Abstract
Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure–activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a Kd of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane.
Highlights
During periods of oxidative or electrophilic stress, one of the body’s main defenses is induction of cytoprotective proteins, including detoxification enzymes, such as those that reduce quinones (e.g., NAD(P)H quinone oxidoreductase 1, NQO1) [1], those that degrade heme [2], and those involved in glutathione synthesis and transfer [3]
Nrf2 is translocated to the nucleus, where it heterodimerizes with the small MAF transcription factors and binds to antioxidant response elements in the promoter regions of many detoxification genes, such as NQO1, GST, heme oxygenase 1 (HMOX1) and glutathione peroxidase [7]
This effect was not seen with the unsubstituted sulfonamides (e.g., 7) and was surprising, given the elements of symmetry suggested by the planar structure
Summary
During periods of oxidative or electrophilic stress, one of the body’s main defenses is induction of cytoprotective proteins, including detoxification enzymes, such as those that reduce quinones (e.g., NAD(P)H quinone oxidoreductase 1, NQO1) [1], those that degrade heme (heme oxygenase 1, HMOX1) [2], and those involved in glutathione synthesis and transfer (e.g., glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase regulatory subunit, glutathione S-transferase, GST) [3] These genes are regulated by the transcription factor, Nrf (nuclear factor-erythroid2-related factor 2), which belongs to a cap ‘n’ collar family of basic leucine zipper transcription factors that comprise seven highly conserved domains (Neh to Neh7) [4]. Nrf is translocated to the nucleus, where it heterodimerizes with the small MAF (sMAF) transcription factors and binds to antioxidant response elements in the promoter regions of many detoxification genes, such as NQO1, GST, HMOX1 and glutathione peroxidase [7]
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