New fused pyrimidine derivatives with anticancer activity: Synthesis, topoisomerase II inhibition, apoptotic inducing activity and molecular modeling study

A new series of triazolopyrimidines and thiazolopyrimidine hydrobromides was designed and prepared as Topoisomerase II inhibitors. Screening of all synthesized compounds was carried out by the National Cancer Institute (NCI) of USA. Activity against 60 human Cancer cell lines representing different Cancer types was determined. Accordingly, compound 3d was the most potent inhibitor especially against the renal cell line A498 causing 92.46% inhibition (IC₅₀ = 3.5 μM). Moreover, cell cycle analysis showed cell cycle arrest caused by compound 3d at the G2/M phase leading to cell proliferation inhibition and pro-apoptotic activity. Also, thiazolopyrimidine 3d showed potent Topoisomerase II inhibitory activity (IC₅₀ 2.89 μM) compared to doxorubicin which was used as a reference compound with (IC₅₀ 2.67 μM). Moreover, molecular modeling study of the synthesized compounds was performed and revealed the binding interactions of compound 3d in the binding site of Topoisomerase II Enzyme rationalizing the significant inhibitory activity of this derivative.