Design, synthesis and in vitro evaluation of novel anti-cancer compounds

Abstract

The purpose of this thesis was the design, synthesis and in vitro appraisal of a novel class of ITP/APN dual inhibitory compounds. Additionally, a class of novel biaryls, which were synthesised within the research group, were assayed to evaluate their ability to inhibit tubulin polymerisation (ITP). The introductory chapter commences with brief overview of the history of cancer and role of natural products in conventional chemotherapeutic regimes and adjuvant immunotherapies. Subsequently, the biological mechanisms of mitosis and metastasis are discussed with special emphasis on the importance of tubulin and the spindle apparatus, and the proteolytic degradation of the extracellular matrix by the angiogenic marker, aminopeptidase N (APN). Following, a review of the structural activity requisites of particular aminopeptidase N and antimitotic compounds, a discussion on the novel development of a novel class of dual ITP/APN inhibitory compoimds ensues. The chapter concludes with the rationalisation of the proposed synthetic strategies, and the obligatory development of tubulin extraction, purification and assay procedures. Chapter 2 proceeds with the synthesis a series of investigational compounds coupling colchicbe to several dicarboxylic amino acids and (2S.3R)-2-hydroxy-3-amino-4- phenylbutanoic acid (AHPA), probing the optimum chain length compulsory to fulfil both requirements of minimal disruption to ITP whilst maintaining fianctionality necessary for APN/CD13 inhibition. Consequent ITP in vitro assay results are analysed and the importance of Aspartic acid (Asp) as a linker molecule discussed.