Discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers

作者：Kemnitzer William; Sirisoma Nilantha; May Chris; Tseng Ben; Drewe John; Cai Sui Xiong^*

来源：Bioorganic & Medicinal Chemistry Letters, 2009, 19(13): 3536-3540.

DOI：10.1016/j.bmcl.2009.04.145

• Apoptosis inducers
• Anticancer agents
• HTS
• SAR
• In vivo activity

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 EC(50) 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.

• 出版日期2009-7-1