NAD(P)H Quinone Oxidoreductase 1 (NQO1) and NRH Quinone Oxidoreductase 2 (NQO2): Their inhibition by Triazoloacridinones and Imidazoacridinones

Abstract

The human enzymes NQO1 and NQO2 are cytosoloic flavoproteins that catalyze the two electron reduction of a broad range of quinone substrates. NQO1 and 2 are over-expressed in several types of tumours, consequently making them attractive targets for drug development. Inhibition of NQO1 and NQO2 has been shown to reduce the development of some cancers. However current agents demonstrate off target effects and therefore more pharmacologically applicable compounds are needed. Initially a computational screen of the NCI database identified NSC 645827, a triazoleacridin-6-one (TA) with an IC50 of 0.7 µM. From this, a range of TAs were synthesised and evaluated for their ability to inhibit NQO1 and NQO2. From these data we identified several TAs which were the most potent inhibitors of NQO2 reported. The most potent compound being 10a (98 ± 10 nM), an N-oxide with low cellular toxicity and no DNA interaction. Taking the main pharmocaphore of the TA, a substructure search of the NCI database identified the imidazoacridin-6-one (IA) C1311, a known DNA binding agent and inhibitor of FLT3 kinase. Quantities of several IAs were obtained from the NCI and were investigated as potential NQO1 and NQO2 inhibitors. NSC 660841 was identified as the most potent inhibitor of NQO2 yet reported (6 ± 3 nM). Compounds were further investigated for potential off target effects.Representative compounds from both series were evaluated for their ability to modulate the cytotoxic effect of doxorubicin (DOX). There was no obvious relationship between the compound structures and the toxicity of DOX. Although no clear relationship could be determined between the compounds, a novel association between DOX, NQO1 and NQO2 was established. Compound A6B1 demonstrated the ability to increase the toxicity of DOX. It is hypothesised that a combination treatment of NQO2 inhibitors and DOX could lead to a greater therapeutic response as apposed to DOX alone. In summary, the results identify TAs and IAs to have the ability to inhibit both NQO1 and NQO2. The low cellular toxicity and high inhibitor potency of the N-oxide compounds makes them a suitable tool to study the enzymes without off target effects. Also these data provide a direction for future compound synthesis

Date of Award	31 Dec 2012
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Ian Stratford (Supervisor)