Zhang Hong-Jian, Li Yan-Fei, Cao Qi, Tian Yu-Shun, Quan Zhe-Shan
Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China.
Department of Pathology, 306 Hospital of PLA, Beijing, 100101, China.
Pharmacol Rep. 2017 Jun;69(3):419-425. doi: 10.1016/j.pharep.2016.12.006. Epub 2016 Dec 14.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely administered drugs for the treatment of inflammation. However, they usually cause some unexpected side effects. Coumarins and their derivatives exhibit broad-spectrum biological activities. In order to develop new anti-inflammatory drugs with high anti-inflammatory activity and less side effects, a series of 9-substituted-9,10-dihydrochromeno[8,7-e][1,3]oxazin-2(8H)-one derivatives were designed, synthesized, and screened for their anti-inflammatory activities.
We investigated the effect of compound 9-(2-chlorophenyl)-9,10-dihydrochromeno[8,7-e][1,3]oxazin-2(8H)-one (B3) on lipopolysaccharide (LPS)-induced cytokine levels in RAW 264.7 cells at concentrations between 6.25μg/ml and 25μg/ml. Concentrations of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Moreover, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) activation was investigated by western blot assay.
Compound B3 could inhibit inflammatory responses via suppression of the NF-κB and MAPK signaling pathways. Docking study of the prepared compounds was performed for the study of interaction of molecules with the active site of TNF-α.
9,10-Dihydrochromeno[8,7-e][1,3]oxazin-2(8H)-one derivatives showed anti-inflammatory activity. Compound B3 was the most potent. The results of this study are encouraging further investigations to develop compound B3 as a novel therapeutic agent for inflammatory disorders.
非甾体抗炎药（NSAIDs）是治疗炎症最广泛使用的药物。然而，它们通常会引起一些意想不到的副作用。香豆素及其衍生物具有广泛的生物活性。为了开发具有高抗炎活性和较少副作用的新型抗炎药，设计、合成了一系列9-取代-9,10-二氢色烯并[8,7-e][1,3]恶嗪-2(8H)-酮衍生物，并对其抗炎活性进行了筛选。
我们研究了化合物9-(2-氯苯基)-9,10-二氢色烯并[8,7-e][1,3]恶嗪-2(8H)-酮（B3）在6.25μg/ml至25μg/ml浓度下对RAW 264.7细胞中脂多糖（LPS）诱导的细胞因子水平的影响。通过酶联免疫吸附测定（ELISA）测量肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的浓度。此外，通过蛋白质印迹分析研究丝裂原活化蛋白激酶（MAPK）和核因子-κB（NF-κB）的激活情况。
化合物B3可通过抑制NF-κB和MAPK信号通路来抑制炎症反应。对制备的化合物进行对接研究，以研究分子与TNF-α活性位点的相互作用。
9,10-二氢色烯并[8,7-e][1,3]恶嗪-2(8H)-酮衍生物具有抗炎活性。化合物B3活性最强。本研究结果鼓励进一步研究将化合物B3开发为治疗炎症性疾病的新型治疗剂。
