Date of Award

5-16-2024

Publication Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

Keywords

Cavitand;Crown ether;Macrocycles;Peptide

Supervisor

John Trant

Abstract

Naturally occurring macrocycles like erythromycin, conotoxins, and rapamycin have diverse biological effects, including antibiotic, anticancer, antifungal, and immunosuppressive properties. Their structural advantages include conformational preorganization for selective binding with minimal entropic cost and flexibility for accommodating other molecules. Additionally, they enhance membrane permeability and stability, especially for cyclic peptides. Despite their potential, limited investigation into macrocycles for drug discovery exists due to the complexity of their structures, requiring significant synthetic efforts, which slows progress. Nonetheless, the synthesis of notably simpler artificial macrocycles is feasible, drawing valuable inspiration from the natural world. Consequently, researchers have identified certain recurring substructures in naturally existing macrocycles. Notable examples include domains like polyketides, heterocycles, peptides, biphenyls, and (bi)aryl ethers. A proposed strategy involves integrating natural product drug discovery with combinatorial chemistry techniques. This approach centers on crafting synthetic compounds using readily available building blocks that incorporate substructural motifs found in nature. As a result, it enables the swift generation of synthetic compound libraries that closely resemble natural products. Of the various bioactive macrocycles known so far, cyclic peptides are of particular significance. In contrast to linear peptides, cyclic variants are more resistant to both exo- and endoproteases, which explains the significant therapeutic potential of this class of molecules. The discovery of Gramicidin S in 1944 by Gause and Brazhnikova was the pivotal point in the history of cyclic peptides. Shortly after its discovery in the midst of the Second World War, Gramicidin S was widely used in the treatment of septic gunshot wounds. Since then, the cyclic peptide class of compounds has experienced sustained growth with thousands of cyclic peptides now known. Many of them have been used as therapeutic agents. Examples include octreotide, calcitonin, cyclosporine A, nisin, polymixin and colistin peptides are of particular significance. The primary objective of this study is to develop cyclic peptides through the utilization of novel cyclization agents and employing milder conditions that can be universally applied to a broad spectrum of peptides. In the initial phase of the research, newly designed turn-inducing elements were synthesized. Subsequently, these turn inducers were incorporated into short peptide sequences and subjected to the cyclization process, which was achieved successfully. The rate of cyclization was then compared to that of a reference pentapeptide lacking any turn-inducing elements. In the next part, we have shown an effective synthetic approach based on a general design for the synthesis of peptides containing regioselective disulfide bonds. We have developed thermosensitive protecting groups that are removed under a variable heat trigger. They differ from one another only by the threshold level of the single physical change, temperature, without requiring the use of multiple deprotection reagents. The utility of these protecting groups has been demonstrated in the synthesis of a short conotoxin peptide analog, previously isolated from Conus venom. And finally in the last part we have conducted supramolecular studies. We have functionalized both upper and lower rim of resorcinarene with various-sized crown ethers. Our primary goal is to do some host-guest chemistry which is a fundamental aspect of supramolecular chemistry, and focuses on the interactions and associations between molecules, often involving a host molecule and a guest molecule. These studies are essential for understanding the non-covalent interactions and molecular recognition processes that underlie supramolecular chemistry. supramolecular systems exploit the principles of molecular recognition to achieve specific and controlled interactions between molecules. This is a powerful approach in chemistry, biology, materials science, and nanotechnology for designing functional systems with applications in areas like drug development, sensing, catalysis, and more.

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