Abstract
Retinoids play a crucial role in the treatment of multiple human cancers, particularly neuroblastoma and leukaemia. However, their utility is often hampered by the inherent toxicities associated with the concentrations necessary for therapeutic benefit, as well as innate or acquired resistance to treatment. This thesis focuses on the discovery and development of novel scaffolds that possess cytotoxic activity mediated through the retinoid pathways.
A protocol for docking scaffolds into the binding site of the retinoic acid receptor β (RARβ) was developed. These docking methodologies were used to identify novel scaffolds as potential RARβ ligands, as well as probe the mechanisms behind the observed structure activity relationships (SAR) of the prepared compounds.
A wide range of novel indole-benzothiazole acetamides were synthesized via PyBOP amide coupling of 3-indoleacetic acids and 2-aminobenzothiazoles. These scaffolds were investigated for their cytotoxic activity against neuroblastoma cells. Several analogues were found to have low micromolar IC50 values, demonstrated selectivity towards cells with high RARβ expression and also were selective for cancerous cells over normal cells. Furthermore, the ability of these compounds to modulate RAR protein expression was demonstrated.
Indole and quinoline-oxadiazoles were synthesized by the dehydrocyclization of bis-hydrazides by 4-toluenesulfonyl chloride. The cytotoxic activity of these scaffolds was investigated with their selectivity towards cells overexpressing different RAR subtypes (α, β, γ) also investigated.
Benzothiazole-thieno[2,3-c]pyrazole amides were also synthesized by the one-pot, single step alkylation-aldol condensation of methyl thioglycolate and formyl-halopyrazoles. The cytotoxicity and SAR of these scaffolds was also explored.