Synthesis of benzenesulfonamide derivatives reveals anti-CCSCs activity by regulating Wnt/β-catenin pathway

Colorectal cancer (CRC) has become one of the most common causes of cancer mortality worldwide. Accumulating studies suggest that the progressive up-regulation of Wnt/β-catenin signaling is a crucial hallmark of CRC, and this pathway is involved in the development and maintenance of colorectal cancer stem cells (CCSCs). Therefore, inhibition of its activity may be an effective strategy for the treatment of CRC.

Based on the reported structural characteristics of LF3 which is a small molecule inhibitor of β-catenin/Transcription Factor 4 (TCF4) and the significant role of the naphthoquinone group in anti-tumor activity, we designed and synthesized a series of benzenesulfonamide derivatives.

The results of anti-CRC activity showed that compound 3gg has anti-proliferation and anti-CCSCs activities by regulating the Wnt/β-catenin signaling pathway in vitro. In addition, compound 3gg could inhibit CCSCs activity through regulating the Wnt/β-catenin signaling pathway in xenografts.

Compound 3gg, which inhibits CCSCs and Wnt/β-catenin signaling pathway activity, could be a promising lead compound for further investigation as a potential anti-cancer agent.