ABSTRACT
To develop multikinase inhibitors with dual PLK1/VEGF-R2 inhibitory activity, the d-annulated 1-benzazepin-2-one scaffold present in the paullone family of kinase inhibitors was investigated as a general structure template suitable for anchoring annulated heterocycles at the hinge region of the ATP binding site. For this purpose, the indole substructure of the paullones was replaced by other nitrogen containing heteroaromatics. The designed scaffolds were synthesized and tested on the indicated kinases. The 2-anilino-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones were found to be VEGF-R2 inhibitors with selectivity against the insulin receptor kinase. The attachment of a methoxy group to the 9-position of the scaffold led to additional PLK1 inhibitory activity, which was explained by an alternative binding mode of the 9-methoxy derivatives. Selected members of the compound class inhibited the VEGF-R2 autophosphorylation in human umbilical vein endothelial cells, the sprouting of human umbilical vein endothelial cell speroids, and the proliferation of diverse cancer cell lines.
Subject(s)
Benzazepines/chemistry , Benzazepines/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Binding Sites , Binding, Competitive , Cell Cycle Proteins/chemistry , Cell Cycle Proteins/metabolism , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins/metabolism , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/chemistry , Vascular Endothelial Growth Factor Receptor-2/metabolism , Polo-Like Kinase 1ABSTRACT
A screening program directed to find new agents against Leishmania donovani, the parasite causing visceral leishmaniasis, revealed that paullones attenuate the proliferation of axenic amastigotes. Because these structures were not active in a test system involving infected macrophages, a structure optimization campaign was carried out. Concomitant introduction of an unsaturated side chain into the 2-position and a tert-butyl substituent into the 9-position of the parent scaffold led to compounds inhibiting also parasites dwelling in macrophages. By inclusion of the so elaborated scaffold into a chalcone substructure, the toxicity against uninfected host cells was significantly reduced. For the synthesis of this new compound class, a novel modification of the Heck-type palladium-catalyzed C,C-cross coupling strategy was used, employing a ketone Mannich base as precursor for the alkene reactant. The so-prepared compounds exhibited improved antileishmanial activity both on axenic amastigotes (GI50 < 1 microM) as well as on parasites in infected macrophages.
