Novel tertiary sulfonamides as potent anti-cancer agents

For adult women in the United States, breast Cancer is the most prevalent form of Cancer. Compounds that target dysregulated signal transduction can be efficacious anti-cancer therapies. A prominent signaling pathway frequently dysregulated in breast Cancer cells is the Wingless-related integration site (Wnt) pathway. The purpose of the work was to optimize a "hit" from a screening campaign. 76,000 compounds were tested in a Wnt transcription assay and revealed potent and reproducible "hit," compound 1. Medicinal chemistry optimization of 1 led to more potent and drug-like molecules, 19, 24 and 25 (i.e., Wnt pathway IC₅₀ values = 11, 18 and 7 nM, respectively). The principal results showed compounds 19, 24 and 25 were potent anti-proliferative agents in breast Cancer cell lines, MCF-7 (i.e., IC₅₀ values = 10, 7 and 4 nM, respectively) and MDA-MB 231 (i.e., IC₅₀ values = 13, 13 and 16 nM, respectively). Compound 19 synergized anti-proliferation with chemotherapeutic Doxorubicin in vitro. A major conclusion was that compound 19 enhanced anti-proliferation of Doxorubicin in vitro and in a xenograft animal model of breast Cancer.

Anti-cancer; Anti-proliferative; Apoptosis; Breast cancer; Doxorubicin synergy; Sulfonamides; Wnt inhibitors; p53 activator.