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

doi:10.3390/molecules25122755

	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
	Han, Haozhen 2,3; Li, Chunpu 1; Li, Man 4; Yang, Lisheng 1; Zhao, Sen 1; Wang, Zhifei 4; Liu, Hong 1; Liu, Dongxiang 2,3
刊名	MOLECULES
	2020-06-01
卷号	25 期号:12 页码:18
关键词	sirtuins inhibitor structure-activity relationship deacetylase
DOI	10.3390/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.
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关键词	DISCOVERY ; MECHANISM ; METABOLISM
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	MDPI
WOS记录号	WOS:000550167800001
内容类型	期刊论文
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.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, 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.Shanghai Univ Tradit Chinese Med, Sch Basic Med, 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.