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Issue 1, 2011
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Library synthesis and cytotoxicity of a family of 2-phenylacrylonitriles and discovery of an estrogen dependent breast cancer lead compound

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Abstract

In our efforts to prevent highly toxic compounds progressing through our anti-parasitic drug development program, we serendipitously discovered a family of 2-phenylacrylonitriles with excellent growth inhibition of a panel of ten human cancer cell lines. Focused library approaches facilitated the identification of a simple pharmacophore, comprising two terminal aromatic moieties linked via a conjugated cyano (acrylonitrile) moiety. Efforts that perturbed this pharmacophore resulted in a significant drop in growth inhibition. Multiple libraries led to the discovery of two key lead compounds. The first, (Z)-2-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)acrylonitrile (31) exhibits broad spectrum growth inhibition with GI50 values of 0.52–3 μM (HT29 and BE2-C cancer cell lines respectively; average = 1.6 μM). Of greater note is (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile (28), a 0.127 ± 0.043 μM growth inhibitor of the estrogen receptor positive (ER+ve) human breast cancer cell line, MCF-7. Analogue 28 displays up to 543 fold selectivity towards MCF-7 cells compared with nine other non-breast derived cancer cell lines. Further screening of 28 against one human, ER−ve breast cancer cell line (MDA-MB231) and one normal non-tumourigenic breast epithelial cell line (MCF-10A) returned poor growth inhibition values of 34 ± 2 and 16 ± 4μM, demonstrating ca. ∼268 and∼126 fold preference for the MCF-7 estrogen dependent breast cancer cells.

Graphical abstract: Library synthesis and cytotoxicity of a family of 2-phenylacrylonitriles and discovery of an estrogen dependent breast cancer lead compound

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Publication details

The article was received on 02 Sep 2010, accepted on 11 Oct 2010 and first published on 15 Nov 2010


Article type: Concise Article
DOI: 10.1039/C0MD00147C
Citation: Med. Chem. Commun., 2011,2, 31-37
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    Library synthesis and cytotoxicity of a family of 2-phenylacrylonitriles and discovery of an estrogen dependent breast cancer lead compound

    M. Tarleton, J. Gilbert, M. J. Robertson, A. McCluskey and J. A. Sakoff, Med. Chem. Commun., 2011, 2, 31
    DOI: 10.1039/C0MD00147C

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