1. Cytotoxic 2-phenyacrylnitriles, the importance of the cyanide moiety and discovery of potent broad spectrum cytotoxic agents
- Author
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Mark Tarleton, Jayne Gilbert, Adam McCluskey, and Jennette A. Sakoff
- Subjects
Male ,Indoles ,Cell Survival ,Stereochemistry ,Cyanide ,Antineoplastic Agents ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Neoplasms ,Nitriles ,Drug Discovery ,Humans ,Structure–activity relationship ,Moiety ,Cytotoxicity ,Acrylic acid ,Pharmacology ,Indole test ,Cyanides ,Molecular Structure ,Cytotoxins ,Organic Chemistry ,General Medicine ,chemistry ,Female ,Drug Screening Assays, Antitumor ,Acrylonitrile ,Pharmacophore - Abstract
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, 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 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 and (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-5-yl)acrylonitrile (20) with an average GI(50) values of 1.4 and 0.53 μM respectively. Five additional (Z)-2-(3,4-dichlorophenyl)-3-(indolyl)acrylonitriles also displayed average GI(50) values of ≤8.4 μM. In the case of indole, this represents a 32-fold increase in broad spectrum cytotoxicity relative to the lead.
- Published
- 2012