The design and sythesis of small molecule modulators of the arylhydrocarbon receptor and NRF2 transcription factors

Abstract

Carcinogenesis is a complex process which requires a number of modifications to the genome in order to progress to tumor formation. Reactive oxygen species (ROS) have been identified as one of the causes of these mutations. The cellular response to ROS is to upregulate the production of an array of detoxifying enzymes. The transcription factors Nrf2 (nuclear factor erythroid 2-p45 related factor 2) and the AhR (arylhydrocarbon receptor) are modulators of antioxidant response element and xenobiotic response element regulated genes respectively. These proteins control biological responses to a range of redox, electrophilic and non-endogenous compounds by controlling the expression of overlapping groups of proteins involved in phase I and II metabolism, redox control and anti-inflammatory activity. In the context of cancer cells, activation of these pathways has been associated with cytoprotective activity in the case of Nrf2 and various activities including cytotoxic activity in the case of the AhR. The ligands that activate or inhibit these transcription factors partially overlap and there is cross-talk between the two signalling pathways. A chemical biology approach was explored to elaborate series of heterocyclic inducers of Nrf2 and the AhR with a focus on flavone-like compounds (flavones, flavanols, flavanones, chalcones) and flavone isosteres (2-phenylbenzothiazole, 2-phenylbenzothiophenes and 3,5-diphenylisoxazolines). The aims were to characterise the behaviour of these isosteric compounds in relation to their Nrf2 inducing activity and/or AhR-dependent cytotoxicity. Structural modifications that develop structure-activity relationships and modify drug-like or drug delivery properties were invistigated. The synthesis of selected compounds and the initial biological studies are presented in this thesis