Protective effects of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols against 4-hydroxynonenal-induced cell death in adult retinal pigment epithelial-19 cells
Protective effects of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols against 4-hydroxynonenal-induced cell death in adult retinal pigment epithelial-19 cells
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DOI：
10.1016/j.bmcl.2017.11.046
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发表时间：
2018-01-15
影响因子：
2.7
通讯作者：
Jeong, Byeong-Seon
中科院分区：
文献类型：
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作者：
Bae, Dawon;Gautam, Jaya;Jeong, Byeong-Seon
视网膜色素上皮（RPE）的功能障碍或进行性变性在导致不可逆视力丧失的年龄相关性黄斑变性（AMD）的初始发病机制中起作用，这使得RPE成为该疾病的主要目标。本研究旨在鉴定通过抑制NADPH氧化酶4（NOX 4）活性来保护4-羟基壬烯醛（4-HNE）诱导的RPE细胞死亡的化合物，而不仅仅是作为自由基清除剂，使用人成人视网膜色素上皮细胞系ARPE-19作为RPE代表。合成并测试了32个新的6-脲基/硫脲基-2，4，5-三甲基吡啶-3-醇衍生物17。我们发现化合物17对4-HNE诱导的APRE-19细胞死亡的保护作用水平与对4-HNE诱导的超氧化物产生的抑制活性水平之间存在强相关性，并且大多数化合物17显示出最小的DPPH自由基清除活性。化合物17-28在10 μ M浓度下对4-HNE诱导的超氧化物产生（79.5%抑制）和细胞死亡（85.1%恢复）显示出最好的保护活性，这优于NOS 2/4抑制剂VAS 2870。此外，化合物17-28以浓度依赖性方式阻断4-HNE诱导的ARPE-19细胞凋亡。结果表明，化合物17-28可能是开发AMD治疗剂的先导化合物。(C)2017爱思唯尔有限公司版权所有
Dysfunction or progressive degeneration of retinal pigment epithelium (RPE) contributes in the initial pathogenesis of age-related macular degeneration (AMD) causing irreversible vision loss, which makes RPE the prime target of the disease. The present study aimed to identify compounds to protect 4-hydroxynonenal (4-HNE)-induced RPE cell death by inhibiting NADPH oxidase 4 (NOX4) activity, not just as free radical scavengers, using ARPE-19, a human adult retinal pigment epithelial cell line, as a RPE representative. Novel thirty-two 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ol derivatives 17 were synthesized and tested. We found that there was a strong correlation between level of protective effect of compounds 17 against 4-HNE-induced APRE-19 cell death and that of inhibitory activity against 4-HNE-induced superoxide production, and that most of the compounds 17 showed minimal DPPH radical scavenging activity. Compound 17-28 showed the best protective activity against 4-HNE-induced superoxide production (79.5% inhibition) and cell death (85.1% recovery) at 10 mu M concentration, which was better than that of VAS2870, a NOX2/4 inhibitor. In addition, compound 17-28 blocked 4-HNE-induced apoptosis of ARPE-19 cells in a concentration-dependent manner. The results indicate that compound 17-28 may be a lead compound to develop AMD therapeutics. (C) 2017 Elsevier Ltd. All rights reserved.