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Discovery of 5-(3-bromo-2-(2,3-dibromo-4,5-dimethoxybenzyl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione as a novel potent protein tyrosine phosphatase 1B inhibitor with antidiabetic properties
Jiang, Bo1,2; Luo, Jiao1; Guo, Shuju1,2; Wang, Lijun1,2
2021-03-01
发表期刊BIOORGANIC CHEMISTRY
ISSN0045-2068
卷号108页码:13
通讯作者Wang, Lijun(wanglijun@qdio.ac.cn)
摘要Protein tyrosine phosphatase 1B (PTP1B) is a well-validated target in therapeutic interventions for type 2 diabetes mellitus (T2DM), however, PTP1B inhibitors containing negatively charged nonhydrolyzable pTyr mimetics are difficult to convert to the corresponding in vivo efficacy owing to poor cell permeability and oral bioavailability. In this work, molecules bearing less acidic heterocycle 2,4-thiazolidinedione and hydantoin were designed, synthesized and evaluated for PTP1B inhibitory potency, selectivity and in vivo antidiabetic efficacy. Among them, compound 5a was identified as a potent PTP1B inhibitor (IC50 = 0.86 mu M) with 5-fold selectivity over the highly homologous TCPTP. Long-term oral administration of 5a at a dose of 50 mg/kg not only significantly reduced blood glucose levels, triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels but also ameliorated insulin sensitivity in diabetic BKS db mice. Moreover, 5a enhanced the insulin-stimulated phosphorylation of IR beta, IRS-1 and Akt in C2C12 myotubes. A histopathological evaluation of liver and pancreas demonstrated that 5a increased liver glycogen storage and improved islet architecture with more beta-cells and fewer alpha-cells in diabetic mice. Thus, our work demonstrated that compound 5a could serve as a lead compound for the discovery of new antidiabetic drugs.
关键词Type 2 diabetes mellitus Protein tyrosine phosphatase 1B inhibitors Thiazolidinedione Insulin signaling Anti-diabetic activities
DOI10.1016/j.bioorg.2021.104648
收录类别SCI
语种英语
资助项目NSFC-Shandong Joint Fund[U1706213]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
WOS类目Biochemistry & Molecular Biology ; Chemistry, Organic
WOS记录号WOS:000624557000003
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
引用统计
被引频次:13[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.qdio.ac.cn/handle/337002/170339
专题实验海洋生物学重点实验室
通讯作者Wang, Lijun
作者单位1.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao 266071, Peoples R China
2.Chinese Acad Sci, Ctr Ocean Mega Sci, 7 Nanhai Rd, Qingdao 266071, Peoples R China
第一作者单位实验海洋生物学重点实验室
通讯作者单位实验海洋生物学重点实验室
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Jiang, Bo,Luo, Jiao,Guo, Shuju,et al. Discovery of 5-(3-bromo-2-(2,3-dibromo-4,5-dimethoxybenzyl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione as a novel potent protein tyrosine phosphatase 1B inhibitor with antidiabetic properties[J]. BIOORGANIC CHEMISTRY,2021,108:13.
APA Jiang, Bo,Luo, Jiao,Guo, Shuju,&Wang, Lijun.(2021).Discovery of 5-(3-bromo-2-(2,3-dibromo-4,5-dimethoxybenzyl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione as a novel potent protein tyrosine phosphatase 1B inhibitor with antidiabetic properties.BIOORGANIC CHEMISTRY,108,13.
MLA Jiang, Bo,et al."Discovery of 5-(3-bromo-2-(2,3-dibromo-4,5-dimethoxybenzyl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione as a novel potent protein tyrosine phosphatase 1B inhibitor with antidiabetic properties".BIOORGANIC CHEMISTRY 108(2021):13.
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