7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors

Abstract

Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.

The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones

“…The synthesis of N-substituted benzazepinones belonging to series II is displayed in Fig 13 . Alkylation of the starting material 11 [ 51 ] with tert -butyl bromoacetate led to ester 12 , which subsequently was deprotected using phosphoric acid in toluene according to a procedure reported by Li et al . [ 52 ].…”

“…The synthesis of the following compounds was prepared according to published procedures: 8-chloro-3,4-dihydro-1 H -benzo[ b ]azepin-2,5-dione ( 6 ) [ 50 , 80 ], 4-iodophenylhydrazine [ 81 ], 1,3,4,5-tetrahydro-2 H -benzo[ b ]azepin-2-one ( 11 ) [ 51 ], 3,3-dimethyl-1,3,4,5-tetrahydro-2 H -benzo[ b ]azepin-2-one ( 14 ) [ 53 , 82 ], 5,7-dihydro-6 H -dibenzo[ b , d ]azepin-6-one ( 17 ) [ 55 , 56 ] and ( E )-5-methoxyimino-1,3,4,5-tetrahydro-2 H -benzo[ b ]azepin-2-one ( 20 ) [ 58 ].…”

“…N 12 -alkylated side products were removed by column chromatography. Cleavage of the tert-butyl esters 8a-c by means of trifluoroacetic acid (TFA) led to the corresponding paullone acetic acids 9a-c, which were The synthesis of N-substituted benzazepinones belonging to series II is displayed in Fig 13 . Alkylation of the starting material 11 [51] with tert-butyl bromoacetate led to ester 12, which subsequently was deprotected using phosphoric acid in toluene according to a procedure reported by Li et al [52]. The resulting acetic acid derivative 13 was coupled to a diverse set of amines resulting in Boc-protected (2b-g), neutral (2h-k) and basic (2l-n) derivatives.…”

Polo-like Kinase 1 Inhibitors in Human Cancer Therapy: Development and Therapeutic Potential

“…Notably, the aforementioned compounds exhibited the potential to be developed into other dual-target inhibitors. For example, studies recently reported the synthesis of potent dual-target Aurora A/VEGF-R inhibitors generated by the reassembly of the pyrimido­[5,4- d ]­[1]­benzazepin-6-one scaffold …”