Synthesis, biological evaluation and molecular docking studies of novel diosgenin derivatives as anti-inflammatory agents

• Published in: Bioorganic chemistry 2022-10, Vol.127, p.105908-105908, Article 105908
• Main Authors: Zhang, Sheng-Nan, Mu, Xiao-Dong, Zhang, Xiao-Fan, Luan, Ming-Zhu, Ma, Guang-Qun, Li, Wei, Meng, Qing-Guo, Chai, Xiao-Yun, Hou, Gui-Ge
• Format: Article
• Language: English
• Subjects: Anti-inflammatory agent; Diosgenin derivatives; Molecular docking studies; Synthesis
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105908

Compound 4m showed promising anti-inflammatory activity with NO inhibitory activity comparable to dexamethasone and could reasonably bind to the active site of p65 protein. [Display omitted] •Thirty-two novel DG F-spiroacetal opened derivatives were synthesized using DG as raw material, and screened for preliminary anti-inflammatory activity.•Structure of the derivatives was further confirmed by the crystal structures.•The anti-inflammatory activities were better after the acetylation of 3-hydroxyl group.•Molecular docking analysis verified that compound 4 m could reasonably bind to the active site of the p65 protein. Thirty-two novel DG F-spiroacetal ring-opening derivatives, including 24 acetylated derivatives and 8 nitrogenous derivatives, were designed and synthesized from diosgenin (DG). The cytotoxicity of the novel derivatives was evaluated by MTT assay, except for compounds 4a, 4e, 4i, 4 l, 5a and 5 h, which were potentially cytotoxic to RAW264.7 cells, all the other derivatives had no significant cytotoxicity. The NO release inhibitory activities of novel derivatives were screened by Griess method. The results showed that the anti-inflammatory activity of the DG acetylated derivatives was stronger than the nitrogenous derivatives, and 4a-4 m containing acetyl groups at the 3-position may have better anti-inflammatory effects than 5a-5 k containing free hydroxyl groups. In ELISA assay, compound 4 m exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by LPS with IC50 values 0.449 ± 0.050 μM. The results of docking experiments showed that 4 m has a good affinity for p65 protein.