Design and Synthesis of Mogrol Derivatives Modified on a Ring with Anti-Inflammatory and Anti-Proliferative Activities

Abstract

A series of novel mogrol derivatives modified on A ring were synthesized. The screening result showed that indole-fused derivatives exhibited lower toxicity and better anti-inflammatory activity in LPS-induced RAW 264.7 cells model than mogrol and other compounds. Compound B8 showed highest inhibition of NO production with an IC 50 value of 5.05 μM, and displayed inhibitory activities of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) through iNOS/NF-κB pathway. Besides, the Cell Counting Kit-8 (CCK8) assay was performed to evaluate their anti-proliferative activity against non-small cell lung cancer (NSCLC) including A549, NCI-H460, H1299 and H1975 cells. Compared with mogrol, compound B8 showed moderate anti-proliferative activities against A549 and H1975 cells, while derivatives bearing α, β-unsaturated ketone scaffold displayed broad-spectrum growth inhibition against four cell lines. Among them, compound A9 showed 12-fold higher activity than mogrol against H1299 and H1975 cells. The suppressive effect on expression level of p-NF-κB p65 might account for the compound A9 -induced cell apoptosis and cell cycle arrest at G1 phase.

Note:
Funding Information: The project was financially supported by National Natural Science Foundation of China (U20A2004), Basic research fund of Guangxi Academy of Sciences (CQZ-C-1901), Key-Area Research and Development Program of Guangdong Province (2020B1111110003), and Guilin Scientific and Technological Project (number 20190210-3).

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Keywords: mogrol, anti-proliferative, anti-inflammatory, indole, α, β-unsaturated ketone, NF-κB