Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical ChaperonesClick to copy article linkArticle link copied!
- Yuto HasegawaYuto HasegawaGraduate School of Natural Science and Technology, Gifu University, Yanagido, Gifu 501-1193, JapanMore by Yuto Hasegawa
- Masanari MotoyamaMasanari MotoyamaGraduate School of Natural Science and Technology, Gifu University, Yanagido, Gifu 501-1193, JapanMore by Masanari Motoyama
- Akie HamamotoAkie HamamotoDepartment of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, JapanGraduate School of Natural Science and Technology, Gifu University, Yanagido, Gifu 501-1193, JapanMore by Akie Hamamoto
- Shintaro KimuraShintaro KimuraThe United Graduate School of Veterinary Sciences, Gifu University, Yanagido, Gifu 501-1193, JapanMore by Shintaro Kimura
- Yuji O. KamatariYuji O. KamatariUnited Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, JapanLife Science Research Center, Gifu University, Yanagido, Gifu 501-1193, JapanInstitute for Glyco-Core Research (iGCORE), Gifu University, Yanagido, Gifu 501-1193, JapanMore by Yuji O. Kamatari
- Hiroaki KamishinaHiroaki KamishinaThe United Graduate School of Veterinary Sciences, Gifu University, Yanagido, Gifu 501-1193, JapanMore by Hiroaki Kamishina
- Kentaro Oh-HashiKentaro Oh-HashiDepartment of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, JapanGraduate School of Natural Science and Technology, Gifu University, Yanagido, Gifu 501-1193, JapanUnited Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, JapanMore by Kentaro Oh-Hashi
- Kyoji Furuta*Kyoji Furuta*Email: [email protected]. Phone: +81-58-230-7636. Fax: +81-58-293-2794.Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, JapanGraduate School of Natural Science and Technology, Gifu University, Yanagido, Gifu 501-1193, JapanUnited Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, JapanMore by Kyoji Furuta
- Yoko Hirata*Yoko Hirata*Email: [email protected]. Phone: +81-58-293-2609.Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, JapanGraduate School of Natural Science and Technology, Gifu University, Yanagido, Gifu 501-1193, JapanUnited Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, JapanMore by Yoko Hirata
Abstract
Endoplasmic reticulum (ER) stress and oxidative stress lead to protein misfolding, and the resulting accumulation of protein aggregates is often associated with the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and prion disease. Small molecules preventing these pathogenic processes may be effective interventions for such neurodegenerative disorders. In this paper, we identify several novel oxindole compounds that can prevent ER stress- and oxidative stress-induced cell death. Among them, derivatives of the lead compound GIF-0726-r in which a hydrogen atom at the oxindole ring 5 position is substituted with a methyl (GIF-0852-r), bromine (GIF-0854-r), or nitro (GIF-0856-r) group potently suppressed global ER stress. Furthermore, GIF-0854-r and -0856-r prevented protein aggregate accumulation in vitro and in cultured hippocampal HT22 neuronal cells, indicating that these two compounds function effectively as chemical chaperones. In addition, GIF-0852-r, -0854-r, and -0856-r prevented glutamate-induced oxytosis and erastin-induced ferroptosis. Collectively, these results suggest that the novel oxindole compounds GIF-0854-r and -0856-r may be useful therapeutics against protein-misfolding diseases as well as valuable research tools for studying the molecular mechanisms of ER and oxidative stress.
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