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Novel naphthoquinone analogs that target Wnt/β-Catenin/TCF4 signaling pathway and clonogenic activity of colon carcinoma cells

Author: 
Hua Sun, Wenjing Bao, Yan Xua, Chaozai Zhang, Peng Yu, Ziwei Huang, Guanlin Yang and Jing An
Subject Area: 
Health Sciences
Abstract: 

The Wnt/β-catenin signaling pathway plays a critical role in cancer development and progression. Our extensive efforts have identified and developed novel small molecule inhibitors that can fight colon cancers caused by aberrant Wnt/β-catenin signaling. A series of naphthoquinone derivatives were designed, synthesized and evaluated using a combination of comprehensive biological and quantitative structure-activity-relationship (QSAR) analysis approaches, which revealed a new class of inhibitors of Wnt/β-catenin/Tcf signaling. In this class, compound 27 (named BC27) was the lead compound. At nanomolar to low micromolar concentrations, BC27 strongly inhibited the colony-forming activity of the β-catenin-overexpressing colon cancer carcinomacells caused by gene mutations of β-catenin and APC and reduced TOP-luciferase activity. This paper presents the chemical synthesis, biological activity and a comparative molecular field analysis (CoMFA) of this new class of compounds to introduce their preliminary structure−activity relationships (SARs).

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