Technische Universitat Braunschweig, Institut für Pharmazeutische Chemie, Beethovenstrasse 55, 38106 Braunschweig, Germany.
J Med Chem. 2010 Mar 25;53(6):2433-42. doi: 10.1021/jm901388c.
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.
为了开发具有双重 PLK1/VEGF-R2 抑制活性的多激酶抑制剂，研究了作为适用于在 ATP 结合位点的铰链区域连接稠合杂环的通用结构模板的存在于保罗酮类激酶抑制剂中的 d-稠合 1-苯并氮杂环酮骨架。为此，将保罗酮的吲哚结构用其他含氮杂芳烃取代。设计的支架被合成并在指示的激酶上进行测试。发现 2-苯胺基-5,7-二氢-6H-嘧啶并[5,4-d][1]苯并氮杂环酮-6-ones 是 VEGF-R2 抑制剂，对胰岛素受体激酶具有选择性。在支架的 9-位上连接甲氧基导致额外的 PLK1 抑制活性，这可以通过 9-甲氧基衍生物的替代结合模式来解释。该化合物类的选定成员抑制了人脐静脉内皮细胞中的 VEGF-R2 自身磷酸化、人脐静脉内皮细胞球体的发芽以及多种癌细胞系的增殖。
