Allene as an alternative functional group for drug design: effect of C--C multiple bonds conjugated with quinazolines on the inhibition of EGFR tyrosine kinase.
A series of allenic quinazolines were synthesized as receptor tyrosine kinase inhibitors by using a simple protocol for palladium-catalyzed allene transformation. Among the compounds synthesized, two allenic 4-anilinoquinazolines selectively suppressed epidermal growth factor receptor (EGFR) tyrosine kinase activity in vitro. According to immunoblot analysis, the allenic quinazolines inhibited the EGF-mediated phosphorylation of EGFR and its downstream kinases in A431 cells. Furthermore, one of these allenic quinazolines decreased the proliferation of A431 cells through the induction of cell-cycle arrest and apoptosis.
Ban
Hyun Seung
HS
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Tokyo 171-8588, Japan.
Onagi
Shinya
S
Uno
Masaharu
M
Nabeyama
Wataru
W
Nakamura
Hiroyuki
H
D000466:Alkadienes / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002384:Catalysis; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D010165:Palladium / Q000737:chemistry; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000466:Alkadienes; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D010165:Palladium; D066246:ErbB Receptors