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  3. Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma

Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma

  • Eur J Med Chem. 2021 Nov 15:224:113736. doi: 10.1016/j.ejmech.2021.113736.
Zhonglei He 1,  Clara Charleton 2,  Robert W Devine 2,  Mark Kelada 2,  John M D Walsh 2,  Gillian E Conway 3,  Sebnem Gunes 4,  Julie Rose Mae Mondala 4,  Furong Tian 5,  Brijesh Tiwari 6,  Gemma K Kinsella 4,  Renee Malone 4,  Denis O'Shea 4,  Michael Devereux 4,  Wenxin Wang 7,  Patrick J Cullen 8,  John C Stephens 9,  James F Curtin 10
Affiliations

Affiliations

  • 1 BioPlasma Research Group, School of Food Science and Environmental Health, Technological University Dublin, Dublin, Ireland; Nanolab, FOCAS Research Institute, Technological University Dublin, Dublin, Ireland; Environmental, Sustainability and Health Research Institute, Technological University Dublin, Dublin, Ireland; Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin, Ireland. Electronic address: zhonglei.he@tudublin.ie.
  • 2 Department of Chemistry, Maynooth University, Maynooth, Co. Kildare, Ireland.
  • 3 BioPlasma Research Group, School of Food Science and Environmental Health, Technological University Dublin, Dublin, Ireland; Environmental, Sustainability and Health Research Institute, Technological University Dublin, Dublin, Ireland; In-Vitro Toxicology Group, Institute of Life Science, Swansea University Medical School, Swansea University, Singleton Park, Swansea, Wales, United Kingdom.
  • 4 BioPlasma Research Group, School of Food Science and Environmental Health, Technological University Dublin, Dublin, Ireland; Environmental, Sustainability and Health Research Institute, Technological University Dublin, Dublin, Ireland.
  • 5 BioPlasma Research Group, School of Food Science and Environmental Health, Technological University Dublin, Dublin, Ireland; Nanolab, FOCAS Research Institute, Technological University Dublin, Dublin, Ireland; Environmental, Sustainability and Health Research Institute, Technological University Dublin, Dublin, Ireland.
  • 6 Department of Food Biosciences, Teagasc Food Research Centre, Ashtown, Dublin, Ireland.
  • 7 Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin, Ireland.
  • 8 School of Chemical and Biomolecular Engineering, University of Sydney, Australia.
  • 9 Department of Chemistry, Maynooth University, Maynooth, Co. Kildare, Ireland; The Kathleen Lonsdale Institute of Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland.
  • 10 BioPlasma Research Group, School of Food Science and Environmental Health, Technological University Dublin, Dublin, Ireland; Nanolab, FOCAS Research Institute, Technological University Dublin, Dublin, Ireland; Environmental, Sustainability and Health Research Institute, Technological University Dublin, Dublin, Ireland. Electronic address: james.curtin@tudublin.ie.
PMID: 34384944 DOI: 10.1016/j.ejmech.2021.113736
Abstract

Pyrazolopyrimidinones 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.

Keywords

Cold atmospheric plasma; Glioblastoma; Pro-drug; Programmable cytotoxicity; Pyrazolopyrimidinone; ROS.

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