5-Thiocyanato-2′-deoxyuridine as a possible radiosensitizer: electron-induced formation of uracil-C5-thiyl radical and its dimerizationElectronic supplementary information (ESI) available: (i) Fig. S1 - ESR spectra recorded at 77 K of matched γ-irradiated (77 K) N2-saturated 7.5 M LiCl-D2O and 7.5 M LiCl-H2O solutions of SCNdU with a hole scavenger, K4[Fe(CN)6]. (ii) Fig. S2 - ESR spectra recorded at 77 K of matched γ-irradiated (77 K) N2-saturated 7.5 M LiCl-H2O and 7.5 M LiBr-H2O solutions of

• Main Authors: Zdrowowicz, Magdalena, Chomicz, Lidia, yndul, Micha, Wityk, Pawe, Rak, Janusz, Wiegand, Tyler J, Hanson, Cameron G, Adhikary, Amitava, Sevilla, Michael D
• Format: Journal Article
• Language: English
• Published: 24.06.2015
• ISSN: 1463-9076; 1463-9084
• DOI: 10.1039/c5cp02081f

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 H 2 O or D 2 O) of these compounds show that electron-induced S-CN bond cleavage occurs to form a thiyl radical (dU-5-S&z.rad; or 6-D-U-5-S&z.rad;) and CN − via the initial π-anion radical (SCNdU&z.rad; − ) intermediate in which the excess electron is on the uracil base. HPLC and LC-MS/MS studies of γ-irradiated N 2 -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&z.rad; − and dU-5-S&z.rad; formation are preferred for the production of the σ-type uracilyl radical (dU&z.rad;) 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&z.rad; and CN − formation was thermodynamically favored by over 15 kcal mol −1 (Δ G ) compared to dU&z.rad; and SCN − production. The activation barriers for C5-S and S-CN bond cleavage in SCNdU&z.rad; − amount to 8.7 and 4.0 kcal mol −1 , respectively, favoring dU-5-S&z.rad; 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&z.rad; 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. ESR along with LC-MS analyses demonstrate electron-induced S-CN and C5-SCN bond cleavage in 5-thiocyanato-2-deoxyuridine (SCNdU). Hence, SCNdU could be a potential radiosensitizer by causing intra-, interstrand, and DNA-protein crosslinking via S-S dimer formation.