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Type: Thesis
Title: New peptide-based templates constrained into a β-strand by Huisgen cycloaddition.
Author: Pehere, Ashok D.
Issue Date: 2012
School/Discipline: School of Chemistry and Physics
Abstract: Chapter One introduces the concept of peptide 'secondary structure' with an emphasis on β-strand geometry in macrocycles. This structural design is crucial for targeting different proteases. The significance of the macrocylic β-strand ‘bioactive’ conformation is discussed in detail. In particular the exploitation of the conformationally constrained peptidomimetic macrocylic backbone, which is constrained by a number of synthetic approaches to lock the ‘bioactive’ conformation in place. Chapter Two describes simple and scalable methodology for the preparation of N-Cbz protected amino acids by reaction with Cbz-Cl which uses a mixture of aqueous sodium carbonate and sodium bicarbonate to maintain the appropriate pH. This method proceeds without the formation of by-products. The method is extended to large scale preparation of an intermediate zofenopril, an ACE inhibitor. Chapter Three describes new peptidic templates constrained into a β-strand geometry by linking acetylene and azide containing P₁ and P₃ residues of a tripeptide by Huisgen cycloaddition. The conformations of the macrocycles are defined by NMR studies and those that best define a β-strand are shown to be potent inhibitors of the protease calpain. The β-strand templates presented and defined here are prepared under optimized conditions and should be suitable for targeting a range of proteases and other applications requiring such geometry. Chapter four describes a new approach to non-covalent peptide-based nanotubular or rodlike structures, whereby the monomeric units are preorganised into a β-strand geometry that templates the formation of an extended and unusual parallel β-sheet rod-like structure. The conformational constraint is introduced by Huisgen cycloaddition to give a triazolebased macrocycle, with the resulting self-assembled structures stabilized by a well-defined series of intermolecular hydrogen bonds. Chapter Five the 26S proteasome has emerged over the past decade as an attractive therapeutic target in the treatment of cancers. Here, we report new tripeptide aldehydes that are highly specific for the chymotrypsin-like catalytic activity of the proteasome. These new CT-L specific proteasome inhibitors demonstrated high potency and specificity for cancer cells, with therapeutic windows superior to those observed for benchmark proteasome inhibitors, MG132 and Bortezomib. Constraining the peptide backbone into the β-strand geometry was associated with decreased activity in vitro and reduced anticancer activity, suggesting that the proteasome prefers to bind a conformationally flexible ligand. Using these new proteasome inhibitors, we show that the presence of an intact p53 pathway significantly enhances cytotoxic activity, thus suggesting that this tumor suppressor is a critical downstream mediator of cell death following proteasomal inhibition. Chapter Six peptide derived protease inhibitors represent an important class of compounds with the potential to treat a wide range of serious medical conditions. Herein we describe the synthesis of a series of triazole containing macrocylic protease inhibitors preorganised in a β-strand conformation and evaluate their selectivity and potency against a panel of protease inhibitors. A series of acyclic azido-alkyne-based aldehydes is also evaluated for comparison. The macrocyclic peptidomimetics showed considerable activity towards Calpain II, Cathepsin L and S and the 26S proteasome chymotrypsin-like activity. Importantly, the first examples of potent and selective inhibitors of Cathepsin S were identified and shown to adopt a well-defined β-strand geometry by NMR, X-ray and molecular docking studies. Chapter Seven describes simple and efficient methodology for the selective acylation and alkylation of biotin at its 3′-nitrogen. This methodology is used to prepare of other biotin derivatives.
Advisor: Abell, Andrew David
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2012
Keywords: peptides; peptidomimetics; Huisgen cycloaddition; macrocycles; β-strand; Nanotube; biological activity; inhibitors; Biotin
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