Synthesis of 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one analogs and their biological evaluation as anticancer agents: mTOR inhibitors

• Microwave assisted synthesis of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one scaffold.
• In vitro anticancer activity: HeLa, CAKI-I, PC-3, MiaPaca-2, A549 cancer cell lines.
• Compound 3m: cell cycle analysis, western blotting, nuclear cell morphology.
• mTOR inhibitory potential of compound 3m with nonomolar potency: IC50 = 203 nM.

A microwave assisted strategy for synthesis of series of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones has been developed and their biological evaluation as anticancer agents is described. The synthetic protocol involves simple procedure by oxidative coupling of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide with different aldehydes in presence of K2S2O8 offering 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds in excellent yields. The in vitro anticancer activity screening against human cancer cell lines HeLa, CAKI-I, PC-3, MiaPaca-2, A549 gave good results. The in detailed mechanistic correlation studies of compound 3m revealed that the compound shows anticancer activity through apoptosis mechanism and also inhibits mTOR with nonomolar potency. The design was based on docking with mTOR protein. The concentration dependent cell cycle analysis, western blotting experiment and nuclear cell morphology studies have been described.

Series of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones are synthesized using microwave assisted strategy. Screened against HeLa, CAKI-I, PC-3, MiaPaca-2, A549 for anticancer activity and 3m was found to be an mTOR inhibitor. Figure optionsDownload as PowerPoint slide