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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

4-Aryl-4H-Chromene-3-Carbonitrile Derivatives: Evaluation of Src Kinase Inhibitory and Anticancer Activities

Author(s): Asal Fallah-Tafti, Rakesh Tiwari, Amir Nasrolahi Shirazi, Tahmineh Akbarzadeh, Deendayal Mandal, Abbas Shafiee, Keykavous Parang and Alireza Foroumadi

Volume 7, Issue 5, 2011

Page: [466 - 472] Pages: 7

DOI: 10.2174/157340611796799258

Price: $65


Src kinase mutations and/or overexpression have been implicated in the development of a number of human cancers including colon, breast, and lung cancers. Thus, designing potent and selective Src kinase inhibitors as anticancer agents is a subject of major interest. A series of 4-aryl substituted derivatives of 2-amino-7-dimethylamino-4H-chromene- 3-carbonitrile were synthesized using one-pot reaction of appropriate substituted aromatic aldehydes, malononitrile, and 3-(dimethylamino)phenol in the presence of piperidine. All 23 compounds were evaluated for inhibition of Src kinase and cell proliferation in human colon adenocarcinoma (HT-29) and leukemia (CCRF-CEM) cell lines. Among the tested compounds, 2-chlorophenyl- (4c), 3-nitrophenyl- (4h), 4-trifluoromethyphenyl- (4i), and 2,3-dichlorophenyl- (4k) substituted chromenes showed Src kinase inhibitory effect with IC50 values of 11.1-18.3 μM. Compound 4c was relatively selective against Src (IC50 = 11.1 μM), when compared with selected kinases, epidermal growth factor receptor (EGFR, IC50 > 300 μM), C-terminal Src kinase (Csk, IC50 = 101.7 μM), and lymphocyte-specific protein tyrosine kinase (Lck, IC50 = 46.8 μM). 3-Chlorophenyl substituted thiazole (4v) and 2-chlorophenylsubstituted thiazole (4u) chromene derivatives inhibited the cell proliferation of HT-29 and CCRF-CEM by 80% and 50%, respectively, at a concentration of 50 μM. The data indicate that 4H-chromene-3-carbonitrile scaffold has the potential to be optimized further for designing more potent Src kinase inhibitors and/or anticancer lead compounds.

Keywords: Anticancer activity, benzopyranones, carbonitrile, chromenes, inhibitor, protein kinase, Src kinase, cancers, Src kinase inhibitors, leukemia, lead compounds

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