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2-(Quinazolin-4-ylamino)-[1,4]benzoquinones as Covalent-Binding, Irreversible Inhibitors of the Kinase Domain of Vascular Endothelial Growth Factor Receptor-2
journal contribution
posted on 2005-12-01, 00:00 authored by Allan Wissner, M. Brawner Floyd, Bernard D. Johnson, Heidi Fraser, Charles Ingalls, Thomas Nittoli, Russell G. Dushin, Carolyn Discafani, Ramaswamy Nilakantan, Joseph Marini, Malini Ravi, Kinwang Cheung, Xingzhi Tan, Sylvia Musto, Tami Annable, Marshall M. Siegel, Frank LoganzoA series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent
covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth
factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of
substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,4]benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were
conducted in the absence and presence of glutathione and plasma. Several of the compounds
inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were
performed to study the reactivity of selected inhibitors toward glutathione. Reactivities
correlated with LUMO energies calculated as averages of those of individual conformers
weighted by the Boltzmann distribution. These results and molecular modeling were used to
rationalize the biological observations. The compounds behave as non-ATP-competitive
inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors
form a covalent interaction with Cys-1045. One member of this series displays antitumor activity
in an in vivo model.