title: Design, synthesis, and structure-activity relationship study of glycyrrhetinic acid derivatives as potent and selective inhibitors against human carboxylesterase 2.
abstract: Human carboxylesterase 2 (hCE2), one of the major carboxylesterases in the human intestine and various tumour tissues, plays important roles in the oral bioavailability and treatment outcomes of ester- or amide-containing drugs or prodrugs, such as anticancer agents CPT-11 (irinotecan) and LY2334737 (gemcitabine). In this study, 18β-glycyrrhetinic acid (GA), the most abundant pentacyclic triterpenoid from natural source, was selected as a reference compound for the development of potent and specific inhibitors against hCE2. Simple semi-synthetic modulation on GA was performed to obtain a series of GA derivatives. Structure-activity relationship analysis brought novel insights into the structure modification of GA. Converting the 11-oxo-12-ene of GA to 12-diene moiety, and C-3 hydroxyl and C-30 carboxyl group to 3-O-β-carboxypropionyl and ethyl ester respectively, led to a significant enhancement of the inhibitory effect on hCE2 and the selectivity over hCE1. These exciting findings inspired us to design and synthesize the more potent compound 15 (IC50 0.02 μM) as a novel and highly selective inhibitor against hCE2, which was 3463-fold more potent than the parent compound GA and demonstrated excellent selectivity (>1000-fold over hCE1). The molecular docking study of compound 15 and the active site of hCE1 and hCE2 demonstrated that the potent and selective inhibition of compound 15 toward hCE2 could partially be attributed to its relatively stronger interactions with hCE2 than with hCE1.
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Zou
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
authors.forename: Yao-Guang
authors.initials: YG
authors.lastname: Li
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China; College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Dalian Medical University, Dalian, 116044, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jin
authors.affiliation: School of Environment and Chemical Engineering, Dalian Jiaotong University, Dalian, 116028, China.
authors.forename: Da-Cheng
authors.initials: DC
authors.lastname: Hao
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China. Electronic address: geguangbo@dicp.ac.cn.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China. Electronic address: yling@dicp.ac.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D043182:Carboxylesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C119129:18alpha-glycyrrhetinic acid; C517204:CES2 protein, human; D043182:Carboxylesterase; D006034:Glycyrrhetinic Acid
keywords: Glycyrrhetinic acid; Human carboxylesterase 2; Selective inhibitor; Structure-activity relationship