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Targeting hepatocellular carcinoma: Synthesis of new pyrazole-based derivatives, biological evaluation, DNA binding, and molecular modeling studies

A new series of pyrazole-based derivatives was synthesized. Their anticancer activity was tested against hepatocellular carcinoma (HepG2) cell line. The DNA-binding activity of the synthesized compounds was evaluated. Compounds 8, 3, and 17 showed the most potent activity. [Display omitted] •A new s...

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Bibliographic Details
Published in:Bioorganic chemistry 2019-07, Vol.88, p.102917-102917, Article 102917
Main Authors: Omran, Dina M., Ghaly, Mariam A., El-Messery, Shahenda M., Badria, Farid A., Abdel-Latif, Ehab, Shehata, Ihsan A.
Format: Article
Language:English
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Summary:A new series of pyrazole-based derivatives was synthesized. Their anticancer activity was tested against hepatocellular carcinoma (HepG2) cell line. The DNA-binding activity of the synthesized compounds was evaluated. Compounds 8, 3, and 17 showed the most potent activity. [Display omitted] •A new series of pyrazole-based derivatives was synthesized.•Their anticancer activity was tested against hepatocellular carcinoma (HepG2) cell line, and their DNA-binding activity was evaluated.•Compounds 8, 3, and 17 showed the most potent activity.•Molecular modeling studies were conducted to rationalize the obtained data.•Flexible alignment and surface mapping explained the different pattern of activity of the tested compounds. A new series of pyrazole derivatives was prepared in this work, including pyrazolopyrimidines, pyrazolotriazines, pyrazolylthienopyridines, and 2-(pyrazolylamino)thiazol-4-ones, utilizing 3-amino-5-methyl-1H-pyrazole as a synthetic precursor. Their in vitro anticancer activity was tested on hepatocellular carcinoma cell line, HepG2. The results revealed that the pyrazolylhydrazonoyl cyanide 8, the pyrazolopyrimidine 3, and the pyrazolylaminothiazolone 17 were the most active with IC50 values of 2, 7, and 7 µM respectively in comparison with 5.5 µM for cisplatin as a reference drug. Interestingly, all the synthesized compounds showed higher selectivity index than cisplatin. DNA binding assay was also carried out for the synthesized compounds to rationalize their mechanism of action. Molecular modeling studies, including docking into DNA minor groove, flexible alignment, and surface mapping, were conducted. Results obtained proved the superior DNA-binding affinity of the most active anticancer compounds.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2019.04.011