合成及体外和体内评价作为潜在的抗神经炎症的克缬氨酰胺类似物。
Synthesis and biological evaluation of clovamide analogues as potent anti-neuroinflammatory agents in vitro and in vivo.
机构信息
State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
Institute of Traditional Chinese Medicine & Natural Products, Jinan University, Guangzhou, 510632, People's Republic of China.
出版信息
Eur J Med Chem. 2018 May 10;151:261-271. doi: 10.1016/j.ejmech.2018.03.081. Epub 2018 Apr 1.
A series of clovamide analogues, namely, 1a-13a and 1b-13b, was synthesized and evaluated for their anti-neuroinflammatory activities using BV-2 microglia cells. Among these compounds, six (1b, 4b-8b) showed NO inhibition with no or weak cytotoxicity (CC > 100 μM), especially 4b, and showed an IC value of 2.67 μM. Enzyme activity and docking assay revealed that the six compounds, especially 4b, target inducible NO synthase (iNOS) and exhibit potent inhibitory effects on iNOS with IC values ranging from 1.01 μM to 29.23 μM 4b significantly suppressed the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated cells. Notably, the oral administration of 4b remarkably improved dyskinesia, reduced the expression of glial fibrillary acidic protein (GFAP)-a marker of neuroinflammation, and increased tyrosine hydroxylase-positive cells in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine-induced Parkinson's disease (PD) mouse models. These observations demonstrated that 4b is an effective and promising candidate for PD therapy.
一系列的邻氨基苯甲酰胺类似物，即 1a-13a 和 1b-13b，被合成并在 BV-2 小胶质细胞中评估其抗神经炎症活性。在这些化合物中，有六种（1b、4b-8b）表现出对 NO 的抑制作用，没有或仅有微弱的细胞毒性（CC>100 μM），特别是 4b，其 IC 值为 2.67 μM。酶活性和对接试验表明，这六种化合物，特别是 4b，靶向诱导型一氧化氮合酶（iNOS），并对 iNOS 表现出很强的抑制作用，IC 值范围为 1.01 μM 至 29.23 μM。4b 显著抑制了脂多糖刺激细胞中促炎细胞因子的表达。值得注意的是，4b 的口服给药显著改善了运动障碍，降低了神经炎症标志物胶质纤维酸性蛋白（GFAP）的表达，并增加了 1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的帕金森病（PD）小鼠模型中酪氨酸羟化酶阳性细胞的数量。这些观察结果表明，4b 是一种有效的、有前景的 PD 治疗候选药物。
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