Synthesis and antiproliferative activity of unsaturated quinoline derivatives

In our previous work Knoevenagel condensation of quinoline 2-, 3- and 4-car baldehyde with malononitrile derivatives was used to produce a series of he teroarylidene malononitrile derivatives, Some of these heteroaromatic tyrph ostins were potent inhibitors of the epidermal growth factor (EGF) receptor kinase, This work has now been extended by using 6-, 7-, and 8-quinoline-c arbaldehyde to prepare 23 new quinoline-tyrphostins 1-23, Most of these com pounds were moderately active against the MCF7 breast cancer cell line. The order of potency was 7- > 6- 8-substituted quinoline, which indicates that increased activity of the 7-substituted quinolines is associated with elec tron deficiency at the 7-position in the quinoline ring, The most active co mpound, 12, formed from 7-quinolinecarbaldehyde and ethyl cyanoacetate, had an IC50 value of 2.3 muM. Compounds 1-23 showed similar IC50 values agains t the MCF7 and MCF7/ADR cell lines (the latter shows fourfold increased pro tein tyrosine kinase activity) except for the compounds 1 and 15 formed fro m 6-quinolinecarbaldehyde and malononitrile and 7-quinolinecarbaldehyde and cyanoacetamide, which showed a significant (11- and 42-fold, respectively) increase in potency against the MCF7/ADR cell line. Furthermore, no associ ation was found between growth inhibition and inhibition of the EGFR protei n tyrosine kinase (PTK), using a cell-free assay. In addition, new compound s were prepared from 2- and 4-quinolinecarbaldehyde with extended conjugati on in the side chains (24-27) or with methoxypolyethoxyethyl esters in the side chain to increase water solubility (28 and 29), These compounds showed substantial cytotoxicity, with IC50 values in the range 1-25 muM, but simi lar values were observed against both cell lines, No association was found between inhibition of PTK and growth inhibition, again indicating that thei r mode of action may not be specific for the EGF receptor.