- Title
- Library synthesis and cytotoxicity of a family of 2-phenylacrylonitriles and discovery of an estrogen dependent breast cancer lead compound
- Creator
- Tarleton, Mark; Gilbert, Jayne; Robertson, Mark J.; McCluskey, Adam; Sakoff, Jennette A.
- Relation
- MedChemComm Vol. 2, Issue 1, p. 31-37
- Publisher Link
- http://dx.doi.org/10.1039/C0MD00147C
- Publisher
- Royal Society of Chemistry
- Resource Type
- journal article
- Date
- 2011
- Description
- 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 mM 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.
- Subject
- breast cancer; estrogen receptors; cytotoxicity; growth inhibition; anti-cancer agents
- Identifier
- http://hdl.handle.net/1959.13/1065792
- Identifier
- uon:17940
- Identifier
- ISSN:2040-2503
- Language
- eng
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