Article

Design, synthesis, and biological evaluation of new diaminoquinazolines as β-catenin/Tcf4 pathway inhibitors.

Department of Pharmacology, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, United States.
Journal of Medicinal Chemistry (impact factor: 4.8). 02/2012; 55(3):1346-59. DOI:10.1021/jm201494a pp.1346-59
Source: PubMed

ABSTRACT 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 (<4 μM) were tested as inhibitors of the β-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 IC(50) values <1 μM for growth inhibition of HCT116 cells and ∼1 μM for SW480 cells, as well as IC(50) values of 1.5-2.5 μM for HCT116 cells with the luciferase reporter assay.

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Keywords

colon carcinoma cell growth inhibition assay
 
comparative molecular field analysis
 
good cell growth inhibitory activities
 
HCT116 cell-based luciferase reporter assay
 
luciferase reporter assay
 
preliminary structure-activity relationship
 
SAR
 
β-catenin/T cell transcription factor 4
 

Yongjun Mao