Discovery of a novel series of N -hydroxypyridone derivatives protecting astrocytes against hydrogen peroxide-induced toxicity via improved mitochondrial functionality
作者:Sarbjit Singh、Ja-Il Goo、Hyojin Noh、Sung Jae Lee、Myoung Woo Kim、Hyejun Park、Hitesh B. Jalani、Kyeong Lee、Chunsook Kim、Won-Ki Kim、Chung Ju、Yongseok Choi
DOI:10.1016/j.bmc.2016.12.052
日期:2017.2
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 membrane-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. (C) 2017 Elsevier Ltd. All rights reserved.