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

Zhonglei He Orcid Logo, Clara Charleton, Robert W. Devine, Mark Kelada, John M.D. Walsh, Gill Conway Orcid Logo, Sebnem Gunes Orcid Logo, Julie Rose Mae Mondala Orcid Logo, Furong Tian, Brijesh Tiwari, Gemma K. Kinsella, Renee Malone Orcid Logo, Denis O'Shea, Michael Devereux Orcid Logo, Wenxin Wang, Patrick J. Cullen, John C. Stephens, James F. Curtin Orcid Logo

European Journal of Medicinal Chemistry, Volume: 224, Start page: 113736

Swansea University Author: Gill Conway Orcid Logo

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DOI (Published version): 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 cance...

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Published in: European Journal of Medicinal Chemistry
ISSN: 0223-5234
Published: Elsevier BV 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa65435
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spelling v2 65435 2024-01-10 Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma e33e0ee5a076ad91fe6615117caa1800 0000-0002-5991-0960 Gill Conway Gill Conway true false 2024-01-10 BMS 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. Journal Article European Journal of Medicinal Chemistry 224 113736 Elsevier BV 0223-5234 Cold atmospheric plasma; Pyrazolopyrimidinone; Pro-drug; ROS; Glioblastoma; Programmable cytotoxicity 15 11 2021 2021-11-15 10.1016/j.ejmech.2021.113736 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University This work is supported by Irish Research Council Government of Ireland Postdoctoral Fellowship Award GOIPD/2020/788 (Z.H., J.C.) and IRCSET EMBARK grant (G.E.C., J.C.); Science Foundation Ireland Grant Numbers 14/IA/2626 (P·C., J.C.) and 17/CDA/4653 (B T., P·C., J.C.); and by the TU Dublin Fiosraigh Scholarship Programme (S·B., J.M., J.C.); Science Foundation Ireland infrastructure grants 16/RI/3399 and 12/RI/2346/SOF; Maynooth University John Hume Scholarship (M.K.); Government of Ireland Postgraduate Scholarship from the Irish Research Council (R. D.); Maynooth University Teaching Studentship (C·C.). 2024-03-21T11:36:41.2682079 2024-01-10T15:27:44.2765365 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Zhonglei He 0000-0001-6533-4974 1 Clara Charleton 2 Robert W. Devine 3 Mark Kelada 4 John M.D. Walsh 5 Gill Conway 0000-0002-5991-0960 6 Sebnem Gunes 0000-0001-8153-9742 7 Julie Rose Mae Mondala 0000-0002-9656-311x 8 Furong Tian 9 Brijesh Tiwari 10 Gemma K. Kinsella 11 Renee Malone 0000-0002-2992-5416 12 Denis O'Shea 13 Michael Devereux 0000-0002-5378-0536 14 Wenxin Wang 15 Patrick J. Cullen 16 John C. Stephens 17 James F. Curtin 0000-0002-9320-9254 18 65435__29627__997b86d799614818bc79e0af7f2b5343.pdf 65435.pdf 2024-03-05T09:54:14.4055146 Output 2506972 application/pdf Version of Record true © 2021 The Authors. This is an open access article under the CC BY license. true eng https://creativecommons.org/licenses/by/4.0/
title Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma
spellingShingle Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma
Gill Conway
title_short Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma
title_full Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma
title_fullStr Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma
title_full_unstemmed Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma
title_sort Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma
author_id_str_mv e33e0ee5a076ad91fe6615117caa1800
author_id_fullname_str_mv e33e0ee5a076ad91fe6615117caa1800_***_Gill Conway
author Gill Conway
author2 Zhonglei He
Clara Charleton
Robert W. Devine
Mark Kelada
John M.D. Walsh
Gill 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
format Journal article
container_title European Journal of Medicinal Chemistry
container_volume 224
container_start_page 113736
publishDate 2021
institution Swansea University
issn 0223-5234
doi_str_mv 10.1016/j.ejmech.2021.113736
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description 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.
published_date 2021-11-15T11:36:38Z
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score 11.03559

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