Design, synthesis, structure–activity relationship and kinase inhibitory activity of substituted 3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ones

A new series of 3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ones having variable substitutions at N5 and C6 positions has been synthesized and characterized. The synthesized compounds were tested for cytotoxicity against K562 and MCF-7 cancer cell lines and for inhibition of protein kinases CDK1/cyclin B, CDK2/cyclin E and Abl. Compounds 5f and 5h killed both K562 and MCF-7 cell lines with IC50 values 8.2, 9.6 μM and 15.3, 10.8 μM, respectively. In addition, 5f and 5h showed antiproliferative effect through arrest in G2/M phase on cell cycle of K562 cancer cell line in a dose-dependant manner. To confirm the mechanism of cell death, activity of caspase-3/7 was measured. Moreover, kinase selectivity profiling of the most potent compound 5f revealed several other sensitive targets, including RSK1 and RIPK2, TrkA and VEGFR. The results provide a starting point for optimization in order to increase their potency against kinases and cancer cell lines.

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