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Substituted 2-arylquinazolinones: Design, synthesis, and evaluation of cytotoxicity and inhibition of topoisomerases

Title
Substituted 2-arylquinazolinones: Design, synthesis, and evaluation of cytotoxicity and inhibition of topoisomerases
Authors
Khadka, Daulat BikramGiap Huu TranShin, SominHang Thi Minh NguyenHue Thi CaoZhao, ChaoJin, YifengHue Thi My VanMinh Van ChauKwon, YoungjooThanh Nguyen LeCho, Won-Jea
Ewha Authors
권영주
SCOPUS Author ID
권영주scopus
Issue Date
2015
Journal Title
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0223-5234JCR Link1768-3254JCR Link
Citation
vol. 103, pp. 69 - 79
Keywords
2-Arylquinazolinone3-ArylisoquinolineTopoisomeraseCytotoxicityMolecular docking
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
A series of 2-arylquinazolinones with structural homology to known 3-arylisoquinolines were designed and synthesized in order to develop safe, effective, and selective cytotoxic agents targeting top-oisomerases (topos). 2-Arylquinzolinones with various substitutions on the aromatic rings were obtained by thermal cyclodehydration/dehydrogenation on reacting anthranilamides and benzaldehydes. The compounds had superior topo I-inhibitory activities but were generally inactive against topo II alpha. Among the 6-methyl-, 6-amino-, and 7-methylquinazolinones, 6-amino-substituted derivatives displayed potent cytotoxicity at submicromolar to nanomolar concentrations against human colorectal adenocarcinoma cells (HCT-15), human ductal breast epithelial tumor cells (T47D), and cervical cancer cells (HeLa). There was a good correlation between topo I inhibition and the cytotoxic effects of 6-aminoquinazolinones. Docking models demonstrated that topo I inhibition by these compounds is owing to intercalation and H-bond interactions with the DNA bases and amino acid residues at the enzymatic site. (C) 2015 Elsevier Masson SAS. All rights reserved.
DOI
10.1016/j.ejmech.2015.08.040
Appears in Collections:
약학대학 > 약학과 > Journal papers
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