title: Discovery of a novel series of N-hydroxypyridone derivatives protecting astrocytes against hydrogen peroxide-induced toxicity via improved mitochondrial functionality.
abstract: Astrocytes play a key role in brain homeostasis, protecting neurons against neurotoxic stimuli such as oxidative stress. Therefore, the neuroprotective therapeutics that enhance astrocytic functionality has been regarded as a promising strategy to reduce brain damage. We previously reported that ciclopirox, a well-known antifungal N-hydroxypyridone compound, protects astrocytes from oxidative stress by enhancing mitochondrial function. Using the N-hydroxypyridone scaffold, we have synthesized a series of cytoprotective derivatives. Mitochondrial activity assay showed that N-hydroxypyridone derivatives with biphenyl group have comparable to better protective effects than ciclopirox in astrocytes exposed to H2O2. N-hydroxypyridone derivatives, especially 11g, inhibited H2O2-induced deterioration of mitochondrial membrane potential and oxygen consumption rate, and significantly improved cell viability of astrocytes. The results indicate that the N-hydroxypyridone motif can provide a novel cytoprotective scaffold for astrocytes via enhancing mitochondrial functionality.
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
authors.forename: Sarbjit
authors.initials: S
authors.lastname: Singh
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Ja-Il
authors.initials: JI
authors.lastname: Goo
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Noh
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Myoung Woo
authors.initials: MW
authors.lastname: Kim
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Hyejun
authors.initials: H
authors.lastname: Park
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Hitesh B
authors.initials: HB
authors.lastname: Jalani
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Nursing, Kyungdong University, Wonju 24695, Kangwon-do, Republic of Korea.
authors.forename: Chunsook
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, Republic of Korea. Electronic address: cj2013@korea.ac.kr.
authors.forename: Chung
authors.initials: C
authors.lastname: Ju
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address: ychoi@korea.ac.kr.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Choi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D011728:Pyridones; D006861:Hydrogen Peroxide
keywords: Astrocytes; Ciclopirox; N-hydroxypyridone; Neuroprotection; Oxidative stress