Soraya Alnabulsi, Elham Santina, Amy Chadwick, Elena Bichenkova, Richard Bryce, Karen Nolan, Constantinos Demonacos, Ian Stratford and Sally Freeman
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
Abstract:
NRH: quinone oxidoreductase 2 (NQO2) enzyme is a potential therapeutic target in cancer, malaria and neurodegenerative diseases. The inhibition of the NQO2 enzyme activity has a role in chemoprevention. The high expression of the NQO2 enzyme in tumour cells and its ability to reduce quinone and nitro compounds was utilized for the targeting of bio-reducible cytotoxic agents to the tumour cells.
The objective of this research is the design and synthesis of novel selective NQO2 inhibitors with no off-target effects, for example binding to DNA. From our previous screening studies of the NCI database, furan-amidines were identified as inhibitors of the NQO2 enzyme (Table 1) [1]. A focused virtual library of amidines and reversed amidines was designed containing related structures, which was computationally screened using the GOLD docking software package. A promising series of asymmetric amidines and reversed-amidines has been identified, synthesized and evaluated for their NQO2 inhibition.
Table 1. Furan-Amidine Leads
R1
R2
NQO2 Inhibition IC50 (nM)
NSC17602
H
H
140 ± 40
NSC305831
C(=NH)NH2
H
630 ± 70
NSC305836
C(=NH)NH2
CH3
50 ± 10
The ability of the synthesized compounds to inhibit the NQO2 enzyme was determined by a spectrophotometric method using a redox dye, DCPIP. In this method, the rate of the DCPIP colour change correlates to the NQO2 activity. The IC50 values of the compounds were in the nano-molar range, with the best compound having an IC50 value of 15 nM.
REFERENCE:
[1] K.A. Nolan, et al., Insilico screening reveals structurally diverse, nanomolar inhibitors of NQO2 that are functionally active in cells and can modulate NF-κB signalling, Mol Cancer Ter 2012; 11(1): 194-203.
