The design and synthesis of novel inhibitors of tubulin polymerisation

Abstract

This thesis is introduced with a review on the principles of tubulin polymerisation and how this process is necessary for cellular replication. This leads on to discussion of the structure-activity relationships of known natural occurring tubulin inhibitors that bind to specific sites on tubulin. The reported biological activity of natural tubulin inhibitors prompted the design and synthesis of several series of novel tubulin inhibitors, the details of which are set out in subsequent chapters. Chapter 2 reports on the design and synthesis of the first series of novel biaryl compounds. This involved the synthesis of an aromatic A-ring fused to an aliphatic B- ring as the cyclic intermediate. The final step in the synthesis of this intermediate involved the novel use of pentafluorophenol to activate the acid functionality of the precursor prior to its cyclisation. Accordingly, this discovery was applied to the synthesis of fifteen benzocycloalkanones. This chapter closes with a description of the method used to couple various aromatic units to four of these benzocycloalkanones, to yield the first series of novel biaryl compounds.