TY - JOUR
T1 - 4-aryl-4h-chromene-3-carbonitrile derivatives
T2 - Evaluation of Src kinase inhibitory and anticancer activities
AU - Fallah-Tafti, Asal
AU - Tiwari, Rakesh
AU - Shirazi, Amir Nasrolahi
AU - Akbarzadeh, Tahmineh
AU - Mandal, Deendayal
AU - Shafiee, Abbas
AU - Parang, Keykavous
AU - Foroumadi, Alireza
PY - 2011/9
Y1 - 2011/9
N2 - 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 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.
AB - 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 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.
KW - Anticancer activity
KW - Benzopyranones
KW - Carbonitrile
KW - Chromenes
KW - Inhibitor
KW - Protein kinase
KW - Src kinase
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U2 - 10.2174/157340611796799258
DO - 10.2174/157340611796799258
M3 - Article
C2 - 21801146
AN - SCOPUS:80051983041
SN - 1573-4064
VL - 7
SP - 466
EP - 472
JO - Medicinal Chemistry
JF - Medicinal Chemistry
IS - 5
ER -