Design, synthesis, HER2 inhibition and anticancer evaluation of new substituted 1,5-dihydro-4,1- benzoxazepines
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AuthorCruz López, Olga María; Ner, Matilde; Jiménez Martínez, Yaiza; Marchal Corrales, Juan Antonio; Boulaiz Tassi, Houria; Campos Rosa, Joaquín María; Conejo García, Ana
Taylor & Francis
AntitumourPyroptosisHER2 receptorMolecular modellingBenzoxazepines
Olga Cruz-López... [et al.] (2021) Design, synthesis, HER2 inhibition and anticancer evaluation of new substituted 1,5-dihydro-4,1-benzoxazepines, Journal of Enzyme Inhibition and Medicinal Chemistry, 36:1, 1553-1563, DOI: [10.1080/14756366.2021.1948841]
SponsorshipJunta de Andalucia P18-RT-1679; Oficina de Transferencia de Resultados de Investigacion of the University of Granada PR/17/006; Instituto de Salud Carlos III European Commission RTI2018-101309-B-C22; Instituto de Salud Carlos III FMM-AP16683-2017; Junta de Andalucia PI-0089-2017
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 mM. 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 mM) does not produce any modification in the expression of pro-caspase 3, but increases the caspase 1 expression, and promotes pyroptosis.