Synthesis, Molecular Docking and Biological Evaluation of Glycyrrhizin Analogs as Anticancer Agents Targeting EGFR

Abstract

Glycyrrhizin (GA) analogs in the form of 3-glucuronides and 18-epimers were synthesized and their anticancer activities were evaluated. Alkaline isomerization of monoglucuronides is reported. In vitro and in vivo studies showed that glycyrrhetinic acid monoglucuronides (GAMGs) displayed higher anticancer activities than those of bisglucuronide GA analogs, while anticancer activity of the 18α-epimer was superior to that of the 18β-epimer. 18α-GAMG was firstly nicely bound to epidermal growth factor receptor (EGFR) via six hydrogen bonds and one charge interaction, and the docking calculation proved the correlation between anticancer activities and EGFR inhibitory activities. Highly active 18α-GAMG is thus of interest for the further studies as a potential anticancer agent.

Anti‐hepatocellular carcinoma, antioxidant, anti‐inflammation and antimicrobial investigation of some novel first and second transition metal complexes

“…Also, the epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that defines a family of tyrosine kinase receptors (TKRs). Mice manganese lacking EGFR show delayed regeneration after partial hepatectomy (PH), which demonstrates that EGFR is a critical regulator of hepatocyte proliferation during liver regeneration . Hence, EGFR has long been an attractive candidate as an anticancer drug target.…”

Glycyrrhetic Acid 3‐O‐Mono‐β‐d‐glucuronide (GAMG): An Innovative High‐Potency Sweetener with Improved Biological Activities

“…To develop anticancer agents, much effort has been made to interfere with the activity of the epidermal growth factor receptor (EFGR), a main anticancer drug target (Ye et al., ). For example, 18α‐GAMG is an effective drug for cancer therapy, exhibiting EGFR inhibitory activity that is stronger than the positive control erlotinib (Yang et al., ). In addition, 18α‐GAMG exhibited inhibition of abnormal cell proliferation and is nontoxic to human normal cell lines (Tang et al., ).…”

“…According to molecular docking and biological assay results, 18α‐GAMG possesses higher binding affinity to EGFR and exhibits a stronger inhibition against identical tumor cell lines compared to 18β‐GAMG, explaining its stronger anticancer activity (Yang et al., ). An analysis of the results of computer‐generated molecular docking showed that binding of 18α‐GAMG to EGFR via six hydrogen bonds with ASP831, GLU738, THR766 (three bonds), and LYS721 and one charge interaction formed by the interaction of the end group of LYS692 with a carboxyl (Figure A).…”

“…(A) 3D model of the interaction between 18α‐GAMG and the 1M17 site. (B) 3D model of the interaction between 18β‐GAMG and the 1M17 site (Yang et al., ).…”

“…GAMG has higher solubility and better taste (less aftertaste) than GL. In recent years, GAMG has been developed as an innovative functional sweetener due to its beneficial health effects (such as anticancer and anti‐inflammatory bioactivities) (Edwards et al., ; Sakagami, ; Yang et al., ).…”