Design, synthesis and evaluation of novel tumour vasculature-targeting agents

Abstract

This thesis is introduced with a review of the 'Hallmarks of Cancer', outlining each one as a potential target for drug therapy. Vascular targeting as a means of cancer growth retardation is specifically discussed. The chapter introduces the highly ordered process of angiogenesis and touches on the vast number of regulatory controls involved in the complex process. This leads on to a discussion of targeting tumour vasculature and the theoretical advantages thereof. The difference between the anti- angiogenic approach and vascular targeting approach is outlined and a number of agents currently undergoing clinical trials are discussed. The use of inhibitors of tubulin polymerisation as anti-vascular agents is reviewed and a novel class of vascular targeting agents, the combretastatins is introduced. The development of a new class of conformationally restricted analogues is discussed along with modifications undertaken as part of this doctoral thesis. Finally the role of Aminopeptidase N (APN) in tumour growth is set out and the idea of incorporating APN inhibitory character into a tubulin-binding molecule is put forward.