TYROSINE KINASE INHIBITORS .2. SYNTHESIS OF 2,2'-DITHIOBIS(1H-INDOLE-3-ALKANAMIDES) AND INVESTIGATION OF THEIR INHIBITORY ACTIVITY AGAINST EPIDERMAL GROWTH-FACTOR RECEPTOR AND PP60(V-SRC) PROTEIN-TYROSINE KINASES

A series of amide analogues of the 2,2'-dithiobis(1H-indole-3-alkanoic acid) class of tyrosine kinase inhibitors have been prepared, by reac tion of 1H-indole-3-alkanamides (8) with S2Cl2, and separation of the desired disulfides from the initial mixtures of mono-, di-, and trisul fides formed. These amides were evaluated in vitro against epidermal g rowth factor receptor and pp60(v-src) protein tyrosine kinases. Inhibi tory activity against EGF receptor tyrosine kinase was chain-length de pendent, with the propanamides being the most effective. Hydrogen bond donor capabilities in the amide function did not appear to be necessa ry, with an N-benzylamide being the most potent (IC50=0.85 mu M). Furt her substitution on the benzyl ring did not increase potency, and subs titution in the ct-position of the propanamide side chain was acceptab le. A water-soluble alpha-NH2 derivative showed good inhibitory activi ty toward the enzyme, was a potent inhibitor of cell growth in fibrobl asts, and selectively inhibited intracellular tyrosine phosphorylation patterns. The nonreceptor kinase pp60(v-src) was in general much more sensitive than EGF receptor kinase to inhibition by these compounds, but with less pronounced structure-activity relationships.