Design, Synthesis, and Biological Evaluation of New Diaminoquinazolines as beta-Catenin/Tcf4 Pathway Inhibitors

作者：Mao Yongjun; Lin Nan; Tian Wang; Han Xiaofeng; Han Xiaobing; Huang Ziwei; An Jing^*

来源：Journal of Medicinal Chemistry, 2012, 55(3): 1346-1359.

DOI：10.1021/jm201494a

More than 50 new diaminoquinazoline derivatives have been synthesized and evaluated in a colon carcinoma cell growth inhibition assay using HCT116 and SW480 cells. Twenty compounds with good cell growth inhibitory activities (%26lt;4 mu M) were tested as inhibitors of the beta-catenin/T cell transcription factor 4 (Tcf4) signaling pathway using a HCT116 cell-based luciferase reporter assay. Results from the biological activities as well as the comparative molecular field analysis (CoMFA) of the properties of the molecules yielded a preliminary structure-activity relationship (SAR). Three potent compounds, 74, 78, and 86, showed IC50 values %26lt;1 mu M for growth inhibition of HCT116 cells and similar to 1 mu M for SW480 cells, as well as IC50 values of 1.5-2.5 mu M for HCT116 cells with the luciferase reporter assay.

• 出版日期2012-2-9