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

• Published in: Physical chemistry chemical physics : PCCP Vol. 17; no. 26; pp. 16907 - 16916
• Main Authors: Zdrowowicz, Magdalena, Chomicz, Lidia, Żyndul, Michał, Wityk, Paweł, Rak, Janusz, Wiegand, Tyler J, Hanson, Cameron G, Adhikary, Amitava, Sevilla, Michael D
• Format: Journal Article
• Language: English
• Published: England 14.07.2015
• Subjects: Bonding; Cleavage; Crosslinking; Deoxyuridine - analogs & derivatives; Deoxyuridine - chemical synthesis; Deoxyuridine - chemistry; Dimerization; Dimers; Electrons; Formations; Free Radicals - chemical synthesis; Free Radicals - chemistry; Molecular Structure; Quantum Theory; Radicals; Radiosensitizers; Solvation; Uracil - analogs & derivatives; Uracil - chemical synthesis; Uracil - chemistry
• 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 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.