A 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.
Hexahydropyrrolo[3,4-b]indoles 6, 10, and 13 are obtained from 2-bromo-3-carboxamides 5, 9, and 12, respectively, by a 1,5-radical translocation process followed by 5-endo-trig cyclization to the indole C-2 position. We wish to describe a new synthesis of hexahydropyrrolo[3,4b]indoles from 2-bromoindole-3-carboxamides involving sequential indole C-2 radical generation, 1,5-hydrogen atom abstraction, and 5-endo-trig cyclization to the indole C-2 position. In connection with our interest in pyrrolo[3,4b]indoles 1 and indolo[2,3-a]quinolizidines, 2 we envisioned the free radical sequence shown in Scheme 1 as an attractive route to these ring systems.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.