Novel 1,5-diphenyl-6-substituted 1H-pyrazolo[3,4- d ]pyrimidin-4(5 H )-ones induced apoptosis in RKO colon cancer cells.

Novel 1,5-diphenyl-6-substituted-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones were synthesized and characterized. All compounds were screened for their anti-proliferative activities in five different cancer cell lines. The results showed that compounds7aand7bcomprising aminoguanidino or guanidino moiety at position6inhibited proliferation of RKO colon cancer cells with IC50of 8 and 4 μM, respectively. Compounds7aand7binduced apoptosis in RKO cells, which was confirmed by TUNEL and annexin V-FITC assays. Flow cytometric analysis indicated that compounds7aand7barrested RKO cells in the G1 phase and the most active compound7bincreased levels of p53, p21, Bax, ERK1/2 and reduced levels of Bcl2 and Akt. Compound7balso activates release of cytochromec, which is consistent with activation of caspase-9. Additionally, compound7bincreased caspase-3 activity and cleaved PARP-1 in RKO cells. Collectively, these findings could establish a molecular basis for the development of new anti-cancer agents. [ABSTRACT FROM PUBLISHER]