Abstract B46: The synthesis and evaluation of quinol-containing natural products as cancer chemopreventive agents
Authors: Jones Gavin , Wells Geoff 
Published: January 2014

Reactive oxygen species (ROS) have been identified as a cause of the mutations required for carcinogenesis. One of the cellular responses to ROS is to upregulate the production of an array of detoxifying enzymes. The interaction between the ubiquitination facilitator protein Keap1 and the transcription factor Nrf2 plays a crucial role in this antioxidant response. Disruption of the Keap1/Nrf2 complex by chemopreventive agents allows translocation of Nrf2 to the nucleus where it interacts with antioxidant response elements (ARE) leading to increased transcription of a range of antioxidant gene products.

A diverse range of compounds are able to disrupt this complex. A common structural feature found among these molecules is the Michael-acceptor. These interact with the sulfhydryl groups of key cysteine residues in Keap1, causing a conformational change which prevents Keap1-dependent ubiquitination of Nrf2. A motif which has been of particular interest to our group is the quinol, a cyclic cross-conjugated cyclohexadienone unit containing two Michael-acceptors. In this study a number of quinol-containing natural products and some closely related analogs have been synthesized and evaluated for their ability to induce Nrf2 activity.

A small series of compounds were synthesized, including quinolic glucosides found in green olives and brominated quinols found in marine sponges. A number of different strategies were employed in the synthesis of these molecules, largely involving the functionalization of phenols followed by oxidation using either a hypervalent iodide reagent or oxone.

The compounds were assessed for their ability to induce Nrf2-dependent transcription using an assay to quantify the activity of NAD(P)H quinone oxidoreductase 1 (NQO1), an enzyme with an ARE in its promoter region. Briefly, mouse hepatocyte Hepa1c1c7 cells were treated with varying concentrations of the compounds and NQO1 activity was determined colorimetrically. Sulforaphane, a known potent inducer of Nrf2 activity was used as a positive control. A large variability to induce Nrf2 activity was found among the compound series, the most potent being jacaranone ethyl ester and a closely related dibrominated quinol ester that induced NQO1 activity at ∼1μM concentrations. However, it was observed that these compounds were cytotoxic at ten-fold higher concentrations.

Those compounds that showed the most promising activity in the NQO1 induction assay were evaluated further to characterize their activity on the Keap1-Nrf2 pathway and their effects on other Nrf2 dependent gene products. The SAR data generated in this study will be applied to the development of potent Nrf2 inducing agents with low cytotoxicity.

Citation Format: Gavin Jones, Geoff Wells. The synthesis and evaluation of quinol-containing natural products as cancer chemopreventive agents. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B46.