Evaluation of pyrrolidine-based analog of jaspine B as potential SphK1 inhibitors against rheumatoid arthritis
Evaluation of pyrrolidine-based analog of jaspine B as potential SphK1 inhibitors against rheumatoid arthritis
复制标题
基于吡咯烷的 jaspine B 类似物作为潜在 SphK1 抑制剂抗类风湿性关节炎的评价
DOI：
10.1016/j.bmcl.2020.127754
复制
发表时间：
2021-02-15
影响因子：
2.7
通讯作者：
Liu, Bo
中科院分区：
文献类型：
--
作者：
Chen, Hai-Jiao;Yang, Hao-Ran;Liu, Bo
类风湿性关节炎（RA）是一种以滑膜炎为主要特征的慢性自身免疫性疾病，其发病机制复杂。鞘氨醇-1-磷酸（Sphingosine-1-phosphate，S1 P）是由鞘氨醇激酶1和2（SphK 1/2）产生的一种脂质，参与了一些最常见的骨骼疾病，如类风湿性关节炎或骨关节炎。为了探索2-表-茉莉碱B类似物作为SphKs抑制剂的抗炎活性，我们以LPS诱导的类风湿关节炎成纤维细胞样滑膜细胞（HFLS-RA）为研究对象，评价了16个2-表-茉莉碱B类似物和新合成的盐CHJ 01的抗炎活性。我们发现盐酸盐形式的2-epi-jaspine B类似物CHJ 01具有优异的SphK 1抑制作用和更好的抗RA作用。CHJ 01在体外表现出与MTX相似的抗炎作用，其IC_（50）值为8.64 μ M。此外，还通过在大鼠模型中使用完全弗氏佐剂（CFA）诱导的关节炎（AIA）来研究CHJ 01的抗RA作用。药理实验表明，CHJ 01可通过降低AIA大鼠的肿胀体积、关节炎评分、脾指数和IL-1 β、TNF-α、IL-6水平，帮助显著改善类风湿关节炎的症状。因此，CHJ 01具有治疗RA的高潜力。
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitise, and its pathogenesis is complicated. Sphingosine-1-phosphate (S1P) is a lipid produced by sphingosine kinase 1 and 2 (SphK1/2), which participate in some of most-spread skeletal diseases such as rheumatoid arthritis or osteoarthritis. To explore the anti-inflammatory activity of 2-epi-jaspine B analogs as SphKs inhibitors, we used LPS-induced rheumatoid arthritis fibroblast-like synovial cells (HFLS-RA) as the research object to evaluate the anti-inflammatory activity of 16 2-epi-jaspine B analogs and the newly synthesized salt CHJ01. We found that 2-epi-jaspine B analog CHJ01 in hydrochloride salt form has excellent SphK1 inhibitory effect and better anti-RA effect. CHJ01 showed an anti-inflammatory effect similar to that of MTX in vitro, its IC50 value is 8.64 mu M. Moreover, the anti-RA effect of CHJ01 was also studied by using a Complete Freund's Adjuvant (CFA)-induced arthritis (AIA) in a rat mode. Pharmacological experiments show that CHJ01 can help to significantly improve the symptoms of rheumatoid arthritis by reducing the swelling volume, arthritis score, spleen index and the level of IL-1 beta, TNF-alpha, IL-6 of AIA rats. Therefore, CHJ01 holds high potential for the treatment of RA.