Design, synthesis, and structure-activity relationships of 2-benzylidene-1-indanone derivatives as anti-inflammatory agents for treatment of acute lung injury.
Design, synthesis, and structure-activity relationships of 2-benzylidene-1-indanone derivatives as anti-inflammatory agents for treatment of acute lung injury.
复制标题
2-亚苄基-1-茚满酮衍生物的设计、合成和构效关系作为治疗急性肺损伤的抗炎剂。
DOI：
10.2147/dddt.s160314
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Liang G
中科院分区：
文献类型：
--
作者：
Xiao S;Zhang W;Chen H;Fang B;Qiu Y;Chen X;Chen L;Shu S;Zhang Y;Zhao Y;Liu Z;Liang G
本研究旨在设计合成新型2-亚苄基-1-茚满酮衍生物，用于治疗急性肺损伤。合成了一系列39个新的2-亚苄基茚满酮结构衍生物，并在脂多糖（LPS）刺激的小鼠原代巨噬细胞中评价了其抗炎活性。所得到的化合物大多能有效抑制LPS诱导的IL-6和TNF-α的表达。发现最具活性的化合物8 f显著减少LPS诱导的肺部炎症，如通过总蛋白浓度、炎性细胞计数以及支气管肺泡灌洗液（BAL）中的肺湿/干比的降低所反映的。此外，8 f在体外和体内有效地抑制LPS攻击后几种炎性细胞因子的mRNA表达。给予8 f还阻断LPS诱导的促炎性NF-κB/MAPK信号通路的激活。这些衍生物的简单合成制备和生物学性质使得这些2-亚苄基-茚满酮支架有希望用于开发用于治疗急性肺损伤的抗炎治疗剂的新实体。
The purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury. A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated murine primary macrophages. Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f, was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway. The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury.