Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives possessing diaryl semicarbazone scaffolds as potent antitumor agents

被引:73
作者
Liu, Zijian [1 ]
Wu, Shasha [1 ]
Wang, Yu [1 ]
Li, Ruijuan [1 ]
Wang, Jian [1 ]
Wang, Lihui [1 ]
Zhao, Yanfang [1 ]
Gong, Ping [1 ]
机构
[1] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Key Lab New Drug Design & Discovery Liaoning Prov, Shenyang 110016, Peoples R China
基金
国家高技术研究发展计划(863计划); 中国国家自然科学基金;
关键词
Synthesis; Thieno[3,2-d]pyrimidine derivatives; Diaryl semicarbazone scaffolds; Antitumor activity; RECEPTOR TYROSINE KINASES; INHIBITORS; IDENTIFICATION; DISCOVERY; THIENOPYRIMIDINE; APOPTOSIS; PATHWAY; TARGETS; RAF; SAR;
D O I
10.1016/j.ejmech.2014.10.022
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of novel thieno[3,2-d]pyrimidine derivatives possessing diaryl semicarbazone scaffolds were designed, synthesized and evaluated for their anticancer activity. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with GDC-0941 and sorafenib. In this study, a promising compound 36 (PI3K alpha IC50 = 0.027 mu M) was identified, which showed the most potent antitumor activities with IC50 values of 0.057 mu M, 0.039 mu M, 0.25 mu M, and 0.23 mu M against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. In addition, the SAR analyses indicated that compounds with 4-morpholino group at the C-4 position of thieno[3,2-d]pyrimidine moiety exhibited superior activities than compounds bearing chain amino groups. In addition, compounds with monomethoxy group at the 3-position or dimethyl groups at the 3,5-position on the terminal phenyl ring were more active. The SAR analyses will guide us to further refine the structure of the thieno[3,2-d]pyrimidine derivatives to achieve optimum anticancer activity. (c) 2014 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:782 / 793
页数:12
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