical biology probe development. Chapter 2 describes the total synthesis of the core structure of the surugatoxin family of natural products. The outlined synthetic strategy features an unprecedented spirooxindole formation that, in a single step, produces the bulk of the complexity of the final natural product. This concise total synthesis represents a viable synthetic route for preparation of natural products and unnatural analogs of this “extinct” natural product family for evaluation of biological activities. Chapter 3 describes a very different application of organic synthesis to build unnatural probe molecules for visualizing the biosynthesis of important macromolecules within living organisms. The goal of this research was to develop a chemical biology method for imaging the production of glycoproteins and glycolipids containing galactose sugar modifications during the process of animal development, which features physiologically important changes in glycosylation. Toward this goal, bioorthogonally tagged analogs of galactose, one of nine monosaccharide building blocks in vertebrate glycans, were synthesized and evaluated in mammalian cells and developing zebrafish embryos. Notably, an alkyne-tagged analog of UDP-galactose, the universal substrate for enzymes that append galactose to glycoconjugates, proved to be an efficient metabolic label that enables visualization of glycosylation in developing zebrafish following a fluorescent click chemistry tagging reaction. Collectively, these studies provide two powerful illustrations of the use of organic synthesis as a tool in natural product synthesis and chemical biology probe development.
bioorthogonal; click chemistry; galactose; glycosylation; imaging; zebrafish
Baskin, Jeremy M.
Lancaster, Kyle M.; Lin, Hening
Chemistry and Chemical Biology
Ph. D., Chemistry and Chemical Biology
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
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