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

Journal of Enzyme Inhibition and Medicinal Chemistry

Houria Boulaiz¹  Juan A. Marchal¹  Yaiza Jiménez-Martínez¹  Hugo Gutiérrez-de-Terán²  Francho Nerín-Fonz²  David Araripe²  Matilde Ner³  Ana Conejo-García³  Joaquín M. Campos³  Olga Cruz-López³ 

[1] Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada;Department of Cell and Molecular Biology, Uppsala University;Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada;

关键词: antitumour;    pyroptosis;    her2 receptor;    molecular modelling;    benzoxazepines;   

DOI  :  10.1080/14756366.2021.1948841

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown