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Discovery of dihydrooxazolo[2,3-a]isoquinoliniums as highly specific inhibitors of hCE2

文献类型：期刊论文

作者Ding, Lixia1,3; Wang, Lu4; Zou, Kun3; Li, Bo3,5; Song, Yunqing4; Zhang, Qihua3; Zhao, Yitian4; Xu, Zhijian3,5; Ge, Guangbo4; Zhao, Bo1
刊名RSC ADVANCES
出版日期2019-11-03
卷号9期号:61页码:35904-35912
DOI10.1039/c9ra07457k
通讯作者Li, Bo(boli@simm.ac.cn) ; Zhao, Yitian(zhaobo@njnu.edu.cn) ; Ge, Guangbo(geguangbo@dicp.ac.cn) ; Zhu, Weiliang(wlzhu@simm.ac.cn)
英文摘要Human carboxylesterase 2 (hCE2) is one of the most abundant esterases distributed in human small intestine and colon, which participates in the hydrolysis of a variety of ester-bearing drugs and thereby affects the efficacy of these drugs. Herein, a new compound (23o) with a novel skeleton of dihydrooxazolo[2,3-a]isoquinolinium has been discovered with strong inhibition on hCE2 (IC50 = 1.19 mu M, K-i = 0.84 mu M) and more than 83.89 fold selectivity over hCE1 (IC50 > 100 mu M). Furthermore, 23o can inhibit hCE2 activity in living HepG2 cells with the IC50 value of 2.29 mu M, indicating that this compound has remarkable cell-membrane permeability and is capable for inhibiting intracellular hCE2. The SAR (structure-activity relationship) analysis and molecular docking results demonstrate that the novel skeleton of oxazolinium is essential for hCEs inhibitory activity and the benzyloxy moiety mainly contributes to the selectivity of hCE2 over hCE1.
WOS关键词HUMAN CARBOXYLESTERASE 2 ; DRUG-METABOLISM ; IRINOTECAN ; DERIVATIVES ; TRITERPENOIDS ; CHEMOTHERAPY ; HYDROLYSIS ; TOXICITY ; PROBE ; ACID
资助项目National Key R & D Program of China[2016YFA0502301] ; National Key R & D Program of China[2017YFC1700200] ; National Key R & D Program of China[2017YFC1702000] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[2018ZX09711002] ; National Natural Science Foundation of China[81573350] ; National Natural Science Foundation of China[81273546] ; National Natural Science Foundation of China[81973286] ; National Natural Science Foundation of China[8192207] ; Natural Science Foundation of Shanghai, China[19ZR1467800] ; Program of Shanghai Academic/Technology Research Leader[18XD1403600]
WOS研究方向Chemistry
语种英语
出版者ROYAL SOC CHEMISTRY
WOS记录号WOS:000498861100062
源URL[http://119.78.100.183/handle/2S10ELR8/282047]  
专题中国科学院上海药物研究所
通讯作者Li, Bo; Zhao, Yitian; Ge, Guangbo; Zhu, Weiliang
作者单位1.Nanjing Normal Univ, Coll Chem & Mat Sci, 1 Wenyuan Rd, Nanjing 210097, Jiangsu, Peoples R China
2.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Shandong, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Shanghai Univ Tradit Chinese Med, 1200 Cailun Rd, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Ding, Lixia,Wang, Lu,Zou, Kun,et al. Discovery of dihydrooxazolo[2,3-a]isoquinoliniums as highly specific inhibitors of hCE2[J]. RSC ADVANCES,2019,9(61):35904-35912.
APA Ding, Lixia.,Wang, Lu.,Zou, Kun.,Li, Bo.,Song, Yunqing.,...&Zhu, Weiliang.(2019).Discovery of dihydrooxazolo[2,3-a]isoquinoliniums as highly specific inhibitors of hCE2.RSC ADVANCES,9(61),35904-35912.
MLA Ding, Lixia,et al."Discovery of dihydrooxazolo[2,3-a]isoquinoliniums as highly specific inhibitors of hCE2".RSC ADVANCES 9.61(2019):35904-35912.

入库方式： OAI收割

来源：上海药物研究所

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