Harwood, Iain and Rooney, Lisa (2015) Towards Novel 1,2,4,5-Tetrazine Mediated Peptide Macrocyclisations. PhD Thesis to be submitted to University of Edinburgh.

Abstract

Interest in linear peptides and peptidomimetics experienced rapid growth within the pharmaceutical industry due to their ability to modulate protein function by allosteric regulation and competitive binding; and their ability to disrupt protein-protein interactions. However, many linear peptides that show therapeutic potential cannot be readily developed into bioavailable pharmaceuticals due to their poor lipophilicity and protease stability; and their unpredictable secondary structures. Macrocyclic peptides show increased lipophilicity and protease stability; and their constrained secondary structures often lead to improved target binding affinity and selectivity. Consequently, there has been a resurgence of interest within the pharmaceutical industry towards peptide based therapeutics and increased research towards novel peptide macrocyclisation strategies.
Progress towards a novel solid-phase peptide macrocyclisation strategy based on the inverse electron demand Diels-Alder reaction of 1,2,4,5-tetrazines is reported in this thesis. The solid-phase oxidation activation peptide macrocyclisation strategy uses the in situ oxidation of an unreactive dihydro-1,2,4,5-tetrazine to trigger the inverse electron demand Diels-Alder reaction and therefore peptide macrocyclisation. Also, this strategy enables selective late stage incorporation of the dihydro-1,2,4,5-tetrazine moiety onto the peptide backbone in the presence of a dienophile. A successful proof of concept in situ oxidation and inverse electron demand Diels-Alder reaction of a dihydro-1,2,4,5-tetrazine was achieved. However, the poor stability of a strained dienophile towards an oxidant was also highlighted. To overcome this problem a library of alternative oxidants and a library of unstrained dienophiles were screened to successfully optimise the chemistry. Once optimised the chemistry was successfully transferred onto solid-phase using resin-bound dienophiles. However, attempts to synthesise resin-bound dihydro-1,2,4,5-tetrazine derivatised amino acids were unsuccessful. Therefore, an alternative dihydro-1,2,4,5-tetrazine was selected whilst screening the reactivity of a library of 1,2,4,5-tetrazines with a library of dienophiles.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/26795