Inhibition of the EGF-stimulated cellular proliferation of ER 22 cells by hydroxybiphenyl derivatives.

Several series of hydroxybiphenyl compounds substituted by a hydrophobic group (tert-butyl or phenyl) and bearing a free or protected carboxylic moiety were synthesized. The compounds were tested for their ability to inhibit the intrinsic tyrosine protein kinase activity of the EGF-receptor in vitro and the EGF-stimulated DNA-synthesis by ER 22 cells. Although the compounds of each series had poor in vitro inhibitory potencies (IC50 >> 100 microM), most of them inhibited the EGF-dependent cellular proliferation of ER 22 cells at relatively low doses (IC50 = 1.1 microM for compound 14). Structure-activity studies based on the cellular results showed that the most interesting series was the linear terphenyl series B of 2'-hydroxy-1,1':4',1"-terphenyl-4-carboxylates. The availability of the hydroxyl group, either protected or unprotected, the linear arrangement of the hydrophobic moiety, the biphenyl skeleton, and the carboxylic group seem to be essential for the activity of the compounds.