Novel tertiary sulfonamides as potent anti-cancer agents. Issue 15 (15th August 2018)

• Record Type: Journal Article
• Authors: Okolotowicz, Karl J.; Dwyer, Mary; Ryan, Daniel; Cheng, Jiongjia; Cashman, Emily A.; Moore, Stephanie; Mercola, Mark; Cashman, John R.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 15(2018)
• Page Start: 4441
• Page End: 4451
• Publication Date: 2018-08-15
• Subjects: Wnt Wingless-related integration site gene -- p53 tumor protein p53 -- Pd/C palladium on carbon -- HCl hydrochloric acid -- (ER+) estrogen receptor-positive -- (ER−) estrogen receptor-negative -- (PR−) progesterone receptor-negative -- (HER2−) human epidermal growth factor receptor 2-negative -- (DMEM) Dulbecco's Modified Eagle's cell culture medium -- (FBS) fetal bovine serum; Anti-proliferative -- Wnt inhibitors -- p53 activator -- Apoptosis -- Sulfonamides -- Breast cancer -- Doxorubicin synergy -- Anti-cancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.07.042
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: 76, 000 compounds were tested for inhibition of a Wnt transcription assay. One "hit" compound was found to be reproducibly potent at Wnt inhibition. The "hit" was optimized by medicinal chemistry and "lead"19 was examined. Compound19 potently inhibited human breast cancer cell lines. 19 synergized Doxorubicin to inhibit cancer proliferation in vitro and in vivo. Abstract: 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, " compound1 . Medicinal chemistry optimization of1 led to more potent and drug-like molecules, 19, 24 and25 (i.e., Wnt pathway IC50 values = 11, 18 and 7 nM, respectively). The principal results showed compounds19, 24 and25 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). Compound19 synergized anti-proliferation with chemotherapeutic Doxorubicin in vitro. A major conclusion was that compound19 enhanced anti-proliferation of Doxorubicin in vitro and in a xenograft animal model of breast cancer.