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Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors

文献类型：期刊论文

作者Yang, Yun2,3; Xiong, Yuan2; Zhu, Guanghao2; Sun, Mengru2; Zou, Kun2; Zhao, Yitian2; Zhang, Yong3; Xu, Zhijian1,3; Li, Yiming2; Zhu, Weiliang1,3
刊名CHEMICO-BIOLOGICAL INTERACTIONS
出版日期2023-06-01
卷号378页码:11
ISSN号0009-2797
关键词Human carboxylesterase 2 (hCES2A) Berberine analogues Structure -activity relationships (SAR) Inhibition kinetics Selectivity
DOI10.1016/j.cbi.2023.110501
通讯作者Jia, Qi(q_jia@126.com) ; Li, Bo(boli@simm.ac.cn) ; Ge, Guangbo(geguangbo@shutcm.edu.cn)
英文摘要Human carboxylesterase 2A (hCES2A) is a key serine hydrolase responsible for the metabolic clearance of large number of compounds bearing the ester- or amide-bond(s). Inhibition of hCES2A can relieve the chemotherapyinduced toxicity and alter the pharmacokinetic bahaviors of some orally administrate esters-containing agents. However, most of the hCES2A inhibitors show poor cell-membrane permeability and poor specificity. Herein, guided by the structure activity relationships (SAR) of fifteen natural alkaloids against hCES2A, fifteen new seven-membered ring berberine analogues were designed and synthesized, and their anti-hCES2A activities were evaluated. Among all tested compounds, compound 28 showed potent anti-hCES2A effect (IC50 = 1.66 mu M) and excellent selectivity over hCES1A (IC50 > 100 mu M). The SAR analysis revealed that the seven-membered ring of these berberine analogues was a crucial moiety for hCES2A inhibition, while the secondary amine group of the ring-C is important for improving their specificity over other serine hydrolases. Inhibition kinetic analyses and molecular dynamic simulation demonstrated that 28 strongly inhibited hCES2A in a mixed-inhibition manner, with an estimated Ki value of 1.035 mu M. Moreover, 28 could inhibit intracellular hCES2A in living HepG2 cells and exhibited suitable metabolic stability. Collectively, the SAR of seven-membered ring berberine analogues as hCES2A inhibitors were studied, while compound 28 acted as a promising candidate for developing highly selective hCES2A inhibitors.
WOS关键词HUMAN CARBOXYLESTERASES ; CATALYTIC-PROPERTIES ; SENSITIVE DETECTION ; FLUORESCENT-PROBE ; SUBSTRATE ; CHEMOTHERAPY ; ACTIVATION ; IRINOTECAN ; ISOZYMES ; ACCURACY
资助项目Chinese Pharmaceutical Association-Yiling Biopharmaceutical Innovation Project[CPAYLJ201908] ; Natural Science Foundation of China[81922070] ; Natural Science Foundation of China[81973286] ; Natural Science Foundation of China[22277129] ; Innovation Team and Talents Cultivation Pro-gram of National Administration of Traditional Chinese Medicine[ZYYCXTD-D-202004] ; Three-year Action Plan for Shanghai TCM Development and Inheritance Program[ZY (2021-2023) -0401]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Toxicology
语种英语
出版者ELSEVIER IRELAND LTD
WOS记录号WOS:000984657000001
源URL[http://119.78.100.183/handle/2S10ELR8/306526]  
专题新药研究国家重点实验室
通讯作者Jia, Qi; Li, Bo; Ge, Guangbo
作者单位1.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
2.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai Frontiers Sci Ctr TCM Chem Biol, Sch Pharm, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Yun,Xiong, Yuan,Zhu, Guanghao,et al. Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors[J]. CHEMICO-BIOLOGICAL INTERACTIONS,2023,378:11.
APA Yang, Yun.,Xiong, Yuan.,Zhu, Guanghao.,Sun, Mengru.,Zou, Kun.,...&Ge, Guangbo.(2023).Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors.CHEMICO-BIOLOGICAL INTERACTIONS,378,11.
MLA Yang, Yun,et al."Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors".CHEMICO-BIOLOGICAL INTERACTIONS 378(2023):11.

入库方式： OAI收割

来源：上海药物研究所

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