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

详细信息    查看全文

• 作者：Sarbjit Singh^a ; ¹ ; Ja-Il Goo^b ; ¹ ; Hyojin Noh^c ; ¹ ; Sung Jae Lee^b ; Myoung Woo Kim^b ; Hyejun Park^b ; Hitesh B. Jalani^b ; Kyeong Lee^a ; Chunsook Kim^d ; Won-Ki Kim^c ; Chung Ju^c ; ^{cj2013@korea.ac.kr} ; Yongseok Choi^b ; ^{ychoi@korea.ac.kr}
• 关键词：Ciclopirox ; N-hydroxypyridone ; Astrocytes ; Oxidative stress ; Neuroprotection
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：25
• 期：4
• 页码：1394-1405
• 全文大小：2912 K
• 卷排序：25

文摘

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.