Abstract:
:A series of amide analogues of the 2,2'-dithiobis(1H-indole-3-alkaonic 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 microM). Further substitution on the benzyl ring did not increase potency, and substitution in the alpha-position of the propanamide side chain was acceptable. A water-soluble alpha-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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Thompson AM,Fry DW,Kraker AJ,Denny WAdoi
10.1021/jm00031a009subject
Has Abstractpub_date
1994-03-04 00:00:00pages
598-609issue
5eissn
0022-2623issn
1520-4804journal_volume
37pub_type
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