Novel sulphonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers.

Tytuł:: Novel sulphonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers.
Autorzy:: Soliman AM; a Department of Drug Radiation Research , National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA) , Nasr City , Egypt.
Alqahtani AS; b Department of Medicinal , Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University , Riyadh , Saudi Arabia.; c Department of Pharmacognosy , College of Pharmacy, King Saud University , Riyadh , Saudi Arabia.
Ghorab M; a Department of Drug Radiation Research , National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA) , Nasr City , Egypt.
Źródło:: Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2019 Dec; Vol. 34 (1), pp. 1030-1040.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Basingstoke, UK : Taylor & Francis, c2002-
MeSH Terms:: Antineoplastic Agents/*pharmacology
Protein Kinase Inhibitors/*pharmacology
Quinazolinones/*pharmacology
Radiation-Sensitizing Agents/*pharmacology
Receptor, ErbB-2/*antagonists & inhibitors
Sulfonamides/*pharmacology
Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/metabolism ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Quinazolinones/chemical synthesis ; Quinazolinones/chemistry ; Radiation-Sensitizing Agents/chemical synthesis ; Radiation-Sensitizing Agents/chemistry ; Receptor, ErbB-2/metabolism ; Structure-Activity Relationship ; Sulfonamides/chemical synthesis ; Sulfonamides/chemistry
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Contributed Indexing:: Keywords: Benzo[g]quinazolinone; EGFR; HER2; apoptosis; benzenesulfonamide
Substance Nomenclature:: 0 (Antineoplastic Agents)
0 (Protein Kinase Inhibitors)
0 (Quinazolinones)
0 (Radiation-Sensitizing Agents)
0 (Sulfonamides)
EC 2.7.10.1 (EGFR protein, human)
EC 2.7.10.1 (ERBB2 protein, human)
EC 2.7.10.1 (ErbB Receptors)
EC 2.7.10.1 (Receptor, ErbB-2)
Entry Date(s):: Date Created: 20190511 Date Completed: 20190610 Latest Revision: 20200225
Update Code:: 20240105
PubMed Central ID:: PMC6522976
DOI:: 10.1080/14756366.2019.1609469
PMID:: 31074303
: Czasopismo naukowe

Pełny tekst

A series of sulphonamide benzoquinazolinones 5-18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC 50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC 50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC 50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors.

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