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

9 Scopus citations

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

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.

FundersFunder number
Wolf Foundation
Bar-Ilan University

    Keywords

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

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