Novel tertiary sulfonamides as potent anti-cancer agents.

Autor: Okolotowicz KJ; Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA., Dwyer M; Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA., Ryan D; Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA., Cheng J; Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA., Cashman EA; Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA., Moore S; Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA., Mercola M; Cardiovascular Institute and Department of Medicine, Stanford University, 300 Pasteur Dr., MC-5501, Stanford, CA 94305, USA., Cashman JR; Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA. Electronic address: JCashman@HBRI.org.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Aug 15; Vol. 26 (15), pp. 4441-4451. Date of Electronic Publication: 2018 Jul 25.
DOI: 10.1016/j.bmc.2018.07.042
Abstrakt: 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 IC 50 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., IC 50 values = 10, 7 and 4 nM, respectively) and MDA-MB 231 (i.e., IC 50 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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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