Synthesis, molecular docking and biological evaluation of glycyrrhizin analogs as anticancer agents targeting EGFR.
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.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China. yangyan73@163.com.
Yong-An
YA
Yang
School of Pharmacy, Anhui Medical University, Hefei 230032, China. tangwjster@gmail.com.
Wen-Jian
WJ
Tang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China. prczhangxin@163.com.
Xin
X
Zhang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China. 363718480@163.com.
Ji-Wen
JW
Yuan
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China. xhliuhx@163.com.
Xin-Hua
XH
Liu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China. zhuhl@nju.edu.cn.
Hai-Liang
HL
Zhu
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism; D005260:Female; D020719:Glucuronides / Q000737:chemistry*; D006034:Glycyrrhetinic Acid / Q000737:chemistry; D019695:Glycyrrhizic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007536:Isomerism; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D019695:Glycyrrhizic Acid; C512478:EGFR protein, human; D066246:ErbB Receptors; D006034:Glycyrrhetinic Acid