Evaluation of pyrrolidine-based analog of jaspine B as potential SphK1 inhibitors against rheumatoid arthritis. (15th February 2021)

• Record Type: Journal Article
• Authors: Chen, Hai-Jiao; Yang, Hao-Ran; Zhi, Ying; Yao, Qing-Qiang; Liu, Bo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 34(2021)
• Publication Date: 2021-02-15
• Subjects: Rheumatoid arthritis -- 2-epi-jaspine B -- SphKs -- Inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127754
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Compared with the original compound YHR1, the pyrrolidine-based analog of jaspine B CHJ01 in the form of hydrochloride salt has a better inhibitory effect against SphK1. Pharmacological experiments also show that CHJ01 can significantly improve the symptoms of rheumatoid arthritis by reducing the swelling volume, arthritis score, spleen index and the level of IL-1β, TNF-α, IL-6 of AIA rats. Abstract: 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 μM. 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-1β, TNF-α, IL-6 of AIA rats. Therefore, CHJ01 holds high potential for the treatment of RA.