期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 205, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112508
关键词
Type 2 diabetes mellitus; PTPlB inhibitors; Selectivity; Geniposide; Genipin
资金
- Medicine and Engineering Interdisciplinary Research Fund of Shanghai Jiao Tong University [YG2015QN03, YG2014MS10, YG2017MS77]
- National Natural Science Foundation of China [81202397]
- Shanghai Natural Science Fund [12ZR1415400]
Herein a series of Geniposide derivatives were designed, synthesized and evaluated as protein tyrosine phosphatase 1B (PTPlB) inhibitors. Most of these compounds exhibited potent in vitro PTPlB inhibitory activities, the representative 7a and 17f were found to be the most potent inhibitors against the enzyme with IC50 values of 0.35 and 0.41 mu M, respectively. More importantly, they showcased 4 to10-fold selectivity over SHP2 and 3-fold over TCPTP. Further biological activity studies revealed that compounds 7a, 17b and 17f could effectively enhance insulin-stimulated glucose uptake with no significant cytotoxicity. Subsequent molecular docking and structural activity relationship analyses demonstrated that the glucose scaffold, benzylated glycosyl groups, and arylethenesulfonic acid ester significantly impact on the activity and selectivity. (C) 2020 Elsevier Masson SAS. All rights reserved.
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