Towards the design and synthesis of alpha-helix mimetics

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.Open Acces

N-Chloroformylimidazolidinone Enolates as 1,3-Dipolar Reagents for the Stereoselective Synthesis of 3,4-Dihydroisoquinolones

N-Chloroformyl imidazolidinone derivatives of enantiopure amino acids may be deprotonated to give remarkably well-behaved enolates with both nucleophilic and electrophilic character. The enolates undergo diastereoselective C-alkylation with benzylic halides. A Bischler–Napieralski-like cyclization reaction onto the chloroformyl group, induced by either nucleophilic (KI, 2,6-lutidine) or Lewis acid (AlCl3) catalysis, gives substituted 3,4-dihydroisoquinolone derivatives in enantioenriched form. The reaction sequence constitutes a formal [3 + 3] route to the six-membered lactam ring of the dihydroisoquinolones

Diels-Alder reactions of α-Amido Acrylates with N-Cbz-1,2-dihydropyridine and Cyclopentadiene

Thermal Diels−Alder reactions of α-amido acrylates with N-Cbz-1,2-dihydropyridine and cyclopentadiene have been explored to investigate the factors influencing the endo/exo selectivity. For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either endo- or exo-ester adducts. For cyclopentadiene, the endo-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids increased the proportion of exo-ester adducts in some cases. These Lewis acids were incompatible with the dihydropyridine diene as they induced its decomposition

Diels–Alder Reactions of α‑Amido Acrylates with <i>N</i>‑Cbz-1,2-dihydropyridine and Cyclopentadiene

Thermal Diels–Alder reactions of α-amido acrylates with <i>N</i>-Cbz-1,2-dihydropyridine and cyclopentadiene have been explored to investigate the factors influencing the <i>endo/exo</i> selectivity. For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either <i>endo-</i> or <i>exo-</i>ester adducts. For cyclopentadiene, the <i>endo</i>-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids increased the proportion of <i>exo</i>-ester adducts in some cases. These Lewis acids were incompatible with the dihydropyridine diene as they induced its decomposition

Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (c log P 116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA2 <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom log D7.4 (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation

Total Synthesis of (+)-Lophirone H and Its Pentamethyl Ether Utilizing an Oxonium–Prins Cyclization

The first total synthesis of (+)-lophirone H (<b>1</b>) and its pentamethyl ether <b>29</b>, featuring an oxonium–Prins cyclization/benzylic cation trapping reaction, is described