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

Abstract

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 0.004microM 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.

• Authors: William Kemnitzer, Nilantha Sirisoma, Chris May, Ben Tseng, John Drewe, Sui Xiong Cai
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 13 Pg. 3536-40 (Jul 01 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19464890 (Publication Type: Journal Article)

Chemical References

• 4-anilino-N-methylthieno(3,2-d)pyrimidine
• Aniline Compounds
• Antineoplastic Agents
• Pyrimidines
• Caspases

Topics

• Aniline Compounds (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis
• Caspases (metabolism)
• Cell Line, Tumor
• Drug Discovery
• Drug Screening Assays, Antitumor
• Humans
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship