title: Tyrphostins. 5. Potent inhibitors of platelet-derived growth factor receptor tyrosine kinase: structure-activity relationships in quinoxalines, quinolines, and indole tyrphostins.
abstract: A series of 3-indoleacrylonitrile tyrphostins, 2-chloro-3-phenylquinolines, and 3-arylquinoxalines were prepared and tested for inhibition of platelet-derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The potency of the inhibitors was found to be quinoxalines > quinolines > indoles. Lipophilic groups (methyl, methoxy) in the 6 and 7 positions and phenyl at the 3 position of quinoxalines and quinolines were essential for potency, in contrast to the hydrophilic catechol group in tyrphostins active against EGFR kinase inhibition at different sites. The inhibitors showed selectivity for PDGF and were not active against EGF receptor and HER-2/c-ErbB-2 receptor.
authors.affiliation: Department of Biological Chemistry, Alexander Silverman Institute of Life Science, Hebrew University of Jerusalem, Givat Ram, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Gazit
authors.forename: H
authors.initials: H
authors.lastname: App
authors.forename: G
authors.initials: G
authors.lastname: McMahon
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Levitzki
authors.forename: F D
authors.initials: FD
authors.lastname: Bohmer
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000302:isolation & purification / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007211:Indoles; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; D011804:Quinolines; D011810:Quinoxalines; D004815:Epidermal Growth Factor; C099852:PDGF receptor tyrosine kinase; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor