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

Bioorg Med Chem. 2021 Aug 15;44:116300. doi: 10.1016/j.bmc.2021.116300. Epub 2021 Jul 1.

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.

Keywords: Keap1; Keap1-Nrf2 interaction; Neuroinflammation; Nrf2; Oxidative stress; Protein-protein interaction inhibitor; Structure-activity relationship.

Publication types

  • Research Support, N.I.H., Extramural

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

Substances

  • Acetates
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Naphthalenes
  • naphthalene