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Why 6-Iodouridine Cannot Be Used as a Radiosensitizer of DNA Damage? Computational and Experimental Studies
[Image: see text] Previous density functional theory (DFT) studies on 6-brominated pyrimidine nucleosides suggest that 6-iodo-2′-deoxyuridine (6IdU) should act as a better radiosensitizer than its 5-iodosubstituted 2′-deoxyuridine analogue. In this work, we show that 6IdU is unstable in an aqueous s...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10041638/ https://www.ncbi.nlm.nih.gov/pubmed/36893332 http://dx.doi.org/10.1021/acs.jpcb.3c00548 |
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author | Falkiewicz, Karina Kozak, Witold Zdrowowicz, Magdalena Spisz, Paulina Chomicz-Mańka, Lidia Torchala, Mieczyslaw Rak, Janusz |
author_facet | Falkiewicz, Karina Kozak, Witold Zdrowowicz, Magdalena Spisz, Paulina Chomicz-Mańka, Lidia Torchala, Mieczyslaw Rak, Janusz |
author_sort | Falkiewicz, Karina |
collection | PubMed |
description | [Image: see text] Previous density functional theory (DFT) studies on 6-brominated pyrimidine nucleosides suggest that 6-iodo-2′-deoxyuridine (6IdU) should act as a better radiosensitizer than its 5-iodosubstituted 2′-deoxyuridine analogue. In this work, we show that 6IdU is unstable in an aqueous solution. Indeed, a complete disappearance of the 6IdU signal was observed during its isolation by reversed-phase high-performance liquid chromatography (RP-HPLC). As indicated by the thermodynamic characteristics for the S(N)1-type hydrolysis of 6IdU obtained at the CAM-B3LYP/DGDZVP++ level and the polarizable continuum model (PCM) of water, 6-iodouracil (6IU) was already released quantitatively at ambient temperatures. The simulation of the hydrolysis kinetics demonstrated that a thermodynamic equilibrium was reached within seconds for the title compound. To assess the reliability of the calculations carried out, we synthesized 6-iodouridine (6IUrd), which was, unlike 6IdU, sufficiently stable in an aqueous solution at room temperature. The activation barrier for the N-glycosidic bond dissociation in 6IUrd was estimated experimentally using an Arrhenius plot. The stabilities in water calculated for 6IdU, 6IUrd, and 5-iodo-2′-deoxyuridine (5IdU) could be explained by the electronic and steric effects of the 2′-hydroxy group present in the ribose moiety. Our studies highlight the issue of the hydrolytic stability of potentially radiosensitizing nucleotides which, besides having favorable dissociative electron attachment (DEA) characteristics, must be stable in water to have any practical application. |
format | Online Article Text |
id | pubmed-10041638 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-100416382023-03-28 Why 6-Iodouridine Cannot Be Used as a Radiosensitizer of DNA Damage? Computational and Experimental Studies Falkiewicz, Karina Kozak, Witold Zdrowowicz, Magdalena Spisz, Paulina Chomicz-Mańka, Lidia Torchala, Mieczyslaw Rak, Janusz J Phys Chem B [Image: see text] Previous density functional theory (DFT) studies on 6-brominated pyrimidine nucleosides suggest that 6-iodo-2′-deoxyuridine (6IdU) should act as a better radiosensitizer than its 5-iodosubstituted 2′-deoxyuridine analogue. In this work, we show that 6IdU is unstable in an aqueous solution. Indeed, a complete disappearance of the 6IdU signal was observed during its isolation by reversed-phase high-performance liquid chromatography (RP-HPLC). As indicated by the thermodynamic characteristics for the S(N)1-type hydrolysis of 6IdU obtained at the CAM-B3LYP/DGDZVP++ level and the polarizable continuum model (PCM) of water, 6-iodouracil (6IU) was already released quantitatively at ambient temperatures. The simulation of the hydrolysis kinetics demonstrated that a thermodynamic equilibrium was reached within seconds for the title compound. To assess the reliability of the calculations carried out, we synthesized 6-iodouridine (6IUrd), which was, unlike 6IdU, sufficiently stable in an aqueous solution at room temperature. The activation barrier for the N-glycosidic bond dissociation in 6IUrd was estimated experimentally using an Arrhenius plot. The stabilities in water calculated for 6IdU, 6IUrd, and 5-iodo-2′-deoxyuridine (5IdU) could be explained by the electronic and steric effects of the 2′-hydroxy group present in the ribose moiety. Our studies highlight the issue of the hydrolytic stability of potentially radiosensitizing nucleotides which, besides having favorable dissociative electron attachment (DEA) characteristics, must be stable in water to have any practical application. American Chemical Society 2023-03-09 /pmc/articles/PMC10041638/ /pubmed/36893332 http://dx.doi.org/10.1021/acs.jpcb.3c00548 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Falkiewicz, Karina Kozak, Witold Zdrowowicz, Magdalena Spisz, Paulina Chomicz-Mańka, Lidia Torchala, Mieczyslaw Rak, Janusz Why 6-Iodouridine Cannot Be Used as a Radiosensitizer of DNA Damage? Computational and Experimental Studies |
title | Why 6-Iodouridine Cannot Be Used as a Radiosensitizer
of DNA Damage? Computational and Experimental Studies |
title_full | Why 6-Iodouridine Cannot Be Used as a Radiosensitizer
of DNA Damage? Computational and Experimental Studies |
title_fullStr | Why 6-Iodouridine Cannot Be Used as a Radiosensitizer
of DNA Damage? Computational and Experimental Studies |
title_full_unstemmed | Why 6-Iodouridine Cannot Be Used as a Radiosensitizer
of DNA Damage? Computational and Experimental Studies |
title_short | Why 6-Iodouridine Cannot Be Used as a Radiosensitizer
of DNA Damage? Computational and Experimental Studies |
title_sort | why 6-iodouridine cannot be used as a radiosensitizer
of dna damage? computational and experimental studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10041638/ https://www.ncbi.nlm.nih.gov/pubmed/36893332 http://dx.doi.org/10.1021/acs.jpcb.3c00548 |
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