Glycyrrhetinic acid derivatives containing aminophosphonate ester species as multidrug resistance reversers that block the NF-κB pathway and cell proliferation. Issue 23 (15th December 2018)

• Record Type: Journal Article
• Authors: Jin, Le; Zhang, Bin; Hua, Shixian; Ji, Min; Huang, Xiaochao; Huang, Rizhen; Wang, Hengshan
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 23/24(2018)
• Page Start: 3700
• Page End: 3707
• Publication Date: 2018-12-15
• Subjects: Glycyrrhetinic acid -- Aminophosphonate ester -- NF-κB -- Drug resistance -- Migration; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.10.025
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Representative compound12e showed significant inhibitory activity against NF-κB. Molecular docking study indicated that 12e strongly binds to the active site of NF-κB. 12e exhibited stronger antitumor activity and lower toxicity than HCPT. 12e effectively induced apoptosis and arrested cell cycle at S stage in A549 cells. Abstract: Novel NF-κB inhibitors based on Glycyrrhetinic acid (GA) derivatives containing aminophosphonate ester moieties were rationally designed and synthesized as well as evaluated their antitumor activities using MTT assay. Many target compounds showed potent antitumor activities against the tested human cancer cell lines including cisplatin-resistant cells, and exhibited significant inhibitory activity to the NF-κB with IC50 values at micromolar concentrations in A549 cells, respectively. Among them, compound12e possessed excellent antitumor activities against the tested human cancer cell lines and showed low cytotoxicity toward to human normal liver cells. Moreover, 12e caused obvious loss of MMP and significantly induced ROS production, and displayed inhibition of cell migration against A549 cells in vitro . Importantly, 12e arrested the cell cycle at the S phases and ultimately induced cell apoptosis in A549 cells through blockage of NF-κB signaling pathway. Our research provided an efficient strategy for targeting NF-κB antitumor drug development.