New methods for the synthesis of biologically active cyclic peptides
AuthorThombare, Varsha Jagannath
AffiliationSchool of Chemistry
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-11-15.
© 2019 Varsha Jagannath Thombare
A number of cyclic peptides have emerged as valuable pharmaceutical templates due to their resistance to chemical or enzymatic hydrolysis and high selectivity. In 2001, the celogentin family of bicyclic peptides was isolated from the seeds of Celosia argentea. The celogentins have been shown to be t potent anti-mitotic agents that inhibit tubulin polymerization, with celogentin C exhibiting four-fold higher activity than the clinically used anti-cancer drug vinblastine.1,2 The celogentins have two unusual side-chain to side-chain cross-links; one between the Beta-position of Leu2 and the indole C-6 of Trp5 and the other between the indole C-2 of Trp5 and the imidazole of the histidine side chain. These unusual cross-links make the chemical synthesis of the celogentins very tedious, lengthy, and low yielding. We have developed a new protocol for the formation of the C–C and C–N cross-links on solid phase to generate celogentin precursors. We have also designed and synthesized simplified celogentin mimetics, including analogues with improved biological activity. The cyclic peptide can form by a different method such as head to tail cyclization, side-chain to side -chain, side-chain to head/tail cyclization. The easy way to synthesize cyclic peptide is head to tail cyclization. Chemical synthesis of head-to-tail cyclic peptides challenging using standard peptide coupling methods forms a dimer of peptide and reaction rate of cyclization is slow. Efforts to overcome the intrinsic limitations of peptide head-to-tail cyclization include metal ion templating, the use of ‘capture’ auxiliaries and ring expansion/contraction approaches. Over recent decades, the preparation of proteins and long peptides has been achieved using either recombinant methods or total chemical synthesis employing native chemical ligation (NCL). These methods each have limitations; recombinant expression techniques cannot be used for unnatural amino acids and modified amino acids, while native chemical ligation requires cysteine at the ligation site. Their several methods have been developed ( including desulfurization of cysteine to alanine) to overcome the limitations of NCL. Nevertheless, all NCL-type methods rely on thioester (or selenoester) exchange as a crucial step. To overcome this significant limitation of NCL methods, We have now developed a novel chemoselective peptide ligation strategy that further exploits the reactivity of peptides containing backbone thioamides. The key accomplishments are reported herein with the goal mentioned above. Firstly, toward of total synthesis of celogentin C two unusual cross-link between Leu–Trp and Trp–His reaction protocol established individually. Secondly, simplified celogentin mimetic developed and which has shown more activity than Vinblastin. Higher yield simplified celogentin analogue can be used for further investigation. Moreover, a new head to tail cyclization method was developed by thioamide Ag(I) promoted chemistry. Further chemoselective peptide ligation strategy was stabilized with the unique reactivity of thioamides. Overall this project established a new head-to-tail cyclization method and a strong foundation for the pharmacological investigation of celogentin C as well as the development of new simplified celogentin mimetic based therapeutics.
KeywordsBicyclic peptide, anti-cancer, tubulin polymerization, Thioamide, cyclisation, Ligation,
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