- Title
- Cytotoxic 2-phenyacrylnitriles, the importance of the cyanide moiety and discovery of potent broad spectrum cytotoxic agents
- Creator
- Tarleton, Mark; Gilbert, Jayne; Sakoff, Jennette A.; McCluskey, Adam
- Relation
- European Journal of Medicinal Chemistry Vol. 57, p. 65-73
- Publisher Link
- http://dx.doi.org/10.1016/j.ejmech.2012.09.019
- Publisher
- Elsevier Masson
- Resource Type
- journal article
- Date
- 2012
- Description
- We previously reported the discovery of a simple conjugated cyano pharmacophore which had led to the development of (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile (1), as a selective inhibitor of oestrogen receptor positive (ER+ve) human breast cancer cell line, MCF-7. Further exploration though modification of the acrylonitrile and aromatic substituents has highlighted key structural components necessary for broad spectrum cytotoxicity. The acrylic acid derivates (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylic acid (8) and (Z)-2-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid (9) were inactive; confirming the importance of the cyanide moiety. The most potent 2-phenylacrylonitriles synthesized were (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-3-yl)acrylonitrile (3) and (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-5-yl)acrylonitrile (20) with an average GI₅₀ values of 1.4 and 0.53 μM respectively. Five additional (Z)-2-(3,4-dichlorophenyl)-3-(indolyl)acrylonitriles also displayed average GI₅₀ values of ≤8.4 μM. In the case of indole 20, this represents a 32-fold increase in broad spectrum cytotoxicity relative to the lead (1).
- Subject
- cytotoxicity; acrylonitrile; focused library; synthesis; cytotoxicity screening
- Identifier
- http://hdl.handle.net/1959.13/1311529
- Identifier
- uon:22226
- Identifier
- ISSN:0223-5234
- Language
- eng
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