Jones, GW; (2014) The design, synthesis and evaluation of novel cyclohexadienones as cancer chemopreventive agents. Doctoral thesis , UCL (University College London).

Abstract

Reactive oxygen species (ROS) have been identified as one cause of genetic mutations associated with carcinogenesis. The cellular response to ROS is to upregulate the production of an array of detoxifying enzymes. Experimental evidence shows that the Keap1/Nrf2 complex plays a crucial role in this antioxidant response. Natural products which have displayed chemopreventive activity by stimulation of this pathway including a number of compounds containing Michael-acceptors. These exert their effects by reacting with critical cysteine residues on the Keap1 surface, conferring an increase in levels of free Nrf2. The application of Nrf2 inducers represent a novel approach to chemoprevention, utilizing the body’s natural defences to detoxify potentially tumorigenic xenobiotics. The aim of this project is to develop a novel, potent, non-toxic compound capable of stimulating the upregulation of Nrf2-dependent gene products for potential application as a cancer chemopreventive agent. An initial series of small cyclohexadienone-containing compounds were designed and synthesized. Compounds were tested for their ability to upregulate the activity of NAD(P)H:quinone oxidoreductase 1 (NQO1), a gene under the influence of the Keap1/Nrf2 pathway. A number of natural products containing Michael-acceptors were synthesized for investigation in the NQO1 assay. Structural analogues of each natural product were designed and synthesized in attempts to investigate any structure-activity relationships (SARs) and maximize potency. Following this, a series of compounds was synthesized containing Michael-acceptors activated by electron-withdrawing groups at the α-position. It was found that the introduction of an acetyl group to the 2-position of the cyclohexadienone structure conferred an increase in potency and low toxicity. Inclusion of a phenyl ring at the 4-position was found to enhance activity further and ‘Topliss analysis’ of the ring substituents led to the discovery of compound 9.83, which displayed promising potency (CD = 0.9 μM) and relatively low toxicity (10 μM) in the NQO1 assay.

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