4-Aryl-4H-chromene-3-carbonitrile derivatives: evaluation of Src kinase inhibitory and anticancer activities

Src kinase mutations and/or overexpression have been implicated in the development of a number of human cancer 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 IC(50) values of 11.1-18.3 µM. Compound 4c was relatively selective against Src (IC(50) = 11.1 µM), when compared with selected kinases, epidermal growth factor receptor (EGFR, IC(50) > 300 µM), C-terminal Src kinase (Csk, IC(50) = 101.7 µM), and lymphocyte-specific protein tyrosine kinase (Lck, IC(50) = 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.