Design, synthesis, HER2 inhibition and anticancer evaluation of new substituted 1,5-dihydro-4,1-benzoxazepines

Cruz-López, O.; Ner, M. 1 Nerín-Fonz, F.; Jiménez-Martínez, Y.; Araripe, D.; Marchal, J.A.; Boulaiz, H.; Gutiérrez-de-Terán, H.; Campos, J.M.; Conejo-García, A.

Revista: Journal of Enzyme Inhibition and Medicinal Chemistry

ISSN: 1475-6374

Año de publicación: 2021

Volumen: 36

Número: 1

Páginas: 1553-1563

DOI: 10.1080/14756366.2021.1948841


A series of 11 new substituted 1,5-dihydro-4,1-benzoxazepine derivatives was synthesised to study the influence of the methyl group in the 1-(benzenesulphonyl) moiety, the replacement of the purine by the benzotriazole bioisosteric analogue, and the introduction of a bulky substituent at position 6 of the purine, on the biological effects. Their inhibition against isolated HER2 was studied and the structure–activity relationships have been confirmed by molecular modelling studies. The most potent compound against isolated HER2 is 9a with an IC50 of 7.31 µM. We have investigated the effects of the target compounds on cell proliferation. The most active compound (7c) against all the tumour cell lines studied (IC50 0.42–0.86 µM) does not produce any modification in the expression of pro-caspase 3, but increases the caspase 1 expression, and promotes pyroptosis.