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

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.

New hybrid bromopyridine-chalcones as in vivo phase II enzyme inducers: potential chemopreventive agents

“…The CIs for all of the studied compounds (Table 3) were higher than 1.0, showing low cytotoxicities at the CDs. 23,24 This assay confirmed that both chalcone-like compounds 8 and 22, unlike derivative 9, are monofunctional inducers due to fact that they displayed the same values of CDs in both cell lines, 11.0 μM in Hepa-1c1c7 and 10.0 μM in BpRc1 for the first derivative and 14.0 μM in Hepa-1c1c7 and 10.0 μM in BpRc1 for the second one (Table 3). In contrast, the controls 2 and t-BHQ had bifunctional behaviors in our assay, needing a hundred-and six-times, respectively, lower doses to induce doubling of the QR activity in the wild-type cells (R B/H , Table 3).…”

“…22 The increment of the enzymatic activity in the mutant cell line concomitant with the increment in the wild-type indicates that the compound tested is a monofunctional inducer (induces only phase II enzymes) however when the increment is only in the wild-type, the compound is considered to be a bifunctional inducer since there is evidence that the pathway that is actually operating is the xenobiotic (aryl hydrocarbon) responsive element receptor (Ahr-XRE), which induces both phase I and phase II enzymes. 21,[23][24][25] In this first approach we determined QR phase-II enzyme induction at 10.0 μM using the ratio of specific activity between the wild and mutant cells, r H/B , as an inducer descriptor where a value near to 1 with the concomitant increment of specific activity in both studied cell lines indicates monofunctional behav-iour. Meanwhile, a value higher than 1 with the concomitant increment of specific activity in both studied cell lines indicates bifunctional behavior (Table 2).…”

“…The CI is defined as the ratio of the concentration which inhibited the growth of cell lines by 50% (IC 50 ) and the concentration that doubled QR specific activity in the same cell line (CD). 24 In order to compare 2, the known Nrf2 activator, 26 t-butylhydroquinone (t-BHQ), and one of our derivatives that was bifunctional in the first analysis (Table 2), 9, were also included in the study. In this case, we used the ratio of CDs between mutant and wild cells for each compound, R B/H , as the monofunctional/bifunctional descriptor where a value near to 1 indicates a monofunctional behaviour while a value higher than 1 indicates a bifunctional behaviour (Table 3).…”

“…1 H-NMR (CDCl 3 , 400 MHz) δ (ppm): 7.55 (m, 3H), 7.62 (m, 1H), 7.67 (d, 1H, J = 15.7), 7.82 (dd, 1H, J 1 = 1.6, J 2 = 8.6), 7.89 (m, 3H), 8.01 (d, 2H, J = 15.7), 8.06 (d, 1H, J = 8.9), 8.09 (d, 1H, J = 7.1). 13 (24), 181 (22), 152 (39), 128 (21), 105 (19), 77 (25). (Found: C, 87.9; H, 5.6%.…”

“…(E)-3-(5-Bromopyridin-3-yl)-1-(1-hydroxynaphthalen-2-yl)-2propen-1-one (24). 5-Bromopyridin-3-carboxaldehyde and 1-hydroxy-2-acetonaphthone were condensed as shown in Scheme 2b to obtain compound 24, which was purified by column chromatography to afford an orange-yellow solid (10%); mp 128.8-129.5 °C.…”