Journal of Medicinal Chemistry p. 598 - 609 (1994)
Update date:2022-07-30
Topics:
Thompson, Andrew M.
Fry, David W.
Kraker, Alan J.
Denny, William A.
A series of amide analogues of the 2,2'-dithiobis(1H-indole-3-alkanoic acid) class of tyrosine kinase inhibitors have been prepared, by reaction of 1H-indole-3-alkanamides (8) with S2Cl2, and separation of the desired disulfides from the initial mixtures of mono-, di-, and trisulfides formed. These amides were evaluated in vitro against epidermal growth factor receptor and pp60v-src protein tyrosine kinases. Inhibitory activity against EGF receptor tyrosine kinase was chain-length dependent, with the propanamides being the most effective. Hydrogen bond donor capabilities in the amide function did not appear to be necessary, with an N-benzylamide being the most potent (IC50 = 0.85 μM). Further substitution on the benzyl ring did not increase potency, and substitution in the α-position of the propanamide side chain was acceptable. A water-soluble α-NH2 derivative showed good inhibitory activity toward the enzyme, was a potent inhibitor of cell growth in fibroblasts, and selectively inhibited intracellular tyrosine phosphorylation patterns. The nonreceptor kinase pp60v-src was in general much more sensitive than EGF receptor kinase to inhibition by these compounds, but with less pronounced structure-activity relationships.
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