Abstract
Novel tetracyclic pyrazolo[1,5-a]pyrimidine derivatives; namely benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a] pyrimidin-2-amines 6a-e and benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2(6H)-ones 15a-d, were designed and synthesized as topoisomerase II alpha inhibitors with potential anticancer activity. The structure and their mechanistic pathway were discussed and confirmed based on spectral data and DFT calculations. Com-pounds 6a, 6c, 15b, 15c and 15d exhibited potent Topo II inhibitory activity at one-digit IC50 values (2.35 - 7.18 mu M). Among the tested compounds, aminopyrazolopyrimidine derivatives 6a (IC50 = 3.44 mu M) and 6c (IC50 = 2.35 mu M) were comparable/equipotent to Doxorubicin (IC50 = 2.71 mu M) against Topo II. The most active compounds in Topo II assay were further investigated in vitro for their cytotoxic potential. The oxo-pyrazolopyrimidine derivative 15c; was the most potent possessing one-digit IC50 values (HCT116 IC50 = 2.32 +/- 0.13 mu M, MCF7 IC50 = 1.137 +/- 0.06 mu M). Compound 15c was two times more potent than Doxorubicin against MCF7 breast cancer cells. 15c exhibited a safety profile much better than that of Doxorubicin against non-cancerous cells. Compound 15c was also found to be a good apoptotic inducer. Moreover, docking result revealed well-fitting and proper orientation of 15c into Topo II-DNA complex.