Abstract
Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation, and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1, and nuclear translocation of Nrf2 in HCT116 cells. In vivo potency of 1 was studied using AOM-DSS models, showing that the development of colorectal adenomas was significantly inhibited. Administration with 1 lowered the expression of IL-6, IL-1β, and promoted Nrf2 nuclear translocation. These results indicated that 1 is a potent Nrf2/ARE activator, both in vitro and in vivo. Forty-one derivatives were synthesized for SAR study, and a more potent compound 17 was identified. To our knowledge, this is a potent ARE activator. Besides, its novel structure makes it promising for further optimization.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Adenoma / chemically induced
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Adenoma / pathology
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Adenoma / prevention & control*
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antioxidant Response Elements / genetics*
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Azoxymethane
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Blotting, Western
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Colorectal Neoplasms / chemically induced
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Colorectal Neoplasms / pathology
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Colorectal Neoplasms / prevention & control*
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Dextran Sulfate
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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HCT116 Cells
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Heme Oxygenase-1 / metabolism
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Hep G2 Cells
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Heterocyclic Compounds, 3-Ring / chemical synthesis
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Interleukin-1beta / metabolism
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Interleukin-6 / metabolism
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Mice
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Mice, Inbred C57BL
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Models, Chemical
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Molecular Structure
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NAD(P)H Dehydrogenase (Quinone) / metabolism
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NF-E2-Related Factor 2 / antagonists & inhibitors*
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NF-E2-Related Factor 2 / metabolism
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
Substances
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3-(2-(3-fluorophenyl)-2-oxoethylidene)-2,3,6,7-tetrahydro-1H-pyrazino(2,1-a)isoquinolin-4(11bH)-one
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Antineoplastic Agents
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Heterocyclic Compounds, 3-Ring
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Interleukin-1beta
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Interleukin-6
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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Dextran Sulfate
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HMOX1 protein, human
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Heme Oxygenase-1
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NAD(P)H Dehydrogenase (Quinone)
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NQO1 protein, human
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Azoxymethane