Abstract

Tyrphostins are a series of benzylidenemalononitrile derivatives synthesized by condensing aromatic aldehydes with malononitrile derivatives. The use of heteroaromatic aldehydes in this process has received little attention. Accordingly, 27 tyrphostins containing a 2-, 3- or 4-substituted quinoline moiety were synthesized, of which 21 are novel compounds. Compounds containing the 2-aminoethene-1,1-dinitrile moiety in each series were the most potent inhibitors of the EGF receptor kinase in a cell-free enzyme assay (compounds 2, 11 and 20), having IC50 values of 1.7, 27.0 and. 4.7 μM respectively. For each R group substitution the order of potency was 2-quinolines > 4-quinolines > 3-quinolines. Compounds 2, 11 and 20 were unable to inhibit the epidermal growth factor (EGF) receptor autophosphorylation in intact cells; however, they were able to inhibit the EGF-dependent phosphorylation of a 50 kDa protein. These three compounds were able to inhibit EGF-dependent proliferation in a fibroblast cell more efficiently than serum-stimulated proliferation, suggesting that their mechanism of action may be linked to the EGF receptor signalling pathway. Compound 2 exhibited a degree of cell line selectivity in the US National Cancer Institute in vitro human tumour cell line panel. The majority of non-small cell lung cancer lines were relatively resistant to compound 2, while most of the colon, CNS, melanoma and renal lines were relatively sensitive. Further work is required to elucidate the mechanism of action of this interesting group of substituted-quinoline compounds and to determine whether for compounds 2, 11 and 20 this is related to inhibition of EGF receptor function.