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 pp60v-src protein tyrosine kinases.
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.
Thompson
A M
AM
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Fry
D W
DW
Kraker
A J
AJ
Denny
W A
WA
D016475:3T3 Cells; D000473:Alkanes / Q000138:chemical synthesis* / Q000494:pharmacology; D000480:Alkynes / Q000138:chemical synthesis* / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D015688:Oncogene Protein pp60(v-src) / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000473:Alkanes; D000480:Alkynes; D000577:Amides; D007211:Indoles; D009281:Naphthalenes; C086211:N-(5,5-dimethylhex-3-yn-1-yl)-N-methyl-1-naphthalenemethanamine; D019000:Phosphotyrosine; D014443:Tyrosine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src)