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Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation

文献类型：期刊论文

作者Che, Jinxin2; Ma, Canliang2,5; Lu, Jialiang2; Chen, Binhui2; Shi, Qiuqiu2; Jin, Xinxin2; Song, Rui6; Xu, Fan2; Gan, Lishe2,7; Li, Jingya1
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-01-15
卷号228页码:25
关键词Seneciobipyrrolidine Phenotypic screening Glucose homeostasis Proteomic analysis L6 myotubes 4E-BP1
ISSN号0223-5234
DOI10.1016/j.ejmech.2021.113954
通讯作者Dong, Xiaowu(dongxw@zju.edu.cn)
英文摘要Modulating the glucose transport in skeletal muscle is a promising strategy for ameliorating glucose homeostasis disorders. However, the complicated mechanisms of glucose transport make it difficult to find compounds therapeutically relevant molecular mechanisms of action, while phenotypic screening is thought to be an alternative approach to mimic the cell state of interest. Here, we report (& PLUSMN;)-sen-eciobipyrrolidine (1a) is first found to enhance glucose uptake in L6 myotubes through phenotype-based screening. Further SAR investigation led to the identfication of compound A27 (EC50 1/4 2.7 mu M). Proteomiic analysis discloses the unique function mechanism of A27 through upregulating the level of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), subsequently enhancing the Akt and AMPK phosphorylation, thereby promoting the glucose uptake. Chronic oral administration of A27 significantly lowers blood glucose and improves glucose tolerance in db/db mice. This work is new research on seneciobipyrrolidine derivatives, providing a promising avenue for ameliorating glucose homeostasis. (c) 2021 Elsevier Masson SAS. All rights reserved.
WOS关键词PROTEIN-KINASE ; MUSCLE ; 4E-BP1 ; INSULIN ; MTOR ; AMPK ; EXERCISE ; S6K1
资助项目National Natural Science Foundation of China[81872878] ; National Natural Science Foundation of China[81973172] ; National Natural Science Foundation of China[82003579] ; Key R&D Program of Zhejiang Province[2020C03010] ; Natural Science Foundation of Zhejiang Province[LR21H300003] ; Natural Science Foundation of Zhejiang Province[LQ21H300005] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[2018ZX09711002-007] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[2018ZX09711002-011-023]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000772045300007
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/299949]  
专题新药研究国家重点实验室
通讯作者Dong, Xiaowu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
3.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Peoples R China
4.Zhejiang Univ, Canc Ctr, Hangzhou 310058, Peoples R China
5.Nanjing Tech Univ, Coll Biotechnol & Pharmaceut Engn, 30 Puzhu South Rd, Nanjing 211816, Peoples R China
6.Zhejiang Univ, Affiliated Hosp 2, Dept Pathol, Sch Med, Hangzhou 310009, Peoples R China
7.Wuyi Univ, Sch Biotechnol & Hlth Sci, Jiangmen 529020, Guangdong, Peoples R China
推荐引用方式
GB/T 7714		 Che, Jinxin,Ma, Canliang,Lu, Jialiang,et al. Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,228:25.
APA Che, Jinxin.,Ma, Canliang.,Lu, Jialiang.,Chen, Binhui.,Shi, Qiuqiu.,...&Dong, Xiaowu.(2022).Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,228,25.
MLA Che, Jinxin,et al."Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 228(2022):25.

入库方式： OAI收割

来源：上海药物研究所

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