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Todorovic, Mihajlo

University of British Columbia

This thesis will describe the application of aromatization-driven, heterocycle forming reactions for peptide cyclization. Chapter 1 introduces protein and peptide structure broadly, followed by describing natural cyclized peptides. It will then briefly give historical context for synthetic peptide cyclization and survey modern synthetic peptide stapling strategies. Chapter 2 introduces the bicyclic peptide natural product, α-amanitin, a classic peptide whose staple and properties inspire much of the intellectual outputs in this thesis and outlines the rationale for a structure activity relationship (SAR) study of the eastern ring of the molecule and describe the synthesis of the unnatural amino acid monomers required for the SAR study. Chapter 3 details the synthesis of a focused library of α-amanitin eastern ring analoguesand report their biological activities. Chapter 4 describes the application the chemistry developed for cyclizing the α-amanitin analogues (the Savige-Fontana reaction, which introduces tryptathionine staples) described in Chapter 3 to forging analogues of a completely unrelated peptide sequence of biological interest, somatostatin. Chapter 4 also describes the discovery of an unexpected side product (a 2-2’ bisindole) of the Savige-Fontana reaction when applied to somatostatin. Chapter 5 describes the application of tryptathionine stapling to synthesizing analogues of another peptide sequence of oncological interest, α-melanocyte stimulating hormone (α-MSH) and the development of intentional 2-2’-bisindole peptide stapling. Chapter 6 outlines the historical uses of ortho-phthalaldehyde (OPA) as a reagent in analytical chemistry and biochemistry for forming fluorescent isoindoles and introduce the idea of employing OPA for stapling peptides. It will then discuss the development of fluorescent isoindole crosslinking (FlICk) chemistry for stapling monocyclic α-MSH analogues and bicyclic α-amanitinα-analogues. Chapter 7 concludes with future directions for the projects described in this thesis.

Text

2025-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83893

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/