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Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators

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journal contribution
posted on 29.03.2016 by AD Jain, H. Potteti, BG Richardson, L. Kingsley, JP Luciano, AF Ryuzoji, H. Lee, A. Krunic, AD Mesecar A, SP Reddy, TW Moore
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.


Supported by: P30 CA023168/CA/NCI NIH HHS/United States R01 ES011863/ES/NIEHS NIH HHS/United States R01 HL058122/HL/NHLBI NIH HHS/United States


Publisher Statement

This is the author’s version of a work that was accepted for publication in European Journal of Medicinal Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Jain, A. D., Potteti, H., Richardson, B. G., Kingsley, L., Luciano, J. P., Ryuzoji, A. F., Lee, H., Krunic, A., Mesecar, A. D., Reddy, S. P. and Moore, T. W. Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators. European Journal of Medicinal Chemistry. 2015. 103: 252-268. 10.1016/j.ejmech.2015.08.049.


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