Wang Xuebao, Han Chao, Wu Kaiqi, Luo Lu, Wang Yu, Du Xuze, He Qin, Ye Faqing
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Eur J Med Chem. 2018 Apr 10;149:10-21. doi: 10.1016/j.ejmech.2018.02.018. Epub 2018 Feb 10.
In order to study the anti-inflammatory activity of novel 6-substituted and 6,9-disubstituted purine derivatives, 20 compounds, L1-10 and W1-10, derived from purine and lacking a gold complex were designed, synthesized and their anti-inflammatory activity was screened. LPS-induced TNF-α, IL-1β, IL-6, PGE2, NO, COX-2 and iNOS mRNA were evaluated, and western blot and NF-κB p65 translocation assay were performed in RAW 264.7 macrophages. Furthermore, carrageenan-induced hind paw edema experiments were performed in mice. Compound L1, L4, W2, and W4 markedly exerted a dose-dependent inhibition of TNF-α, IL-1β, IL-6 and PGE2 release induced by LPS in RAW 264.7 macrophages. Moreover, these compounds strongly inhibited LPS-induced NO, COX-2 and iNOS mRNA in the same cells. Anti-inflammatory activity tests in vivo showed that L1 and L4 were more effective than Au(L)(PPh), a known anti-inflammatory agent, at 2-5 h, and W4 was the most effective at 3-5 h after dosing. Thus, W2, W4, and L1, L4, could effectively inhibit LPS-induced inflammatory response in vitro and in vivo suggesting a promising role as anti-inflammatory agents.
为了研究新型6-取代和6,9-二取代嘌呤衍生物的抗炎活性，设计、合成了20种源自嘌呤且不含金配合物的化合物L1-10和W1-10，并对其抗炎活性进行了筛选。评估了脂多糖（LPS）诱导的TNF-α、IL-1β、IL-6、PGE2、NO、COX-2和iNOS mRNA，并在RAW 264.7巨噬细胞中进行了蛋白质免疫印迹和NF-κB p65易位分析。此外，还在小鼠身上进行了角叉菜胶诱导的后爪水肿实验。化合物L1、L4、W2和W4在RAW 264.7巨噬细胞中对LPS诱导的TNF-α、IL-1β、IL-6和PGE2释放均表现出明显的剂量依赖性抑制作用。此外，这些化合物还强烈抑制了同一细胞中LPS诱导的NO、COX-2和iNOS mRNA。体内抗炎活性测试表明，在给药后2-5小时，L1和L4比已知的抗炎剂Au(L)(PPh)更有效，而W4在给药后3-5小时最有效。因此，W2、W4以及L1、L4能够在体外和体内有效抑制LPS诱导的炎症反应，显示出作为抗炎剂的潜在作用。
