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 language | English |
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Pages (from-to) | 320-333 |
Number of pages | 14 |
Journal | ChemPlusChem |
Volume | 83 |
Issue number | 5 |
DOIs | |
State | Published - May 2018 |
Bibliographical note
Publisher Copyright:© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Funding
This study was supported by a Bar-Ilan University new faculty grant for A.G. Bar-Ilan University, Ramat Gan and Rabin Medical Center, Petah-Tikva, both in Israel, provided a grant for A.G. and D.O. (Collaborative Grant in Biomedical Research—2013). In addition, S.K. is thankful for the support of her work by the Wolf Foundation. We would like to thank Nechama-Sara Cohen for the English editing of the manuscript.
Funders | Funder number |
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Wolf Foundation | |
Bar-Ilan University |
Keywords
- Nrf2
- medicinal chemistry
- oxidative stress
- oxopyrrolidine derivatives
- virtual screening