Synthesis of Homo A-CD Estrogens for Potential Use in Hormone Replacement Therapy

Abstract

Hormone replacement therapy (HRT) has been subject to much debate due to concerns that long term use of such treatment of menopause increases the risk of breast and uterine cancer. This is thought to be caused by estradiol (1) binding to the estrogen receptor α (ERα) resulting in increased cell proliferation. Another possible mechanism relates to toxicity of the estrodiol metabolites, which are thought to be genotoxic ortho-quinones. In a previous project, a series of A-CD estrogens (2) were synthesised as non-carcinogenic estradiol agonists where the cis CD ring junction was thought to be the cause of the desirable selectivity for ERβ. In this thesis, homo A-CDs were synthesised (3) with expansion of the D ring thought to increase the selecitivty for ERβ. Relative Binding Affinities (RBA) were determined with selectivity to ERα and ERβ. Most ligands showed decreased selectivity when compared to the original A-CD series. However, compounds carrying the CF3 moiety continued to show very high potency. In addition, novel synthetic routes were employed in the preparation of certain compounds.