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Bioorg Med Chem. 2017 Feb 15;25(4):1394-1405. doi: 10.1016/j.bmc.2016.12.052. Epub 2017 Jan 3.

Discovery of a novel series of N-hydroxypyridone derivatives protecting astrocytes against hydrogen peroxide-induced toxicity via improved mitochondrial functionality.

Author information

1
College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
2
School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
3
Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
4
Department of Nursing, Kyungdong University, Wonju 24695, Kangwon-do, Republic of Korea.
5
Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, Republic of Korea. Electronic address: cj2013@korea.ac.kr.
6
School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address: ychoi@korea.ac.kr.

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.

KEYWORDS:

Astrocytes; Ciclopirox; N-hydroxypyridone; Neuroprotection; Oxidative stress

PMID:
28089588
DOI:
10.1016/j.bmc.2016.12.052
[Indexed for MEDLINE]

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