Abstract
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.
Highlights
We found new inducers of quinone reductase and glutation S-transferase, with excellent in vitro chemopreventive indexes, the 1,2,5-oxadiazol-2-oxide (3), the 1,2,4-triazine-4-oxides (23) and (32) and the tetrahydropyrimidinones (28) and (49), confirming that Nrf2 nuclear translocation is the operative molecular mechanism that allows compound (3) to exert protection
(18) and 0.65 for the benzo-derivative, (19), probably extra mechanisms were operative in this cell that increased the quinone reductase (QR) activity in the mutant line BpRc1; unlike the compound (5) the new evaluated 1,2,4-thiadiazoles, (20–22), displayed an intermediate profile between monofunctional and bifunctional behaviors having the 1,2,4-thiadiazol-5-one (22) the most bifunctional activity maybe as result of the structural change in the heterocycles system; derivatives of 1,2,4-triazine chemotype displayed very diverse behavior while compound (23) was clearly monofunctional the corresponding dioxidized analog, that is, (24), was bifunctional and the simplest analog (25) was intermediate, between monofunctional and bifunctional, almost reaching three fold the values of QR-specific activity, with respect to untreated cells, at the assayed conditions in both cellular systems tested; derivatives
In order to confirm that the mechanism of enzyme II induction is via antioxidant response element (ARE) activation [38], we evaluated the Nrf2 nuclear translocation ability, using the 1,2,5-oxadiazole (3) as the model compound
Summary
Selected from our chemical library, namely: pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiazole and 1,3,4-oxathiazole, belonging to heteroatom–heteroatom bond containing five memberring category; thienyl hydrazone, α,β-unsaturated oxime, benzimidazole 1,3-dioxide and 1,2,4-triazine 4-oxide, belonging to α,β-unsaturated heterocarbonyl category; coumarin, 4-carboxaldehydeimidazole and tetrahydropyrimidine, belonging to α,β-unsaturated carbonyl category. We could state from the different chemotypes the following conclusions (Table 2): conversion of pyrazole to indazole made the chemotype as bifunctional, that is, indazole (17) (rH/B = 8.06); the rest of analyzed 1,2,5-oxadiazoles, like the compounds (6) and (7), showed a particular biological behavior where the induction is preferential in the mutant cells, rH/B = 0.72 for 1,2,5-oxadiazol (18) and 0.65 for the benzo-derivative, (19), probably extra mechanisms were operative in this cell that increased the QR activity in the mutant line BpRc1; unlike the compound (5) the new evaluated 1,2,4-thiadiazoles, (20–22), displayed an intermediate profile between monofunctional and bifunctional behaviors (rH/B = 1.28, 1.03 and 1.47, respectively) having the 1,2,4-thiadiazol-5-one (22) the most bifunctional activity maybe as result of the structural change in the heterocycles system; derivatives of 1,2,4-triazine chemotype displayed very diverse behavior while compound (23) was clearly monofunctional the corresponding dioxidized analog, that is, (24), was bifunctional and the simplest analog (25) was intermediate, between monofunctional and bifunctional, almost reaching three fold the values of QR-specific activity, with respect to untreated cells, at the assayed conditions in both cellular systems tested; derivatives. Preparation of cytosolic fraction & assay procedure A suspension containing 8.0 × 104 cells in 1.0 ml of milieu was seeded in 24-well plate and incubated 24 h
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