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
文献类型：期刊论文
| 作者 | Jiang, Bo1,2; Luo, Jiao2; Guo, Shuju1,2; Wang, Lijun1,2 |
| 刊名 | BIOORGANIC CHEMISTRY
 |
| 出版日期 | 2021-03-01 |
| 卷号 | 108页码:13 |
| ISSN号 | 0045-2068 |
| 关键词 | Type 2 diabetes mellitus Protein tyrosine phosphatase 1B inhibitors Thiazolidinedione Insulin signaling Anti-diabetic activities |
| DOI | 10.1016/j.bioorg.2021.104648 |
| 通讯作者 | Wang, Lijun(wanglijun@qdio.ac.cn) |
| 英文摘要 | 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. |
| 资助项目 | NSFC-Shandong Joint Fund[U1706213] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| WOS记录号 | WOS:000624557000003 |
| 源URL | [http://ir.qdio.ac.cn/handle/337002/170338]  |
| 专题 | 海洋研究所_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, Ctr Ocean Mega Sci, 7 Nanhai Rd, Qingdao 266071, Peoples R China 2.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao 266071, Peoples R China |
| 推荐引用方式 GB/T 7714 | 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. |
入库方式： OAI收割
来源：海洋研究所
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