Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma
Devine, Robert W.
Walsh, John M.D.
Conway, Gillian E.
Mondala, Julie Rose Mae
Kinsella, Gemma K.
Cullen, Patrick J.
Stephens, John C.
Curtin, James F.
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CitationZhonglei He, Clara Charleton, Robert W. Devine, Mark Kelada, John M.D. Walsh, Gillian E. Conway, Sebnem Gunes, Julie Rose Mae Mondala, Furong Tian, Brijesh Tiwari, Gemma K. Kinsella, Renee Malone, Denis O'Shea, Michael Devereux, Wenxin Wang, Patrick J. Cullen, John C. Stephens, James F. Curtin, Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma, European Journal of Medicinal Chemistry, Volume 224, 2021, 113736, ISSN 0223-5234, https://doi.org/10.1016/j.ejmech.2021.113736.
AbstractPyrazolopyrimidinones are fused nitrogen-containing heterocyclic systems, which act as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. In this study using glioblastoma U-251MG cell line, we tested the cytotoxic effects of 15 pyrazolopyrimidinones, synthesised via a two-step process, in combination with cold atmospheric plasma (CAP). CAP is an adjustable source of reactive oxygen and nitrogen species as well as other unique chemical and physical effects which has been successfully tested as an innovative cancer therapy in clinical trials. Significantly variable cytotoxicity was observed with IC50 values ranging from around 11 μM to negligible toxicity among tested compounds. Interestingly, two pyrazolopyrimidinones were identified that act in a prodrug fashion and display around 5–15 times enhanced reactive-species dependent cytotoxicity when combined with cold atmospheric plasma. Activation was evident for direct CAP treatment on U-251MG cells loaded with the pyrazolopyrimidinone and indirect CAP treatment of the pyrazolopyrimidinone in media before adding to cells. Our results demonstrated the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy and provide screened scaffolds that can be used for further development of pyrazolopyrimidinone prodrug derivatives.
FunderIrish Research Council Government of Ireland Postdoctoral Fellowship Award; Science Foundation Ireland; TU Dublin Fiosraigh Scholarship Programme; Science Foundation Ireland; Maynooth University John Hume Scholarship; Government of Ireland Postgraduate Scholarship from the Irish Research Council; Maynooth University Teaching Studentship (C·C.)
Grant NumberGOIPD/2020/788; 14/IA/2626; 17/CDA/4653; 16/RI/3399; 12/RI/2346/SOF
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