中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Discovery of 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones as Highly Potent and Selective SIRT1 Inhibitors

文献类型：期刊论文

作者Li, Chunpu1,2,3; Hu, Sha-Sha4; Yang, Lisheng1,2; Wang, Min4; Long, Jian-Dong1; Wang, Bing4,5; Han, Haozhen4,5; Zhu, Haoran1,2,5; Zhao, Sen1,2; Liu, Jing-Gen1
刊名ACS MEDICINAL CHEMISTRY LETTERS
出版日期2021-03-11
卷号12期号:3页码:397-403
关键词SIRT1 inhibitor structure-activity relationship interaction deacetylase
ISSN号1948-5875
DOI10.1021/acsmedchemlett.0c00559
通讯作者Liu, Jing-Gen(jgliu@simm.ac.cn) ; Liu, Dongxiang(dxl@mail.shcnc.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要SIRT1, a member of the sirtuin family, catalyzes the deacetylation of proteins with the transformation of NAD(+) into nicotinamide and 2'-O-acetyl-ADP-ribose. Selective SIRT1/2 inhibitors have potential application in the chemotherapy of colorectal carcinoma, prostate cancer, and myelogenous leukemia. Here we identified novel SIRT1 inhibitors with the scaffold of 5-benzylidene-2-phenyl-1,3-dioxane-4,6-dione. The most potent inhibitor 12n displayed an IC50 of 460 nM and a selectivity for SIRT1 over SIRT2, SIRT3, and SIRTS of 113.5-, 254.3-, and 10.83-fold, respectively. It did not affect the activity of SIRT6. To elucidate the inhibitory mechanism, we determined the inhibition type of the inhibitor by enzyme kinetic analysis, showing that the inhibitor was competitive to the acetyl peptide and noncompetitive to NAD(+). Further, the interaction of the inhibitor in SIRT1 was studied by using molecular docking, which was validated by the structure-activity relationship analysis of the inhibitors and the site-directed mutagenesis of SIRT1. Consistent with the in vitro assays, the inhibitors increased the acetylation level of p53 in a concentration-dependent manner in cells.
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] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020375] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050411] ; SA-SIBS Scholarship Program ; Youth Innovation Promotion Association CAS
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000629174700008
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/295446]  
专题新药研究国家重点实验室
通讯作者Liu, Jing-Gen; Liu, Dongxiang; Liu, Hong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Zhejiang, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Pharmacol 3, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Li, Chunpu,Hu, Sha-Sha,Yang, Lisheng,et al. Discovery of 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones as Highly Potent and Selective SIRT1 Inhibitors[J]. ACS MEDICINAL CHEMISTRY LETTERS,2021,12(3):397-403.
APA Li, Chunpu.,Hu, Sha-Sha.,Yang, Lisheng.,Wang, Min.,Long, Jian-Dong.,...&Liu, Hong.(2021).Discovery of 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones as Highly Potent and Selective SIRT1 Inhibitors.ACS MEDICINAL CHEMISTRY LETTERS,12(3),397-403.
MLA Li, Chunpu,et al."Discovery of 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones as Highly Potent and Selective SIRT1 Inhibitors".ACS MEDICINAL CHEMISTRY LETTERS 12.3(2021):397-403.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。