title: 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 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.
authors.affiliation: Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland. janusz.rak@ug.edu.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zdrowowicz
authors.forename: Lidia
authors.initials: L
authors.lastname: Chomicz
authors.forename: Michał
authors.initials: M
authors.lastname: Żyndul
authors.forename: Paweł
authors.initials: P
authors.lastname: Wityk
authors.forename: Janusz
authors.initials: J
authors.lastname: Rak
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Wiegand
authors.forename: Cameron G
authors.initials: CG
authors.lastname: Hanson
authors.forename: Amitava
authors.initials: A
authors.lastname: Adhikary
authors.forename: Michael D
authors.initials: MD
authors.lastname: Sevilla
mesh_terms: D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D019281:Dimerization; D004583:Electrons; D005609:Free Radicals / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D011789:Quantum Theory; D014498:Uracil / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C000605897:5-thiocyanato-2'-deoxyuridine; D005609:Free Radicals; D014498:Uracil; D003857:Deoxyuridine