@article{1398bddba90b497ea6efa3fb47a051e3,
title = "Computer-Aided Design and Synthesis of 1-\{4-[(3,4-Dihydroxybenzylidene)amino]phenyl\}-5-oxopyrrolidine-3-carboxylic Acid as an Nrf2 Enhancer",
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.",
keywords = "Nrf2, medicinal chemistry, oxidative stress, oxopyrrolidine derivatives, virtual screening",
author = "Shirin Kahremany and Ilana Babaev and Pinhas Hasin and Tamir, \{Tigist Y.\} and Tali Ben-Zur and Guy Cohen and Zhengyu Jiang and Sagiv Weintraub and Daniel Offen and Shai Rahimipour and Major, \{M. Ben\} and Hanoch Senderowitz and Arie Gruzman",
note = "Publisher Copyright: {\textcopyright} 2018 Wiley-VCH Verlag GmbH \& Co. KGaA, Weinheim",
year = "2018",
month = may,
doi = "10.1002/cplu.201700539",
language = "אנגלית",
volume = "83",
pages = "320--333",
journal = "ChemPlusChem",
issn = "2192-6506",
publisher = "John Wiley and Sons Inc.",
number = "5",
}