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Computer‐Aided Design and Synthesis of 1‐{4‐[(3,4‐Dihydroxybenzylidene)amino]phenyl}‐5‐oxopyrrolidine‐3‐carboxylic Acid as an Nrf2 Enhancer
Author(s) -
Kahremany Shirin,
Babaev Ilana,
Hasin Pinhas,
Tamir Tigist Y.,
BenZur Tali,
Cohen Guy,
Jiang Zhengyu,
Weintraub Sagiv,
Offen Daniel,
Rahimipour Shai,
Major M. Ben,
Senderowitz Hanoch,
Gruzman Arie
Publication year - 2018
Publication title -
chempluschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.801
H-Index - 61
ISSN - 2192-6506
DOI - 10.1002/cplu.201700539
Subject(s) - chemistry , keap1 , enhancer , ubiquitin ligase , signal transducing adaptor protein , carboxylic acid , stereochemistry , biochemistry , signal transduction , ubiquitin , transcription factor , gene
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.