Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, PR China; Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, PR China.
Eur J Med Chem. 2020 May 1;193:112216. doi: 10.1016/j.ejmech.2020.112216. Epub 2020 Mar 8.
Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic chalcones possess a wide range of bioactivities. In this work, thirty-nine chalcones and three related compounds, including several novel ones, based on bioactive kava chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 μM (IC = 6.4 μM) with the lowest cytotoxicity (IC > 80 μM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can dock into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava chalcones based analogs was also depicted.
炎症是一种对刺激的复杂生物反应。激活的巨噬细胞过度释放促炎细胞因子和介质，如内源性自由基一氧化氮 (NO)，在多种炎症性疾病的进展中发挥重要作用。天然和合成查尔酮具有广泛的生物活性。在这项工作中，设计、合成了 39 种查尔酮和 3 种相关化合物，包括几种基于生物活性卡瓦查尔酮的新型化合物，并评估了它们对 RAW 264.7 细胞中 NO 产生的抑制作用。新型化合物（E）-1-（2'-羟基-4'，6'-二甲氧基苯基）-3-（3-甲氧基-4-（3-吗啉代丙氧基）苯基）丙烯-2-酮（53）在 10 μM 时对 NO 产生的抑制活性（84.0%）（IC=6.4 μM）最好，且在测试的化合物中细胞毒性最低（IC>80 μM）。此外，Western blot 分析表明，化合物 53 是诱导型一氧化氮合酶（iNOS）蛋白的有效下调剂。对接研究表明，化合物 53 也可以与 iNOS 的活性位点结合。此外，在 10 mg/kg/天的剂量下，化合物 53 可以显著抑制胶原诱导性关节炎（CIA）和佐剂诱导性关节炎（AIA）模型中炎症的进展。此外，还描绘了基于卡瓦查尔酮的类似物的构效关系（SAR）。
