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Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5

文献类型：期刊论文

作者Han, Haozhen2,3; Li, Chunpu4; Li, Man1; Yang, Lisheng4; Zhao, Sen4; Wang, Zhifei1; Liu, Hong4; Liu, Dongxiang2,3
刊名MOLECULES
出版日期2020-06-01
卷号25期号:12页码:18
关键词sirtuins inhibitor structure-activity relationship deacetylase
DOI10.3390/molecules25122755
通讯作者Wang, Zhifei(zfwang4911@163.com) ; Liu, Hong(hliu@simm.ac.cn) ; Liu, Dongxiang(dxl@mail.shcnc.ac.cn)
英文摘要Sirtuins (SIRT1-7) are a family of NAD(+)-dependent deacetylases. They regulate many physiological processes and play important roles in inflammation, diabetes, cancers, and neurodegeneration diseases. Sirtuin inhibitors have potential applications in the treatment of neurodegenerative diseases and various cancers. Herein, we identified new sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1H-purine-2,6-dione. To elucidate the inhibitory mechanism, the binding modes of the inhibitors in SIRT3 were established by molecular docking, showing that the inhibitors occupy the acetyl lysine binding site and interact with SIRT3, mainly through hydrophobic interactions. The interactions were validated by site-directed mutagenesis of SIRT3 and structure-activity relationship analysis of the inhibitors. Consistently, enzyme kinetic assays and microscale thermophoresis showed that these compounds are competitive inhibitors to the acetyl substrate, and mix-type inhibitors to NAD(+). Furthermore, we demonstrated that the compounds are potent SIRT1/2/3/5 pan-inhibitors. This study provides novel hits for developing more potent sirtuin inhibitors.
WOS关键词DISCOVERY ; MECHANISM ; METABOLISM
资助项目National Natural Science Fund of China[21672233] ; National Natural Science Fund of China[81973239] ; National Natural Science Fund of China[81620108027] ; National Natural Science Fund of China[21632008] ; National Natural Science Fund of China[91229204] ; National Natural Science Fund of China[81220108025] ; National Natural Science Fund of China[81602975]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000550167800001
出版者MDPI
源URL[http://119.78.100.183/handle/2S10ELR8/291996]  
专题中国科学院上海药物研究所
通讯作者Wang, Zhifei; Liu, Hong; Liu, Dongxiang
作者单位1.Shanghai Univ Tradit Chinese Med, Sch Basic Med, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Pharmacol 3, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Coll Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Han, Haozhen,Li, Chunpu,Li, Man,et al. Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5[J]. MOLECULES,2020,25(12):18.
APA Han, Haozhen.,Li, Chunpu.,Li, Man.,Yang, Lisheng.,Zhao, Sen.,...&Liu, Dongxiang.(2020).Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5.MOLECULES,25(12),18.
MLA Han, Haozhen,et al."Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5".MOLECULES 25.12(2020):18.

入库方式： OAI收割

来源：上海药物研究所

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