Dual-acting antitumor agents targeting the A2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives
文献类型：期刊论文
| 作者 | Zhang, Jinfeng1,2; Luo, Ziwei2,3; Duan, Wenwen1; Yang, Kexin2,3; Ling, Lijun2; Yan, Wenzhong1; Liu, Ruiquan1; Wuthrich, Kurt1,6; Jiang, Hualiang2,3,4 ; Xie, Chengying4,5
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2022-06-05 |
| 卷号 | 236页码:114326 |
| ISSN号 | 0223-5234 |
| 关键词 | Bifunctional Structure-based Cancer Immunotherapy |
| DOI | 10.1016/j.ejmech.2022.114326 |
| 文献子类 | Article |
| 英文摘要 | Based on its inhibition by antagonists, the A(2A) adenosine receptor (A(2A)AR) has attracted attention as an anti-tumor drug target; however, in preclinical models and clinical trials, A(2A)AR antagonists have so far shown only limited efficacy as standalone therapies. The design of dual-acting compounds, targeting the A(2A)AR and histone deacetylases (HDACs), is used here as an approach to the discovery of novel and more potent antitumor agents. Based on the core structures of the A(2A)AR antagonists V-2006 and CPI-444, novel 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives were designed as such dualacting compounds. The binding affinities for A(2A)AR of all the new compounds were tested, and their HDAC inhibitory activity was evaluated. Compounds with balanced A(2A)AR antagonism and HDAC inhibition were tested for their in vitro anti-proliferative activity and pharmacokinetic properties. One of the compounds, 14c (4-(2-(6-Amino-4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-N-(2-aminophenyl)benzamide) showed an overall favorable pharmacokinetic profile; in the mouse MC38 xenograft model, it showed potent anti-tumor effects with inhibition rates of 44% (90 mg/kg, po, bid) and 85% (60 mg/kg, ip, bid), respectively. (C) 2022 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | INHIBITORS |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:000821147500007 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309354]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Jiang, Hualiang; Xie, Chengying; Cheng, Jianjun |
| 作者单位 | 1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China; 2.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China; 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 5.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China; 6.Scripps Res, Dept Integrated Struct & Computat Biol, La Jolla, CA 92037 USA |
| 推荐引用方式 GB/T 7714 | Zhang, Jinfeng,Luo, Ziwei,Duan, Wenwen,et al. Dual-acting antitumor agents targeting the A2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,236:114326. |
| APA | Zhang, Jinfeng.,Luo, Ziwei.,Duan, Wenwen.,Yang, Kexin.,Ling, Lijun.,...&Cheng, Jianjun.(2022).Dual-acting antitumor agents targeting the A2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,236,114326. |
| MLA | Zhang, Jinfeng,et al."Dual-acting antitumor agents targeting the A2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 236(2022):114326. |
入库方式： OAI收割
来源：上海药物研究所
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