Tarleton, Mark, Gilbert, Jayne, Robertson, Mark J., McCluskey, Adam, and Sakoff, Jennette A. (2011) Library synthesis and cytotoxicity of a family of 2-phenylacrylonitriles and discovery of an estrogen dependent breast cancer lead compound. MedChemComm, 2 (1). pp. 31-37.

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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. [similar]268 and[similar]126 fold preference for the MCF-7 estrogen dependent breast cancer cells.

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