靶向 A2A 腺苷受体和组蛋白脱乙酰酶的双效抗肿瘤药物：4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine 衍生物的设计与合成,European Journal of Medicinal Chemistry

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靶向 A2A 腺苷受体和组蛋白脱乙酰酶的双效抗肿瘤药物：4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine 衍生物的设计与合成
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2022-03-29 , DOI: 10.1016/j.ejmech.2022.114326
Jinfeng Zhang ₁ , Ziwei Luo ₂ , Wenwen Duan ₃ , Kexin Yang ₂ , Lijun Ling ₄ , Wenzhong Yan ₃ , Ruiquan Liu ₃ , Kurt Wüthrich ₅ , Hualiang Jiang ₆ , Chengying Xie ₇ , Jianjun Cheng ₃

Affiliation

iHuman Institute, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
iHuman Institute, ShanghaiTech University, Shanghai, 201210, China; Department of Integrated Structural and Computational Biology, Scripps Research, La Jolla, CA, 92037, USA.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.

基于拮抗剂的抑制作用，A _2A腺苷受体（A _2A AR）作为抗肿瘤药物靶点引起了人们的关注。然而，在临床前模型和临床试验中，迄今为止，A _{2A AR 拮抗剂作为独立疗法仅显示出有限的疗效。}_{针对 A 2A} AR 和组蛋白脱乙酰酶 (HDAC)的双效化合物的设计在这里被用作发现新型和更有效的抗肿瘤药物的方法。基于 A _2A AR 拮抗剂 V-2006 和 CPI-444 的核心结构，设计了新型 4-(furan-2-yl)-1 H - pyrazolo[3,4- d ]pyrimidin-6-amine 衍生物这种双重作用的化合物。A 的结合亲和力_{测试了所有新化合物的2A} AR，并评估了它们的HDAC抑制活性。测试了具有平衡 A _2A AR 拮抗作用和 HDAC 抑制作用的化合物的体外抗增殖活性和药代动力学特性。其中一种化合物，14c (4-(2-(6-Amino-4-(furan-2-yl)-1 H - pyrazilo[3,4- d ]pyrimidin-1-yl)ethyl) -N- ( 2-氨基-苯基）苯甲酰胺）显示出总体有利的药代动力学特征；在小鼠 MC38 异种移植模型中，它显示出有效的抗肿瘤作用，抑制率分别为 44%（90 mg/kg，po，bid）和 85%（60 mg/kg，ip，bid）。

"点击查看英文标题和摘要"

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

Based on its inhibition by antagonists, the A_2A adenosine receptor (A_2AAR) has attracted attention as an anti-tumor drug target; however, in preclinical models and clinical trials, A_2AAR antagonists have so far shown only limited efficacy as standalone therapies. The design of dual-acting compounds, targeting the A_2AAR 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_2AAR antagonists V-2006 and CPI-444, novel 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives were designed as such dual-acting compounds. The binding affinities for A_2AAR of all the new compounds were tested, and their HDAC inhibitory activity was evaluated. Compounds with balanced A_2AAR 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-amino-phenyl)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.

更新日期：2022-03-29

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