The design, synthesis and biochemical evaluation of novel flexible and conformationally restrained antiestrogens

Abstract

This thesis is presented in four different sections. In the first section the synthesis of a number of structural (novel flexible) analogues of the antiestrogen drug tamoxifen is described. Preparation of novel conformationally restrained analogues using benzoxepins as precursors is investigated in the second section. In the third section the prepared compounds are biochemically analysed for their binding, antiproliferative and cytotoxicity affinity for human MCF-7 breast adenocarcinoma cancer cells. In the final section highly resolved computational docking procedures are used to ascertain the degree of interaction of these novel compounds with specific activity-related residues in a model of the estrogen receptor. Interest in the use of triphenylethylenes as anti-cancer agents has increased due to the clinical success of tamoxifen in breast cancer. The structure and pharmacological activity of tamoxifen and its clinical analogues are iterated in Chapter 1. In Chapter 2, a series of triphenylethylene flexible analogues possessing an extra benzylic group were prepared using a seven step synthetic route and via the McMurry coupling reaction.