Synthesis and antiproliferative activity of tyrphostins containing heteroaromatic moieties

V. G. Brunton, M. J. Lear, D. J. Robins, S. Williamson, P. Workman

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12 Citations (Scopus)


A series of benzylidenemalononitrile derivatives previously synthesized by condensing aromatic aldehydes with malononitrile derivatives are known as tyrphostins. In this study, 32 tyrphostins were synthesized, 19 of which are novel compounds. Both hydroxylated derivatives and compounds containing heteroaromatic moieties were prepared. We have confirmed and extended the observation that the tyrphostins displayed an enhancement in their ability to inhibit the epidermal growth factor (EGF) receptor tyrosine kinase domain as the number of hydroxyl groups on the aromatic portion was increased. IC50 values of 1-5 μM were readily achieved. Some inhibitory activity was seen with the heteroaromatic structures, with two compounds exhibiting IC50 values of 56 and 77 μM. However, these derivatives were poor inhibitors of the EGF receptor tyrosine kinase activity as compared to the hydroxylated derivatives. The ability of the 32 tyrphostins synthesized in the present study to inhibit proliferation of a human breast adenocarcinoma cell line (MCF-7) was determined using [3H]thymidine incorporation as a measure of DNA synthesis. Some of the compounds containing pyridine, imidazole or thiophene portions displayed antiproliferative activity comparable to that of tyrphostins prepared from 3,4,5-trihydroxybenzaldehyde. The lack of inhibitory effect of these heteroaromatic compounds on the EGF receptor tyrosine kinase activity suggests that their antiproliferative activity is not related to inhibition of EGF receptor function. As the growth of the MCF-7 cell line is governed by other factors, such as the insulin-like growth factors (IGFs) and oestradiol, it is also still to be established whether the antiproliferative activity of the hydroxylated tyrphostins is directly related to inhibition of the EGF receptor tyrosine kinase activity.

Original languageEnglish
Pages (from-to)291-309
Number of pages19
JournalAnti-Cancer Drug Design
Issue number4
Publication statusPublished - 1994 Jan 1


  • Antiproliferative activity
  • Knoevenagel reaction
  • Protein tyrosine kinases
  • Tyrphostins

ASJC Scopus subject areas

  • Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Oncology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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