Oxetane-based peptidomimetics

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Abstract

This thesis describes the synthesis, structural preferences and biological properties of oxetane-containing peptidomimetics in which one of the amide C=O bonds of a peptide backbone is replaced by an oxetane ring. Chapter 1 gives a brief introduction on peptidomimetics, oxetanes in medicinal chemistry and oxetane-containing peptidomimetics.

Chapter 2 describes the development of a simple two-step sequence to spirocyclic analogues of 2,5-diketopiperazines. Conjugate addition of α-amino methyl esters to nitroalkenes, generated from oxetan-3-one or N-Boc-azetidin-3-one, followed by reduction of the nitro group with Raney Ni under an atmosphere of hydrogen provides, after spontaneous cyclisation of the primary amine, the spirocycles in good overall yields. These novel spirocycles can be functionalised by selective N-alkylations as well as by carbonyl reduction to the corresponding piperazines.

Chapter 3 describes the development of a practical route to oxetane-modified peptides (OMPs) using solid-phase peptide synthesis (SPPS) techniques. Our approach involves the application of oxetane-containing dipeptide building blocks which are easily prepared in three steps in solution. The building blocks are then integrated into peptide chains using conventional Fmoc/ t Bu SPPS. This approach was used to prepare a range of OMPs in high purity including oxetane analogues of Met- and Leu-enkephalin and the nonapeptide bradykinin.

Chapter 4 explores the impact of oxetane-modification on the structure and stability of α- helices. Initially, an asymmetric route to a dipeptide building block in which the oxetane- residue is based on alanine is described. Following this, the SPPS methodology described in Chapter 3 was used to prepare oxetane-modified analogues of an alanine-based α- helical peptide in which a single alanine residue is replaced with an oxetane-modified residue. The structural preferences of the oxetane-modified analogues were then studied using circular-dichroism (CD) spectroscopy. These studies revealed that introduction of an oxetane-modification results in a helix-destabilising effect.

Chapter 5 gives a summary of the key findings and possible future work.

Chapter 6 provides detailed experimental procedures for the work carried out in Chapters 2-4.

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