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-triflu...

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Main Authors:	Paulina Spisz, Witold Kozak, Lidia Chomicz-Mańka, Samanta Makurat, Karina Falkiewicz, Artur Sikorski, Anna Czaja, Janusz Rak, Magdalena Zdrowowicz
Format:	Article
Language:	English
Published:	MDPI AG 2020-09-01
Series:	International Journal of Molecular Sciences
Subjects:	radiosensitizer uracil derivatives modified nucleobases electron-induced degradation DFT calculations
Online Access:	https://www.mdpi.com/1422-0067/21/17/6352

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spelling	doaj-68f2a311c0b84f1297d393315eb63d972020-11-25T04:00:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-09-01216352635210.3390/ijms211763525-(<i>N</i>-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into <i>N</i>-uracil-5-yloxamic AcidPaulina Spisz0Witold Kozak1Lidia Chomicz-Mańka2Samanta Makurat3Karina Falkiewicz4Artur Sikorski5Anna Czaja6Janusz Rak7Magdalena Zdrowowicz8Department of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, PolandHypoxia—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-(<i>N</i>-trifluoromethylcarboxy) aminouracil (CF<sub>3</sub>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 <i>tert</i>-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—<i>N</i>-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<sub>3</sub>CONHU. Finally, a clonogenic assay and flow cytometric analysis of histone H2A.X phosphorylation proved the radiosensitization in vitro.https://www.mdpi.com/1422-0067/21/17/6352radiosensitizeruracil derivativesmodified nucleobaseselectron-induced degradationDFT calculations
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Paulina Spisz Witold Kozak Lidia Chomicz-Mańka Samanta Makurat Karina Falkiewicz Artur Sikorski Anna Czaja Janusz Rak Magdalena Zdrowowicz
spellingShingle	Paulina Spisz Witold Kozak Lidia Chomicz-Mańka Samanta Makurat Karina Falkiewicz Artur Sikorski Anna Czaja Janusz Rak Magdalena Zdrowowicz 5-(<i>N</i>-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into <i>N</i>-uracil-5-yloxamic Acid International Journal of Molecular Sciences radiosensitizer uracil derivatives modified nucleobases electron-induced degradation DFT calculations
author_facet	Paulina Spisz Witold Kozak Lidia Chomicz-Mańka Samanta Makurat Karina Falkiewicz Artur Sikorski Anna Czaja Janusz Rak Magdalena Zdrowowicz
author_sort	Paulina Spisz
title	5-(<i>N</i>-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into <i>N</i>-uracil-5-yloxamic Acid
title_short	5-(<i>N</i>-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into <i>N</i>-uracil-5-yloxamic Acid
title_full	5-(<i>N</i>-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into <i>N</i>-uracil-5-yloxamic Acid
title_fullStr	5-(<i>N</i>-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into <i>N</i>-uracil-5-yloxamic Acid
title_full_unstemmed	5-(<i>N</i>-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into <i>N</i>-uracil-5-yloxamic Acid
title_sort	5-(<i>n</i>-trifluoromethylcarboxy)aminouracil as a potential dna radiosensitizer and its radiochemical conversion into <i>n</i>-uracil-5-yloxamic acid
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1661-6596 1422-0067
publishDate	2020-09-01
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-(<i>N</i>-trifluoromethylcarboxy) aminouracil (CF<sub>3</sub>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 <i>tert</i>-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—<i>N</i>-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<sub>3</sub>CONHU. Finally, a clonogenic assay and flow cytometric analysis of histone H2A.X phosphorylation proved the radiosensitization in vitro.
topic	radiosensitizer uracil derivatives modified nucleobases electron-induced degradation DFT calculations
url	https://www.mdpi.com/1422-0067/21/17/6352
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5-(<i>N</i>-Trifluoromethylcarboxy)aminouracil as a Potential DNA Radiosensitizer and Its Radiochemical Conversion into <i>N</i>-uracil-5-yloxamic Acid

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