Publication: Design, synthesis, HER2 inhibition and anticancer evaluation of new substituted 1,5-dihydro-4,1-benzoxazepines
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Identifiers
Date
2021-07-12
Authors
Cruz-López, Olga
Ner, Matilde
Nerín-Fonz, Francho
Jiménez-Martínez, Yaiza
Araripe, David
Marchal, Juan A.
Boulaiz, Houria
Gutiérrez-de-Terán, Hugo
Campos, Joaquín M.
Conejo-García, Ana
Advisors
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Publisher
Taylor & Francis
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Abstract
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.
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MeSH Terms
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor
Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation
Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Dose-Response Relationship, Drug
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Drug Screening Assays, Antitumor
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Molecular
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Molecular Structure
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptor, erbB-2
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Structure-Activity Relationship
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery::Drug Design
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Effector::Caspase 3
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Initiator::Caspase 1
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor
Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation
Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Dose-Response Relationship, Drug
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Drug Screening Assays, Antitumor
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Molecular
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Molecular Structure
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptor, erbB-2
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Structure-Activity Relationship
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery::Drug Design
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Effector::Caspase 3
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Initiator::Caspase 1
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50
DeCS Terms
CIE Terms
Keywords
Antitumour, Pyroptosis, HER2, Receptor, Molecular modelling, Benzoxazepines, Cancer cell line, Antineoplásicos, Piroptosis, Genes erbB-2, Modelos moleculares, Línea celular tumoral
Citation
Cruz-López O, Ner M, Nerín-Fonz F, Jiménez-Martínez Y, Araripe D, Marchal JA, et al. Design, synthesis, HER2 inhibition and anticancer evaluation of new substituted 1,5-dihydro-4,1-benzoxazepines. J Enzyme Inhib Med Chem. 2021 Dec;36(1):1553-1563