DICP OpenIR
Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1
Zou, Li-Wei1,2; Dou, Tong-Yi3; Wang, Ping1,2; Lei, Wei2,4; Weng, Zi-Miao4; Hou, Jie4; Wang, Dan-Dan1; Fan, Yi-Ming3; Zhang, Wei-Dong1; Ge, Guang-Bo1,2; Yang, Ling1
关键词Human Carboxylesterase 1 (Hce1) Ursolic Acid Oleanolic Acid Structure-activity Relationship (Sar) Selective Inhibitors
刊名FRONTIERS IN PHARMACOLOGY
2017-06-30
DOI10.3389/fphar.2017.00435
8
收录类别SCI
文章类型Article
WOS标题词Science & Technology ; Life Sciences & Biomedicine
类目[WOS]Pharmacology & Pharmacy
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]HUMAN LIVER ; MAMMALIAN CARBOXYLESTERASES ; CATALYTIC-PROPERTIES ; DRUG DISCOVERY ; TUMOR-TISSUE ; HYDROLYSIS ; IDENTIFICATION ; ISOZYMES ; SPECIFICITY ; DERIVATIVES
英文摘要Human carboxylesterase 1 (hCE1), one of the most important serine hydrolases distributed in liver and adipocytes, plays key roles in endobiotic homeostasis and xenobiotic metabolism. This study aimed to find potent and selective inhibitors against hCE1 from phytochemicals and their derivatives. To this end, a series of natural triterpenoids were collected and their inhibitory effects against human carboxylesterases (hCEs) were assayed using D-Luciferin methyl ester (DME) and 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as specific optical substrate for hCE1, and hCE2, respectively. Following screening of a series of natural triterpenoids, oleanolic acid (OA), and ursolic acid (UA) were found with strong inhibitory effects on hCE1 and relative high selectivity over hCE2. In order to get the highly selective and potent inhibitors of hCE1, a series of OA and UA derivatives were synthesized from OA and UA by chemical modifications including oxidation, reduction, esterification, and amidation. The inhibitory effects of these derivatives on hCEs were assayed and the structure-activity relationships of tested triterpenoids as hCE1 inhibitors were carefully investigated. The results demonstrated that the carbonyl group at the C-28 site is essential for hCE1 inhibition, the modifications of OA or UA at this site including esters, amides and alcohols are unbeneficial for hCE1 inhibition. In contrast, the structural modifications on OA and UA at other sites, such as converting the C-3 hydroxy group to 3-O-beta-carboxypropionyl (compounds 20 and 22), led to a dramatically increase of the inhibitory effects against hCE1 and very high selectivity over hCE2. 3D-QSAR analysis of all tested triterpenoids including OA and UA derivatives provide new insights into the fine relationships linking between the inhibitory effects on hCE1 and the steric-electrostatic properties of triterpenoids. Furthermore, both inhibition kinetic analyses and docking simulations demonstrated that compound 22 was a potent competitive inhibitor against hCE1-mediated DME hydrolysis. All these findings are very helpful for medicinal chemists to design and develop highly selective and more potent hCE1 inhibitors for biomedical applications.
语种英语
WOS记录号WOS:000404509000001
引用统计
文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/152127
专题中国科学院大连化学物理研究所
作者单位1.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China
3.Dalian Univ Technol, Sch Life Sci & Med, Panjin, Peoples R China
4.Dalian Med Univ, Coll Basic Med Sci, Dept Biotechnol, Dalian, Peoples R China
推荐引用方式
GB/T 7714
Zou, Li-Wei,Dou, Tong-Yi,Wang, Ping,et al. Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1[J]. FRONTIERS IN PHARMACOLOGY,2017,8.
APA Zou, Li-Wei.,Dou, Tong-Yi.,Wang, Ping.,Lei, Wei.,Weng, Zi-Miao.,...&Yang, Ling.(2017).Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1.FRONTIERS IN PHARMACOLOGY,8.
MLA Zou, Li-Wei,et al."Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1".FRONTIERS IN PHARMACOLOGY 8(2017).
条目包含的文件
条目无相关文件。
个性服务
推荐该条目
保存到收藏夹
查看访问统计
导出为Endnote文件
谷歌学术
谷歌学术中相似的文章
[Zou, Li-Wei]的文章
[Dou, Tong-Yi]的文章
[Wang, Ping]的文章
百度学术
百度学术中相似的文章
[Zou, Li-Wei]的文章
[Dou, Tong-Yi]的文章
[Wang, Ping]的文章
必应学术
必应学术中相似的文章
[Zou, Li-Wei]的文章
[Dou, Tong-Yi]的文章
[Wang, Ping]的文章
相关权益政策
暂无数据
收藏/分享
所有评论 (0)
暂无评论
 

除非特别说明,本系统中所有内容都受版权保护,并保留所有权利。