Design, synthesis and characterization of N9/N7-substituted 6-aminopurines as VEGF-R and EGF-R inhibitors.
In this study we report on the design, synthesis and biological characterization of novel N(9) or N(7) arylethanone-substituted 6-aminopurines and 6-methoxypurines, respectively, as EGF-R and VEGF-R inhibitors. The compounds were initially profiled in a panel of 24 cancer-relevant protein kinases. Dependent on the regio-substitution of the purine core we found inhibition activity for EGF-R and VEGF-R with IC(50) values in the microM range. The two novel N(9)/N(7) 2-(6-amino-purine)-1-(1H-indole-3-yl)ethanone derivatives were characterized in an enhanced panel of 78 kinases showing the N(9) derivative to also inhibit MNK1 and IRR while the N(7) isomer was found to be specific for VEGF-R2.
Department of Pharmacy, Eberhard-Karls-University, Auf der Morgenstelle 8, D-72076 Tübingen, Germany. christian.peifer@uni-tuebingen.de
Christian
C
Peifer
Stefanie
S
Bühler
Dominik
D
Hauser
Katrin
K
Kinkel
Frank
F
Totzke
Christoph
C
Schächtele
Stefan
S
Laufer
D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009369:Neoplasms / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D047428:Protein Kinase Inhibitors; D011687:Purines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor