AbstractThe NRH: quinone oxidoreductase 2 enzyme (NQO2) is a potential therapeutic target in cancer, malaria and neurodegenerative diseases. The inhibition of NQO2 enzyme activity may have a role in cancer chemoprevention and chemotherapy. The objective of this research is the design, synthesis and evaluation of novel selective NQO2 inhibitors with no off-target effects, for example binding to DNA. From previous virtual screening studies of the NCI database, symmetric and asymmetric furan-amidines were identified as lead inhibitors of the NQO2 enzyme, with IC50 values of 630 nM for 4,4'-(furan-2,5-diyl)dibenzamidine, 50 nM for 4,4'-(3,4-dimethylfuran-2,5-diyl)dibenzamidine and 140 nM for 4-(5-phenylfuran-2-yl)benzamidine. A synthetic pathway for the synthesis of the asymmetric furan-amidines was established, which involved the cyclisation of the 1,4-diketone intermediates to give the furan ring. Several furan analogues with a range of substitutents on the aromatic ring (e.g. fluoro, bromo, nitro, methyl, ethyl, isopropyl, tert-butyl, methoxy) were prepared. In addition, isosteres of the amidine group were made, including imidate, N-aryl amidine (reversed amidine), N-aryl amide and N-hydroxyamidine (amidoxime). The furan ring was replaced with other 5-membered heterocycles, including pyrrole, N-methylpyrrole, thiophene, imidazole, N-methylimidazole and oxazole. All compounds were fully characterized by 1H and 13C NMR spectroscopy, IR spectroscopy and mass spectrometry. The synthesized asymmetric furan-amidines and their analogues showed potent NQO2 inhibition activity with IC50 values in the nano-molar range. The most active compounds were asymmetric furan-amidines with meta- and para-nitro substitution on the aromatic ring, with IC50 values of 15 nM. In contrast to the symmetric furan-amidines, which showed potent intercalation in the minor grooves of DNA, the synthesized asymmetric furan-amidines and N-methylpyrrole-amidine showed no affinity towards DNA, as shown by DNA melting temperature experiment. The high NQO2 inhibition activity of some analogues together with their high toxicity against several breast cancer cell lines, make these lead compounds worthy of further development and optimization as potential drugs.
|Date of Award||1 Aug 2014|
- The University of Manchester
|Supervisor||Sally Freeman (Supervisor) & Ian Stratford (Supervisor)|
- Cancer, NQO2 enzyme, symmetric furan-amidines, asymmetric furan-amidines, cancer chemotherapy, inhibitors