Synthesis and in vitro cytotoxic activity of novel pyrazolo [1,5-a]pyrimidines towards breast adenocarcinoma MCF-7 cell line, cell cycle analysis and QSAR studies

World Congress on Breast Cancer

August 03-05, 2015 Birmingham, UK

Magda M F Ismail

Azhar University, Egypt

Posters-Accepted Abstracts: J Cancer Sci Ther

Abstract :

The cyclin-dependent kinases (CDKsa) are a family of serine/threonine protein kinases that play essential roles in the regulation of cell division. Individual CDKs phosphorylate distinct substrates in different phases of the cell cycle. Motivated by the widely reported anticancer activity of 4 arylazo-3,5-diamino-1H-pyrazoles as a novel cytotoxic agents against CDK2- cyclin E, new series of 3,5-diamino-4-arylazopyrazoles (3,4), were synthesized by cycloaddition of N2H4 on aryl(diazenyl) malononitrile 1 in 1:1 or 1:2 molar ratios. In addition, 5,7-diarylpyrazolo[1,5-a] pyrimidines possessing CDK2 inhibitory activity have been reported. Herein, we described the synthesis of 2-amino-3-arylazopyrazolo[1,5-a]pyrimidine derivatives (5-18) by reflux of 3,4 with ethoxymalononitrile, chalcones or arylidinemalononitriles in EtOH/Pip. 16 compounds were evaluated for the in vitro cytotoxic activityagainst human breast adenocarcinoma MCF-7cell line using MTT technique. Some of the tested compounds exploited moderate growth inhibitory activity (IC50â��s = 15.32-40.70 �¼M); in particular compound 7 exhibited superior potency (IC50 = 3.25 �¼M). Its effect was furtherstudied on cell cycle progression. A significantincrease in the percentage of cells at S-phase by 1.4 folds compared to control which indicates that the mechanism of action is related to S cell cycle arrest. Molecular docking simulation was also carried out for CDK2 enzyme to investigate their binding affinity. A 2D QSAR model was builtto explore the structural requirements controlling the observed cytotoxic properties.