The synthesis of novel spirocyclic heterocycles as potential cancer therapeutics targeting the cell-cycle

The spirocyclic ring structure is a feature of a number of naturally-occurring and synthetic products that possess interesting biologically activities. This thesis describes our efforts towards synthesising various spirocyclic heterocycles as potential cancer therapeutics targeting the cell-cycle. Three different spirocyclic scaffolds, A-C, were accessed through a variety of cycloaddition reactions and several of these were investigated for their cytostaticity and protein-inhibition properties. To gain further insights into the development of novel CDK2 inhibitors, part of this research was conducted at the Anti-Cancer Drug Design Initiative (ADDI) laboratory, University of Newcastle upon the Tyne, UK. This thesis is divided into three primary synthetic chemistry chapters, based upon discussion surrounding the main chemistries used to derive the various spirocyclic oxindole scaffolds of the types A-C. Chapter 2 describes the use of the phosphine-catalysed [3+2]-cycloaddition reaction to synthesise racemic and enantio-enriched versions of spirocycles of type A. Chapter 3 describes the use of the cyclopropanation reaction to synthesise spirocycles of type B. Lastly, Chapter 4 describes the employment of the [1,3]-dipolar cycloaddition reaction of nitrones to the synthesis of spirocycles of type C. A discussion on the CDK2 research, performed in the UK, towards a new synthetic strategy employing directed ortho metalation chemistry is then provided in Chapter 5. The cellular cytostaticity screening against the cancer cell lines, H460, MCF-7 and SF-268, and protein inhibition studies against the cell-cycle proteins CDK2, CDK5, gSK-3 and MDM2, for a range of the spirocycles synthesised in Chapters 2-4, is then given and discussed in Chapter 6. Final conclusions and future work are drawn together in Chapter 7. All synthetic methods and physical and spectroscopic data are provided for all compounds in Chapter 8. Lastly, an appendix including all X-ray crystal structures and their crystallographic data, and also a section on the biological testing procedures is provided.