Uracil-5-yl O-Sulfamate: An Illusive Radiosensitizer. Pitfalls in Modeling the Radiosensitizing Derivatives of Nucleobases

Abstract

Efficient radiotherapy requires the concomitant use of ionizing radiation (IR) and a radiosensitizer. In the present work uracil-5-yl O -sulfamate (SU) is tested against its radiosensitizing potential. The compound possesses appropriate dissociative electron attachment (DEA) characteristics calculated at the M06-2X/6-31++G(d,p) level. Crossed electron–molecular beam experiments in the gas phase demonstrate that SU undergoes efficient DEA processes, and the single C–O or S–O bond dissociations account for the majority of fragments induced by electron attachment. Most DEAs proceed already for electrons with kinetic energies of ∼0 eV, which is supported by the exothermic thresholds calculated at the M06-2X/aug-cc-pVTZ level. However, in water solution under reductive conditions and physiological pH, SU does not undergo radiolysis, which demonstrates the crucial influence of aqueous environment on the radiosensitizing properties of modified nucleosides.

Electron-Induced Decomposition of Uracil-5-yl O-(N,N-dimethylsulfamate): Role of Methylation in Molecular Stability

“…For 127 u, we obtained a sharp peak at ~0 eV, another resonance at 0.3 eV and a broad resonance around 1.3 eV. Similar resonance positions were observed upon DEA to SU [ 22 ], indicating that the presence of methyl groups does not interfere with the anion formation processes. The adiabatic electron affinity (AEA) of UO was determined to be 2.40 eV which is close to 2.38 eV predicted in the case of OTfU [ 21 ].…”

“…Rak and co-workers have suggested several 5-substituted pyrimidine derivatives as potential radiosensitizers of hypoxic cells. These molecules comprise 5-trifluoromethanesulfonyl-uracil (OTfU), uracil-5-yl O -sulfamate (SU) and 5-selenocyanatouracil (SeCNU), and have been studied both theoretically and experimentally through stationary radiolysis in an aqueous solution and crossed electron-molecular beam (CEMB) experiments in the gas phase [ 21 , 22 , 23 ]. While SeCNU and OTfU could work as potential radiosensitizers, SU was dubbed an “illusive radiosensitizer” which, contrary to expectations, is not prone to the DEA process in water [ 22 ].…”

“…The recent DEA studies with SU ( Figure 1 a) demonstrated low-energy electron-induced decomposition yielding various anionic and radical products due to simple and complex fragmentation pathways upon electron attachment to SU in the gas phase [ 22 ]. The results of the CEMB experiments were supported by quantum chemical calculations, which justified the assumed pathways of the DEA processes.…”

“…The results of the CEMB experiments were supported by quantum chemical calculations, which justified the assumed pathways of the DEA processes. However, steady-state radiolysis in water shows that these DEA channels are quenched irrespectively of pH or incident radiation dose, demonstrating unexpected stability of SU against electron attachment in an aqueous solution [ 22 ]. These findings highlighted the limitations of the methodology used to determine whether the molecule under investigation can be classified as a radiosensitizer.…”

“…We synthesized the dimethyl derivative of SU, since introducing methyl groups into the molecular structure of SU allows us to examine whether methylation influences the dynamics of DEA. Moreover, the O — and NH 2 — fragment anions might form in the CEMB experiments for SU carried out recently [ 22 ]. The mass resolution of the mass spectrometer utilized did not allow differentiation between these isobaric species.…”