New hits as phase II enzymes inducers from a focused library with heteroatom–heteroatom and Michael-acceptor motives

The increased activity of phase-II-detoxification enzymes, such as quinone reductase (QR) and glutation S-transferase (GST), correlates with protection against chemically induced carcinogenesis. Herein we studied 11 different chemotypes, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiazole, 1,3,4-oxathiazole, thienyl hydrazone, α,β-unsaturated-oxime, α,β-unsaturated-N-oxide, coumarin and α,β-unsaturated-carbonyl, as phase-II enzymes inducers in order to identify new pharmacophores with chemopreventive activity. Fifty-four compounds were analyzed on wild-type mouse-hepatoma Hepa-1c1c7 and on the aryl-hydrocarbon-nuclear-translocator (Arnt)-defective mutant BpRc1 cells. New monofunctional inducers of QR and GST were identified, the 1,2,5-oxadiazol-2-oxide (3), the 1,2,4-triazine-4-oxides (23) and (32) and the tetrahydropyrimidinones (28) and (49). It was confirmed that Nrf2 nuclear translocation is the operative molecular mechanism that allows compound (3) to exert protective effects via expression of downstream phase-II enzymes.