Imidazoacridin-6-ones as novel inhibitors of the quinone oxidoreductase NQO2

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Abstract

The purpose of the work was to identify novel inhibitors of the enzyme NQO2. Using computational molecular modelling, a QSAR (R2 = 0.88) was established, relating inhibitory potency with calculated binding affinity. From this, the imidazoacridin-6-one, NSC660841, was identified as the most potent inhibitor of NQO2 yet reported (IC50 = 6 nM).

Graphical abstract

Electrostatic surface representation of NQO2 with NSC660841 docked in the binding pocked. NSC660841 is identified as the most potent inhibitor of NQO2 yet reported (IC50 = 6 nM).

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Acknowledgements

This work was supported by an MRC programme grant to I.J.S. (G0500366) and a project grant from AICR (I.J.S., R.B. and K.A.N.). We thank the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, for the supply of the imidazoacridin-6-ones used in this work. Professor Nicola Tirelli is thanked for providing the facilities to carry out the DNA binding analysis. Dr. Roger Whitehead and Mr. John Barnes are thanked for providing the

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