CINNAMAMIDE ANALOGS AS INHIBITORS OF PROTEIN-TYROSINE KINASES

Protein tyrosine kinases (PTK) are important signal transducting enzym es involved in the modulation of normal cellular growth and differenti ation and have been associated with the etiology of various human canc ers. The development of properly designed inhibitors, which block thei r function by interfering with the substrate binding, may therefore of fer an unique target for selective anticancer chemotherapy. Here we de scribe synthesis and biochemical testing of a novel series of non-pept ide PTK inhibitors which have as characteristic active pharmacophore t he cinnamamide moiety. For testing we used an exogenous substrate kina se assay based on the phosphorylation of (Val5)-angiotensin II with ra diolabelled ATP by the catalytic domain of the PTK encoded by the v-ab l oncogene (p45 v-abl). The most potent compounds were found in the cl ass of 3-arylidene-2-oxindoles (II) with IC50 values in the 1 muM rang e. Among these the 2-tetralylmethylene-, 4-quinolylmethylene-, 5-quino lylmethylene- and 3-indolylmethylene-2-oxindole compounds of formulae 16, 20, 21 and 24 respectively were selected for further investigation .