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National Institute of Environmental Health Sciences

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Publication Detail

Title: Optimization of 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acids as inhibitors of Keap1-Nrf2 protein-protein interaction to suppress neuroinflammation.

Authors: Abed, Dhulfiqar Ali; Lee, Sumi; Wen, Xia; Ali, Ahmed R; Mangipudy, Vaibhav; Aleksunes, Lauren M; Hu, Longqin

Published In Bioorg Med Chem, (2021 08 15)

Abstract: The protein-protein interaction (PPI) between kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) is recognized as a promising target for the prevention and treatment of oxidative stress-related inflammatory diseases. Herein, a series of novel 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid analogs (7p-t and 8c) were designed to further explore the structure-activity relationships of the series. Their activities were measured first with a fluorescence polarization (FP) assay and more potent compounds were further evaluated using a more sensitive time-resolved fluorescence energy transfer (TR-FRET) assay, demonstrating IC50 values between 7.2 and 31.3 nM. In cytotoxicity studies, the naphthalene derivatives did not show noticeable toxicity to human HepG2-C8 and mouse brain BV-2 microglia cells. Among them, compound 7q bearing oxygen-containing fused rings was shown to significantly stimulate the cellular Nrf2 signaling pathway, including activation of antioxidant response element (ARE)-controlled expression of Nrf2 target genes and proteins. More importantly, 7q suppressed up-regulation of several pro-inflammatory cytokines in lipopolysaccharide (LPS)-challenged BV-2 microglial cells, representing a potential therapeutic application for controlling neuroinflammatory disorders.

PubMed ID: 34252790 Exiting the NIEHS site

MeSH Terms: Acetates/chemical synthesis; Acetates/chemistry; Acetates/pharmacology*; Dose-Response Relationship, Drug; Humans; Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors*; Kelch-Like ECH-Associated Protein 1/chemistry; Kelch-Like ECH-Associated Protein 1/metabolism; Molecular Structure; NF-E2-Related Factor 2/antagonists & inhibitors*; NF-E2-Related Factor 2/chemistry; NF-E2-Related Factor 2/metabolism; Naphthalenes/chemical synthesis; Naphthalenes/chemistry; Naphthalenes/pharmacology*; Neuroinflammatory Diseases/drug therapy*; Neuroinflammatory Diseases/metabolism; Protein Binding; Structure-Activity Relationship

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