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5-Thiocyanato-2′-deoxyuridine as a possible radiosensitizer: electron-induced formation of uracil-C5-thiyl radical and its dimerization
Abstrakt
In this work, we have synthesized 5-thiocyanato-2′-deoxyuridine (SCNdU) along with the C6-deuterated nucleobase 5-thiocyanatouracil (6-D-SCNU) and studied their reactions with radiation-produced electrons. ESR spectra in γ-irradiated nitrogen-saturated frozen homogeneous solutions (7.5 M LiCl in H2O or D2O) of these compounds show that electron-induced S–CN bond cleavage occurs to form a thiyl radical (dU-5-S˙ or 6-D-U-5-S˙) and CN−via the initial π-anion radical (SCNdU˙−) intermediate in which the excess electron is on the uracil base. HPLC and LC-MS/MS studies of γ-irradiated N2-saturated aqueous solutions of SCNdU in the presence of sodium formate as a OH-radical scavenger at ambient temperature show the formation of the dU-5S-5S-dU dimer in preference to dU by about 10 to 1 ratio. This shows that both possible routes of electron-induced bond cleavage (dUC5–SCN and S–CN) in SCNdU˙− and dU-5-S˙ formation are preferred for the production of the σ-type uracilyl radical (dU˙) by 10 fold. DFT/M06-2x/6-31++G(d,p) calculations employing the polarizable continuum model (PCM) for aqueous solutions show that dU-5-S˙ and CN− formation was thermodynamically favored by over 15 kcal mol−1 (ΔG) compared to dU˙ and SCN− production. The activation barriers for C5–S and S–CN bond cleavage in SCNdU˙− amount to 8.7 and 4.0 kcal mol−1, respectively, favoring dU-5-S˙ and CN− formation. These results support the experimental observation of S–CN bond cleavage by electron addition to SCNdU that results in the formation of dU-5-S˙ and the subsequent dU-5S-5S-dU dimer. This establishes SCNdU as a potential radiosensitizer that could cause intra- and inter-strand crosslinking as well as DNA–protein crosslinking via S–S dimer formation.
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Autorzy (9)
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Magdalena Zdrowowicz
- Uniwersytet Gdański/Wydział Chemii Chemii Fizycznej
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Lidia Chomicz
- Uniwersytet Gdański/Wydział Chemii Chemii Fizycznej
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Michał Żyndul
- Uniwersytet Gdański/Wydział Chemii Chemii Fizycznej
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Janusz Rak Prof.
- Uniwersytet Gdański/Wydział Chemii Chemii Fizycznej
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Tyler Wiegand
- Oakland Univeristy
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Cameron Hanson
- Oakland Univeristy
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Amitava Adhikary
- Oakland Univeristy
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Michael Sevilla
- Oakland Univeristy
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Informacje szczegółowe
- Kategoria:
- Publikacja w czasopiśmie
- Typ:
- artykuł w czasopiśmie wyróżnionym w JCR
- Opublikowano w:
-
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
nr 17,
wydanie 26,
strony 16907 - 16916,
ISSN: 1463-9076 - Język:
- angielski
- Rok wydania:
- 2015
- Opis bibliograficzny:
- Zdrowowicz M., Chomicz L., Żyndul M., Wityk P., Rak J., Wiegand T., Hanson C., Adhikary A., Sevilla M.: 5-Thiocyanato-2′-deoxyuridine as a possible radiosensitizer: electron-induced formation of uracil-C5-thiyl radical and its dimerization// PHYSICAL CHEMISTRY CHEMICAL PHYSICS. -Vol. 17, iss. 26 (2015), s.16907-16916
- DOI:
- Cyfrowy identyfikator dokumentu elektronicznego (otwiera się w nowej karcie) 10.1039/c5cp02081f
- Weryfikacja:
- Politechnika Gdańska
wyświetlono 136 razy
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