4-aryl-4h-chromene-3-carbonitrile derivatives: Evaluation of Src kinase inhibitory and anticancer activities

Asal Fallah-Tafti, Rakesh Tiwari, Amir Nasrolahi Shirazi, Tahmineh Akbarzadeh, Deendayal Mandal, Abbas Shafiee, Keykavous Parang, Alireza Foroumadi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)466-472
Number of pages7
JournalMedicinal Chemistry
Volume7
Issue number5
DOIs
StatePublished - Sep 2011
Externally publishedYes

Keywords

  • Anticancer activity
  • Benzopyranones
  • Carbonitrile
  • Chromenes
  • Inhibitor
  • Protein kinase
  • Src kinase

ASJC Scopus subject areas

  • Drug Discovery

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  • Cite this

    Fallah-Tafti, A., Tiwari, R., Shirazi, A. N., Akbarzadeh, T., Mandal, D., Shafiee, A., Parang, K., & Foroumadi, A. (2011). 4-aryl-4h-chromene-3-carbonitrile derivatives: Evaluation of Src kinase inhibitory and anticancer activities. Medicinal Chemistry, 7(5), 466-472. https://doi.org/10.2174/157340611796799258