TYROSINE KINASE INHIBITORS .3. STRUCTURE-ACTIVITY-RELATIONSHIPS FOR INHIBITION OF PROTEIN-TYROSINE KINASES BY NUCLEAR-SUBSTITUTED DERIVATIVES OF THIOBIS(1-METHYL-N-PHENYL-1H-INDOLE-3-CARBOXAMIDE)

A series of indole-substituted hiobis(1-methyl-N-phenyl-1H-indole-3-ca rboxamides) were prepared and evaluated for their ability to inhibit t he tyrosine kinase activity of both the epidermal growth factor recept or (EGFR) and the nonreceptor pp60(v-src) tyrosine kinase. The compoun ds were synthesized by conversion of appropriate 1-methyloxindoles to 1-methyl-2-indolinethiones with P2S5 followed by subsequent reaction w ith NaH and phenyl isocyanate and oxidative dimerization of the result ing ihydro-N-phenyl-2-thioxo-1H-indole-3-carboxamides. The parent comp ound and many of the substituted analogues were moderately potent inhi bitors of both kinase enzymes, but no clear relationships were seen be tween substitution on the indole ring and inhibitory activity, While 4 -substituted compounds were generally inactive, 5-substituted derivati ves with electron-withdrawing groups showed inhibitory activity. Howev er, none of the substituted compounds showed significantly better acti vity than the unsubstituted parent compound. There was generally a goo d correlation between activity against the EGFR and pp60(v-src) kinase s, but several compounds did show some specificity (>20-fold) of inhib ition; 5-Cl and 5-Br derivatives preferentially inhibited pp60(v-src), while the 5-CF3 compound preferentially inhibited EGFR. Selected comp ounds from the series were found to inhibit the growth of Swiss 3T3 fi broblasts with IC(50)s in the range 2-25 mu M, the most active being 4 -substituted derivatives. The compounds inhibited bFGF-mediated protei n tyrosine phosphorylation in intact cells more effectively than EGFR- or PDGF-mediated phosphorylation.