INHIBITION OF THE EGF-STIMULATED CELLULAR PROLIFERATION OF ER-22 CELLS BY HYDROXYBIPHENYL DERIVATIVES

Several series of hydroxybiphenyl compounds substituted by a hydrophob ic group (tert-butyl or phenyl) and bearing a free or protected carbox ylic moiety were synthesized. The compounds were tested for their abil ity to inhibit the intrinsic tyrosine protein kinase activity of the E GF-receptor in vitro and the EGF-stimulated DNA-synthesis by ER 22 cel ls. Although the compounds of each series had poor in vitro inhibitory potencies (IC50 >> 100 mu M), most of them inhibited the EGF-dependen t cellular proliferation of ER 22 cells at relatively low doses (IC50 = 1.1 mu M for compound 14). Structure-activity studies based on the c ellular results showed that the most interesting series was the linear terphenyl series B of 2'-hydroxy-1, 1':4',1''-terphenyl-4-carboxylate s. The availability of the hydroxyl group, either protected or unprote cted, the linear arrangement of the hydrophobic moiety, the biphenyl s keleton, and the carboxylic group seem to be essential for the activit y of the compounds.