Computer-Aided Design and Synthesis of 1-{4-[(3,4-Dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic Acid as an Nrf2 Enhancer

Shirin Kahremany, Ilana Babaev, Pinhas Hasin, Tigist Y. Tamir, Tali Ben-Zur, Guy Cohen, Zhengyu Jiang, Sagiv Weintraub, Daniel Offen, Shai Rahimipour, M. Ben Major, Hanoch Senderowitz, Arie Gruzman

Research output: Contribution to journalArticlepeer-review

Abstract

The design and synthesis of a novel nuclear factor erythroid 2-related factor 2 (Nrf2) enhancer is reported. Using a structure-based virtual screening approach, several commercially available compounds were identified as having high probability to interact with the Nrf2-binding pocket in the Kelch-like ECH-associated protein 1 (Keap1). Keap1 is an adaptor protein that recruits Nrf2 to a cullin-3-dependent ubiquitin ligase complex. The identified compounds were tested against rat pheochromocytoma PC-12 cells for their cytoprotective activity, and one compound (SKT359126) demonstrated an Nrf2-mediated cell-protective effect. Based on the structure of SKT359126, 23 novel derivatives were synthesized and evaluated. Of the screened derivatives, 1-{4-[(3,4-dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic acid demonstrated better activity than the parent molecules in activating the Nrf2 transduction pathway in a dose- and time-dependent manner. This compound represents a promising starting point for the development of therapeutics for the treatment of oxidative-stress-related diseases.

Original languageEnglish
Pages (from-to)320-333
Number of pages14
JournalChemPlusChem
Volume83
Issue number5
DOIs
StatePublished - May 2018

Keywords

  • Nrf2
  • medicinal chemistry
  • oxidative stress
  • oxopyrrolidine derivatives
  • virtual screening

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