Design, synthesis and biochemical evaluation of dual-acting, estrogen receptor ligand conjugates

Abstract

Selective targeting of malignancies over healthy cells is an important goal in cancer therapies. Knowledge of environmental and biological differences between tumours and healthy tissue can present suitable targets for designing novel chemotherapeutic agents. Breast cancer is often hormone dependent in its early stage of development. In this study, the main objectives are to design, synthesise and biochemically evaluate dual-acting, estrogen-receptor targeting, conjugated compounds. The conjugate prototype structure comprises of an estrogen-receptor (ER) ligand component chemically-bound via a linker to another bioactive agent. The aim is to synthesise conjugates that can selectively target ER-dependent breast cancers and exert a potent anticancer activity though ER-antagonism and other cytotoxic effects. The thesis is divided into a number of sections. In chapter one, an introduction to the thesis incorporating a literature review and including an outline of the project objectives is presented. In the chapter two, the synthesis of a number of ER-ligands based on endoxifen, a metabolite of tamoxifen, is reported. Combretastatin A-4 (CA4) is a potent antimitotic agent and attractive lead compound for development; in chapter three, the synthesis of CA4 and a number of analogues is discussed. The fourth chapter covers the synthesis of ER-targeting conjugate prototypes containing a variety of different cytotoxic agents coupled with selected ER-ligands. Compounds in the thesis were fully characterised using infra-red spectroscopy (IR), nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectroscopy (HR-MS).