146535-11-7

Protein tyrosine kinase (PTK) inhibitors are potential antiproliferative agents for diseases caused by the hyperactivity of PTKs. Tyrphostins are a class of antiproliferative compounds which act as PTK blockers. PTK inhibitors specific for platelet-derived growth factor (PDGF) receptor kinase could help in the treatment of atherosclerosis, restenosis, pulmonary fibrosis, and gliomas. AG-1296 is a potent and selective inhibitor of PDGF receptor kinase with an IC₅₀ value of about 0.4 μM both in vitro and in cells (Swiss 3T3 cells). It inhibits ligand-stimulated DNA synthesis in platelet-derived growth factor receptor and stem cell factor/kit receptor transfected cells with an IC₅₀ values of 1.5 and 1.8 μM, respectively. Treatment of sis oncogene transfected NIH3T3 cells with AG-1296 reverses the transformed phenotype.

A potent inhibitor of PDGF receptor tyrosine kinase (IC50=1 μM). Also inhibits FGF receptor tyrosine kinase and c-kit. Induces apoptosis in a small-cell lung cancer cell line (H526).

ChEBI: 6,7-dimethoxy-2-phenylquinoxaline is a quinoxaline derivative.

GENERAL METHODS: Triphenyltin (35.5 mg, 0.1 mmol, 10 mol%) and 4,5-dimethoxy-1,2-phenylenediamine (1.2 mmol) were sequentially added to a solution of 2-hydroxyacetophenone (1 mmol) in toluene (6 mL) under air atmosphere. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography (TLC). Upon completion of the reaction, the solvent was removed by concentration under reduced pressure and the resulting residue was purified by silica gel column chromatography with dichloromethane (CH2Cl2) as eluent. The structure of the final product, 6,7-dimethoxy-2-phenylquinoxaline, was analyzed by melting point determination, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) and confirmed by comparison with literature data.

PDGFR

PDGFRα; PDGFRβ

1) Kovalenko et al. (1997), Phosphorylation site-specific inhibition of platelet-derived growth factor beta-receptor autophosphorylation by the receptor blocking tyrphostin AG1296; Biochemistry, 36 6260 2) Krystal et al. (1997), Induction of apoptosis and inhibition of small cell lung cancer growth by the quinoxaline tyrphostins; Cancer Res., 57 220 3) Strutz et al. (2001), TGF-beta 1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2); Kidney Int., 59 579