Synthesis and anti-inflammatory activity of ent-kaurene derivatives

A series of kaurene derivatives (1–63) were prepared and evaluated for anti-inflammatory activity. Thirteen of the tested compounds were able to inhibit NO production with an IC50 between 2 and 10 μM. Compounds 11, 12, 14 and 23 showed low percentage of cell viability, whereas compounds 9, 10, 17, 28, 37, 48, 55, 61 and 62 were non-cytotoxic at the concentration up to 25 μM. Some structure–activity relationships were outlined. Compounds 28, 55 and 62, were selected as representative compounds and they potently inhibited the protein expression of NOS-2. We also determined that inhibition of NF-κB activation might be the mechanism involved in anti-inflammatory effects of these kaurene derivatives. As expected, cytokines IL-6, IL-1α, TNF-α and IFN-γ were downregulated in the presence of compound 28, 55 and 62 after stimulation with LPS. These results indicate that kaurene derivatives might be used for the design of new anti-inflammatory agents.

Graphical abstractSeveral ent-kaurene derivatives resulted be potent inhibitors of LPS-induced NO and the protein expression of NOS-2. The inhibition of NF-κB is the mechanism involved.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► We synthesized a series of kaurene derivatives. ► Three compounds were potent inhibitors of NO release without cytotoxicity effects. ► IL-6, IL-1α, TNF-α and IFN-γ were also inhibited by kaurene derivatives. ► Inhibitory effects were mediated by NF-F06BB inhibition.