Optimization of 1, 4-bis(arylsulfonamido)naphthalene-N, N'-diacetic acids as inhibitors of Keap1-Nrf2 protein-protein interaction to suppress neuroinflammation. (15th August 2021)

• Record Type: Journal Article
• Authors: Abed, Dhulfiqar Ali; Lee, Sumi; Wen, Xia; Ali, Ahmed R.; Mangipudy, Vaibhav; Aleksunes, Lauren M.; Hu, Longqin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 44(2021)
• Publication Date: 2021-08-15
• Subjects: Keap1 -- Nrf2 -- Keap1-Nrf2 interaction -- Protein-protein interaction inhibitor -- Oxidative stress -- Structure-activity relationship -- Neuroinflammation; Aβ amyloid-β -- AD Alzheimer's disease -- ARE antioxidant response element -- COPD chronic obstructive pulmonary disease -- Cul3 cullin3 -- DCM dichloromethane -- DMF dimethyl fumarate -- DMF N, N-dimethylformamide -- DMSO dimethyl sulfoxide -- FDA food and drug administration -- FITC fluorescein isothiocyanate -- FP fluorescence polarization -- GST glutathione S-transferase -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- HO-1 heme-oxygenase-1 -- HRMS high resolution mass spectrometry -- IFN interferon -- IL interleukin -- Keap1 Kelch-like ECH-associated protein 1 -- LC-MS liquid chromatography mass spectrometry -- LPS lipopolysaccharide -- Maf musculoaponeurotic fibrosarcoma -- MS multiple sclerosis -- MsCl mesyl chloride -- ND neurodegenerative disease -- Neh Nrf2-ECH homology -- NQO1 NAD(P)H:quinone oxidoreductase 1 -- Nrf2 nuclear factor erythroid 2-related factor 2 -- PD Parkinson's disease -- PPI protein-protein interaction qRT-PCR, quantitative real-time polymerase chain reaction -- RNS reactive nitrogen species -- ROS reactive oxygen species -- SAR structure–activity relationship -- SFN sulforaphane -- TEA triethylamine -- TFA trifluoroactic acid -- TFAA trifluoroacetic anhydride -- THF tetrahydrofuran -- TNF tumor necrosis factor -- TR-FRET time-resolved fluorescence resonance energy transfer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116300
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.