Synthesis, EGFR inhibition and anti-cancer activity of new 3,6-dimethyl-1-phenyl-4-(substituted-methoxy)pyrazolo[3,4-d] pyrimidine derivatives.

Abdellatif K, Bakr R, Mehany A et al.

Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt.

Anti-cancer agents in medicinal chemistry. Feb 2017.

A new series of hybrid pyrazolo[3,4-d]pyrimidine scaffold with a heteroaryl moiety as pyrazole, oxadiazole, triazole or phthalimide moiety (14a-f, 16, 17, 19, 20) was synthesized and biologically evaluated for the cytotoxicity against human liver cancer cell line (HEPG-2), human breast cancer cell line (MCF-7) and human colon cancer cell line (HCT-116). While the pyrazolo hybrid compounds (14a-f) showed good activity against HEPG-2, MCF-7 and HCT-116 cell lines (IC50 = 3.65 – 39.98, 1.45 – 54.19 and 2.00 – 50.6 µM respectively) in comparison with doxorubicin (IC50 = 5.66, 2.60 and 8.48 µM respectively), the triazolo derivatives (17, 19) showed considerable potency (IC50 = 22.20 – 54.61, 14.98 – 88.78, and 10.79 – 53.40 µM respectively), the oxadiazolo hybrid compound (16, IC50 = 149.91, 115.89 and 110.07 µM respectively) and phthalimido hybrid compound (20, IC50 = 96.02, 131.19 and 120.36 µM respectively) showed low potency. The pyrazolo derivative (14d, IC50 = 3.65, 1.45 and 2.00 µM) was the most potent among all compounds against HEPG-2, MCF-7 and HCT-116 cell lines respectively. Also, the hybrid pyrazolo[3,4-d]pyrimidine derivatives were evaluated for their inhibitory activity to epidermal growth factor receptor tyrosine kinase (EGFR-TK) and they showed a good inhibitory activity (IC50 = 8.27 – 19.03 µM). With the exception of the pyrazolo derivative (14c, IC50 = 18.82 µM), the inhibitory activity against EGFR-TK was consistent with the in vitro cytotoxic activity against HEPG-2, MCF-7 and HCT-116 cell lines. Moreover, molecular docking studies were performed and the results were in agreement with that obtained from the in vitro inhibition assays.


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