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

European Journal of Medicinal Chemistry
Daulat Bikram KhadkaWon-Jea Cho

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 topoisomerases (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 IIα. 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.

References

Sep 23, 2006·Nature Reviews. Cancer·Yves Pommier
Apr 21, 2009·Nature Reviews. Cancer·John L Nitiss
Apr 25, 2013·Expert Opinion on Therapeutic Patents·Daulat B Khadka, Won-Jea Cho

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Citations

Mar 28, 2016·European Journal of Medicinal Chemistry·Concepción AlonsoFrancisco Palacios
Oct 31, 2018·Archiv der Pharmazie·Emre MenteşeMustafa Emirik
Oct 30, 2019·Mini Reviews in Medicinal Chemistry·Bhushan Shakya, Paras Nath Yadav
Nov 28, 2020·European Journal of Medicinal Chemistry·Ranju Bansal, Anjleena Malhotra

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