Issue 26, 2015

5-Thiocyanato-2′-deoxyuridine as a possible radiosensitizer: electron-induced formation of uracil-C5-thiyl radical and its dimerization

Abstract

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 CNvia 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−1G) 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.

Graphical abstract: 5-Thiocyanato-2′-deoxyuridine as a possible radiosensitizer: electron-induced formation of uracil-C5-thiyl radical and its dimerization

Supplementary files

Article information

Article type
Paper
Submitted
09 Apr 2015
Accepted
26 May 2015
First published
27 May 2015

Phys. Chem. Chem. Phys., 2015,17, 16907-16916

Author version available

5-Thiocyanato-2′-deoxyuridine as a possible radiosensitizer: electron-induced formation of uracil-C5-thiyl radical and its dimerization

M. Zdrowowicz, L. Chomicz, M. Żyndul, P. Wityk, J. Rak, T. J. Wiegand, C. G. Hanson, A. Adhikary and M. D. Sevilla, Phys. Chem. Chem. Phys., 2015, 17, 16907 DOI: 10.1039/C5CP02081F

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