Towards the design and synthesis of alpha-helix mimetics
File(s)
Author(s)
Abas, Hossay
Type
Thesis
Abstract
Liver receptor homolog-1 (LRH-1) is a nuclear receptor (NR) that has been implicated to play a critical role in the development of breast cancer owing to its role in the direct regulation of breast cancer cell growth, whereby it acts in concert with the estrogen receptor (ER). Ligand-bound NRs, such as LRH-1, induce their transcriptional activity via the recruitment of coactivator proteins. Described herein is research directed at developing small drug-like molecules that can competitively bind to the coactivator binding site on LRH-1 and act as antagonists of the transcriptional activity of LRH-1. Such coactivator binding inhibitors (CBIs) are expected to be complementary to existing NR modulators which competitively bind at the ligand-binding pocket (LBP) of the NR ligand-binding domain (LBD).
Our aim in this work was to develop the synthesis of a non-peptidic α-helix mimetic capable of representing the key α-helical regions of a coactivator protein involved in binding to LRH-1. A majority of the work described in this thesis focusses on the design and synthesis of a bicyclic scaffold capable of reproducing up to five amino acid residues projecting from three different faces of an α-helix.
Our aim in this work was to develop the synthesis of a non-peptidic α-helix mimetic capable of representing the key α-helical regions of a coactivator protein involved in binding to LRH-1. A majority of the work described in this thesis focusses on the design and synthesis of a bicyclic scaffold capable of reproducing up to five amino acid residues projecting from three different faces of an α-helix.
Version
Open Access
Date Issued
2017-02
Date Awarded
2018-03
Advisor
Spivey, Alan
Sponsor
Engineering and Physical Sciences Research Council
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)