Design, synthesis, and biological evaluation of thieno[3,2-d]pyrimidine derivatives as potential simplified phosphatidylinositol 3-kinase alpha inhibitors | |
Yang, Xiuyan3; Deng, Meng3; Zhang, Xi1; Wang, Yi1; Song, Kun3; Cong, Ruan3; Meng, Linghua1; Zhang, Jian2,3 | |
刊名 | CHEMICAL BIOLOGY & DRUG DESIGN |
2019-12-01 | |
卷号 | 94期号:6页码:2013-2022 |
关键词 | PI3K alpha inhibitors proliferation inhibition thieno[3 2-d]pyrimidine derivatives |
ISSN号 | 1747-0277 |
DOI | 10.1111/cbdd.13425 |
通讯作者 | Meng, Linghua(lhmeng@simm.ac.cn) ; Zhang, Jian(jian.zhang@sjtu.edu.cn) |
英文摘要 | A series of thieno[3,2-d]pyrimidine derivatives as phosphatidylinositol 3-kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21. Determination of a co-crystal structure of 7 complexed with PI3K alpha provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments. |
WOS关键词 | PHOSPHOINOSITIDE ; PATHWAY ; CANCER ; MUTATIONS ; IDENTIFICATION ; PROLIFERATION ; DISCOVERY ; INSIGHTS ; ISOFORM ; DOCKING |
WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
语种 | 英语 |
出版者 | WILEY |
WOS记录号 | WOS:000499105200002 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/282038] |
专题 | 中国科学院上海药物研究所 |
通讯作者 | Meng, Linghua; Zhang, Jian |
作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai, Peoples R China 2.Shanghai Jiao Tong Univ, Renji Hosp, Basic Clin Res Ctr, Sch Med, Shanghai, Peoples R China 3.Shanghai Jiao Tong Univ, Dept Pathophysiol, Key Lab Cell Differentiat & Apoptosis, Sch Med,Chinese Minist Educ, Shanghai, Peoples R China |
推荐引用方式 GB/T 7714 | Yang, Xiuyan,Deng, Meng,Zhang, Xi,et al. Design, synthesis, and biological evaluation of thieno[3,2-d]pyrimidine derivatives as potential simplified phosphatidylinositol 3-kinase alpha inhibitors[J]. CHEMICAL BIOLOGY & DRUG DESIGN,2019,94(6):2013-2022. |
APA | Yang, Xiuyan.,Deng, Meng.,Zhang, Xi.,Wang, Yi.,Song, Kun.,...&Zhang, Jian.(2019).Design, synthesis, and biological evaluation of thieno[3,2-d]pyrimidine derivatives as potential simplified phosphatidylinositol 3-kinase alpha inhibitors.CHEMICAL BIOLOGY & DRUG DESIGN,94(6),2013-2022. |
MLA | Yang, Xiuyan,et al."Design, synthesis, and biological evaluation of thieno[3,2-d]pyrimidine derivatives as potential simplified phosphatidylinositol 3-kinase alpha inhibitors".CHEMICAL BIOLOGY & DRUG DESIGN 94.6(2019):2013-2022. |
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