Design and synthesis of macrocycles, peptides and coiled coils with sugar connections

Abstract

Migrastatin is a secondary metabolite that is formed from the bacterium Streptomyces platensis. This compound has shown promising anti-metastatic activity by inhibiting tumour cell migration. Published derivatives of this bioactive molecule in the past have shown that the omission of a glutarimide side chain enhanced the IC50 in vitro by ~1000 fold. The work carried out as part of this thesis focused on synthesising analogues that centred around the core ring structure of migrastatin. Derivatives of migrastatin’s congener, Dorrigocin A, in which there is a change in one of the olefin’s geometry, have also been successfully synthesised. Some of these analogues have been biologically evaluated and show comparable results to potent analogues published in literature. A second batch of compounds is currently being screened over a wider range of tumour cell lines.

The second chapter of this thesis describes the synthesis of peptide scaffolds for displaying sugar moieties. Scaffolds are an important element of bioactive molecules for displaying pharmacophores with a defined distance and spatial orientation. Such parameters are required for effective receptor-ligand binding. Previous work within the Murphy group has explored diverse scaffolds with various ligands, length of linker ligand and valency of ligands. To add to the diversity of such scaffolds, de novo peptides have now been designed to self-assemble into trimeric coiled coils when exposed to aqueous media. Lactose ligands were grafted onto the side of these coiled coils generating glycoclusters. These glycoclusters are currently under biological evaluation to ascertain their lectin inhibitory potential. This work has been published in Tetrahedron Letters (Sweeney, S. M. et al., Tet. Lett. 2016, 57 (13), 1414-1417.)

The final chapter describes the synthesis of peptidomimetic analogues of an endogenous endocrine hormone, somatostatin. Acromegaly is a disease that arises from the overexpression of natural growth hormone, which subsequently leads to the formation of enlarged hands and feet. Typically this disease originates from a tumour growth located on the hormone producing pituitary gland. Somatostatin opposes the action of growth hormone by inhibiting its secretion, however, somatostatin has a short half-life. Peptidomimetic analogues were designed to include a N-Acetylglucosamine to help stabilise a β-turn that is a structural feature present in somatostatin’s pharmacophoric region. These peptides have shown activity in the μM region.