SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF TYRPHOSTINS CONTAINING HETEROAROMATIC MOIETIES

A series of benzylidenemalononitrile derivatives previously synthesize d 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 com pounds containing heteroaromatic moieties were prepared. We have confi rmed and extended the observation that the tyrphostins displayed an en hancement 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 mu M were readi ly achieved. Some inhibitory activity was seen with the heteroaromatic structures, with two compounds exhibiting IC50 values of 56 and 77 mu M. However, these derivatives were poor inhibitors of the EGF recepto r tyrosine kinase activity as compared to the hydroxylated derivatives . The ability of the 32 tyrphostins synthesized in the present study t o inhibit proliferation of a human breast adenocarcinoma cell line (MC F-7) was determined using [H-3]thymidine incorporation as a measure of DNA synthesis. Some of the compounds containing pyridine, imidazole o r thiophene portions displayed antiproliferative activity comparable t o 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 antiproliferati ve 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 a s the insulin-like growth factors (IGFs) and oestradiol, it is also st ill to be established whether the antiproliferative activity of the hy droxylated tyrphostins is directly related to inhibition of the EGF re ceptor tyrosine kinase activity.