Investigations on aurones as chemopreventive agents

Abstract

This thesis aims to investigate the hypothesis that the flavonoid aurones are potential chemopreventive agents via the induction of the phase 2 enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1). This study was motivated by: (1) the presence of a Michael acceptor motif (a common feature of many NQO1 inducing compounds) in the aurone structure, and (2) that systematic functionalization of the template may uncover derivatives with improved activity. To this end, 87 compounds were synthesized. Evaluation of NQO1 induction on mouse hepatoma Hepa1c1c7 identified 31 active compounds with ten having submicromolar concentrations to double NQO1 activity, the most potent of its class to date. Structural features for good activity were the presence of an intact Michael acceptor and lipophilic and size-contributing functionalities which were further supported by a QSAR analysis. Assays on the mutant AhR (Aryl hydrocarbon Receptor) deficient hepatoma BpRc1 cell line and CYP1A1 induction indicated that these aurone derivatives acted on the AhR pathway to induce NQO1. However, several of the potent derivatives were able to increase glutathione levels and thioredoxin reductase activity as well as upregulate Nrf2, a pathway responsible solely for phase 2 cytoprotective proteins induction. Thus, aurones may be mixed activators of both AhR and Nrf2 pathways, a class of chemopreventive agents that exploit the cross-talk between both pathways for phase 2 response induction. These findings provide the lead for the future development of aurones as cancer chemopreventive agents.