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5-(N-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into N-Uracil-5-yloxamic Acid
Hypoxia—a hallmark of solid tumors—dramatically impairs radiotherapy, one of the most common anticancer modalities. The adverse effect of the low-oxygen state can be eliminated by the concomitant use of a hypoxic cell radiosensitizer. In the present paper, we show that 5-(N-trifluoromethylcarboxy) a...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504071/ https://www.ncbi.nlm.nih.gov/pubmed/32883013 http://dx.doi.org/10.3390/ijms21176352 |
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author | Spisz, Paulina Kozak, Witold Chomicz-Mańka, Lidia Makurat, Samanta Falkiewicz, Karina Sikorski, Artur Czaja, Anna Rak, Janusz Zdrowowicz, Magdalena |
author_facet | Spisz, Paulina Kozak, Witold Chomicz-Mańka, Lidia Makurat, Samanta Falkiewicz, Karina Sikorski, Artur Czaja, Anna Rak, Janusz Zdrowowicz, Magdalena |
author_sort | Spisz, Paulina |
collection | PubMed |
description | Hypoxia—a hallmark of solid tumors—dramatically impairs radiotherapy, one of the most common anticancer modalities. The adverse effect of the low-oxygen state can be eliminated by the concomitant use of a hypoxic cell radiosensitizer. In the present paper, we show that 5-(N-trifluoromethylcarboxy) aminouracil (CF(3)CONHU) can be considered as an effective radiosensitizer of DNA damage, working under hypoxia. The title compound was synthesized in the reaction of 5-aminouracil and trifluoroacetic anhydride in trifluoroacetic acid. Then, an aqueous and deoxygenated solution of the HPLC purified compound containing tert-butanol as a hydroxyl radical scavenger was irradiated with X-rays. Radiodegradation in a 26.67 ± 0.31% yield resulted in only one major product—N-uracil-5-yloxamic acid. The mechanism that is possibly responsible for the formation of the observed radioproduct has been elucidated with the use of DFT calculations. The cytotoxic test against the PC3 prostate cancer cell line and HDFa human dermal fibroblasts confirmed the low cytotoxicity of CF(3)CONHU. Finally, a clonogenic assay and flow cytometric analysis of histone H2A.X phosphorylation proved the radiosensitization in vitro. |
format | Online Article Text |
id | pubmed-7504071 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75040712020-09-24 5-(N-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into N-Uracil-5-yloxamic Acid Spisz, Paulina Kozak, Witold Chomicz-Mańka, Lidia Makurat, Samanta Falkiewicz, Karina Sikorski, Artur Czaja, Anna Rak, Janusz Zdrowowicz, Magdalena Int J Mol Sci Article Hypoxia—a hallmark of solid tumors—dramatically impairs radiotherapy, one of the most common anticancer modalities. The adverse effect of the low-oxygen state can be eliminated by the concomitant use of a hypoxic cell radiosensitizer. In the present paper, we show that 5-(N-trifluoromethylcarboxy) aminouracil (CF(3)CONHU) can be considered as an effective radiosensitizer of DNA damage, working under hypoxia. The title compound was synthesized in the reaction of 5-aminouracil and trifluoroacetic anhydride in trifluoroacetic acid. Then, an aqueous and deoxygenated solution of the HPLC purified compound containing tert-butanol as a hydroxyl radical scavenger was irradiated with X-rays. Radiodegradation in a 26.67 ± 0.31% yield resulted in only one major product—N-uracil-5-yloxamic acid. The mechanism that is possibly responsible for the formation of the observed radioproduct has been elucidated with the use of DFT calculations. The cytotoxic test against the PC3 prostate cancer cell line and HDFa human dermal fibroblasts confirmed the low cytotoxicity of CF(3)CONHU. Finally, a clonogenic assay and flow cytometric analysis of histone H2A.X phosphorylation proved the radiosensitization in vitro. MDPI 2020-09-01 /pmc/articles/PMC7504071/ /pubmed/32883013 http://dx.doi.org/10.3390/ijms21176352 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Spisz, Paulina Kozak, Witold Chomicz-Mańka, Lidia Makurat, Samanta Falkiewicz, Karina Sikorski, Artur Czaja, Anna Rak, Janusz Zdrowowicz, Magdalena 5-(N-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into N-Uracil-5-yloxamic Acid |
title | 5-(N-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into N-Uracil-5-yloxamic Acid |
title_full | 5-(N-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into N-Uracil-5-yloxamic Acid |
title_fullStr | 5-(N-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into N-Uracil-5-yloxamic Acid |
title_full_unstemmed | 5-(N-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into N-Uracil-5-yloxamic Acid |
title_short | 5-(N-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into N-Uracil-5-yloxamic Acid |
title_sort | 5-(n-trifluoromethylcarboxy)aminouracil as a potential dna radiosensitizer and its radiochemical conversion into n-uracil-5-yloxamic acid |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504071/ https://www.ncbi.nlm.nih.gov/pubmed/32883013 http://dx.doi.org/10.3390/ijms21176352 |
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