Discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers
Discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers
复制标题
DOI：
10.1016/j.bmcl.2009.04.145
复制
发表时间：
2009-07-01
影响因子：
2.7
通讯作者：
Cai, Sui Xiong
中科院分区：
文献类型：
--
作者：
Kemnitzer, William;Sirisoma, Nilantha;Cai, Sui Xiong
我们报告使用我们专有的基于细胞和半胱天冬酶的 ASAP HTS 测定发现了 N-((苯并[d][1,3]二氧杂醇-5-基)甲基)-6-苯基噻吩并[3,2-d]嘧啶-4-胺 (2a) 作为细胞凋亡诱导剂，并对 HTS 命中 2a 进行了 SAR 研究，从而发现了 4-苯胺基-N-甲基噻吩并[3,2-d] 嘧啶和4-苯胺基-N-甲基噻吩并[2,3-d]嘧啶作为有效的细胞凋亡诱导剂。化合物5d和5e在T47D人乳腺癌细胞中是最有效的，EC50值分别为0.008和0.004μM。发现化合物 5d 在 MX-1 乳腺癌模型中具有高度活性。从功能上讲，化合物 5d 和 5e 均通过抑制微管蛋白聚合来诱导细胞凋亡。 (C) 2009 Elsevier Ltd. 保留所有权利。
We report the discovery of N-((benzo[d][1,3]dioxol-5-yl)methyl)-6-phenylthieno[3,2-d] pyrimidin-4-amine (2a) as an apoptosis inducer using our proprietary cell-and caspase-based ASAP HTS assay, and SAR study of HTS hit 2a which led to the discovery of 4-anilino-N-methylthieno[3,2-d] pyrimidines and 4-anilino-N-methylthieno[2,3-d] pyrimidines as potent apoptosis inducers. Compounds 5d and 5e were the most potent with EC50 values of 0.008 and 0.004 mu M in T47D human breast cancer cells, respectively. Compound 5d was found to be highly active in the MX-1 breast cancer model. Functionally, compounds 5d and 5e both induced apoptosis through inhibition of tubulin polymerization. (C) 2009 Elsevier Ltd. All rights reserved.