**4.3. Radiosensitizers**

simultaneous formation of new bonds. Therefore, the mechanism of DEA to sugars near 0 eV is not fully understood. It is however proposed to occur via the formation of a "shape" resonance. In a sugar molecule, the extra orbital can be a σ\* orbital of the O–H bond. As was observed for alcohols [52], the σ\* orbital of the hydroxyl group for the dehydrogenation channels appears at higher energy for simple alcohols than for cyclic alcohols. Moreover, it was found that larger numbers of hydroxyl groups present in a molecule could enhance the dissociation of an O–H bond, by decreasing the energy of the thermodynamic threshold. This mechanism has been suggested for 2‐deoxy‐D‐ribose and D‐ribose, which contain three and four hydroxyl groups, respectively [2]. In addition, experiments with the ribose analogs tetrahydrofuran and 3‐hydroxytetrahydrofuran showed that DEA cross sections were greatly enhanced by the presence of OH groups [50]. However, for alcohols, their molecular dissoci‐ ation involved simple bond cleavage, while in sugars, fragmentation of several different bonds occurs. One of the proposed models for sugar dissociation was provided from ab initio calculations of VFRs formed initially by a dipole‐bound state of sugar due to a large dipole moment [53]. Other quantum chemical calculations confirmed this model, showing that the sugar ring can convert into an open chain by intramolecular charge transfer. This mechanism can lead to dissociation by loss of a water molecule, assuming that the barrier for such a transfer is sufficiently low [54]. It was also calculated through quantum dynamics scattering theory that the formation of shape resonances for D‐ribose is excluded at low energies, but they can

In the case of thymidine, in which sugar is covalently bound to thymine, the DEA study showed two resonant structures (**Figure 3b**) [45]. The one at lower energy was associated with a reaction in which the excess electron is initially localized in the sugar moiety, leading to the glycosidic bond cleavage. The second resonance was attributed to a reaction in which the excess electron was localized on the thymine moiety, resulting in the loss of a neutral H atom from the N3 site, as was mentioned for thymine. Since nucleosides can be easily decomposed due to the elevated temperatures necessary for evaporating samples, no experimental data for other gas‐phase nucleosides or nucleotides are reported, besides those for thymidine [45],

Similarly, due to experimental difficulties, the phosphate group in the gas phase could not easily be investigated as an isolated compound. Its simplest analog, H3PO4 (phosphoric acid), is not easily vaporized for gas‐phase experiments or molecular deposition for thin film experiments [11]. Therefore, to understand the DEA process within the phosphate group, several compounds involving phosphoric acid derivatives, for example, dibutylphosphate and triethylphosphate [57], were examined. DEA to these compounds lead to P–O and C–O bond cleavages, which correspond to a direct single‐strand break. As for sugars, many fragmentation channels occurred close to 0 eV; however, these low‐energy channels are most likely driven by the large electron affinity of PO3 (4.95 eV). The cross sections for DEA to the sugar and phosphate group analogs were relatively small, that is, about one magnitude lower than those for nucleobases [50]. These gas‐phase results on sugars and phosphate units revealed that LEE attachment can induce single‐strand breaks by electron localization either on the sugar moiety

followed by the electron transfer to the backbone or directly on the phosphate group.

be formed at higher energies [55].

190 Radiation Effects in Materials

cytidine [56], and 2‐deoxycytidine 5‐monophosphate [56].

An important characteristic of many current and potential radiosensitizers used in radiother‐ apy (or potential ones) is a high cross section for DEA. Since halogenated pyrimidines, mainly substituted uracil derivatives, exhibit high sensitivity to electron attachment and a rich fragmentation pattern from DEA, they have attracted considerable interest as radiosensitizers. From a medical point of view, the substitution of pyrimidines in the genetic sequence of cellular DNA does not affect the gene expression, and additionally enhances the sensitivity of living cells to radiation. A large number of gas‐phase experimental and theoretical studies of several halogenated pyrimidines (e.g., 5‐bromouracil [58–63], 5‐chlorouracil [58, 59, 61, 64, 65], 5‐ fluorouracil [58, 59, 61, 65], 5‐iodouracil [59, 62], 6‐chlorouracil [58,66]) were performed in recent years and report orders of magnitude of higher cross sections for DEA relative to their nonsubstituted precursors. Further to the DEA studies, other electron spectroscopic techniques and theoretical calculations at the ab initio and density functional theory levels were utilized to characterize electronic structure and reveal the fragmentation mechanisms of halogenated pyrimidines [67]. These studies elucidated the energies of vertical transitions to π\* and σ\* orbitals, showing that the ground TMA state of pyrimidine with the additional π\* electron is a few tens of eV more unstable than the neutral ground state, whereas the vertical electron affnities of the halogenated derivatives were found to lie close to 0 eV. Moreover, DEA studies revealed that the lowest π\* anion states of the halogenated pyrimidines follow similar fragmentation channels, resulting in the formation of the halide fragment anion. These studies also revealed that the total anion yields for bromopyrimidine were much larger than those measured for the chloro‐derivatives. These results indicate that bromopyrimidines carry the greatest potential as radiosensitizers for damage by SEs, which, via DEA to bromo‐substituted DNA, will enhance radiation‐induced damage to the cell. Recently, gas‐phase DEA studies on halogenated purines (e.g., chloroadenine [68]) and fluorinated nucleosides (2‐deoxy‐5‐ fluorocytidine and 2,2‐difluorocytidine (gemcitabine) [69]) have been initiated to determine in what ways their radiosensitizing properties are derived from LEE‐driven chemistry.

In addition to the halogenated nucleobases, several aromatic compounds containing nitro groups have been recently investigated in the gas phase. For instance, DEA studies performed for 5‐nitrouracil showed the formation of a long‐lived parent anion, as well as a rich fragmen‐ tation pattern via formation of either "shape" or "core‐excited" resonances at low electron energies [70, 71]. The properties of 5‐nitrouracil showed a radiosensitizing nature similar to that of the halogenated pyrimidines. Interestingly, while in the case of halogenated pyrimi‐ dines, the most dominant fragment formed was a halide anion, that for 5‐nitrouracil is an anion of the pyrimidine without a nitro group. Therefore, the counterpart fragment of this dissoci‐ ation channel is the formation of the NO2 radical, which is formed in close vicinity to DNA and can lead to the activation of lethal cluster damage in living cells.

There is also a great potential for other nitro‐containing compounds such as nitroimidazolic compounds to be used in radiotherapy, since LEEs effectively induce their dissociation [72, 73]. Similarly, their decomposition via DEA involves a range of unimolecular fragmentation channels from simgle‐bond cleavages to complex reactions, possibly leading to a complete degradation of the target molecule. However, these studies revealed that the entire rich chemistry induced by DEA was completely suppressed by methylation in the electron energy range below 2 eV.

In recent years, platinum‐based drugs were also investigated regarding their decomposition by LEEs. It was suggested that in concomitant treatment in which chemotherapeutic drugs and radiotherapy are combined, one possible mechanism responsible for the observed synergy between treatments is the enhancement in the number of secondary species induced by primary radiation in the vicinity of the binding site of the platinum compounds in DNA (see Section 8). The gas‐phase DEA studies of PtBr<sup>2</sup> in the electron energy range between 0 and 10 eV showed the formation of the Br anion via two possible channels. The most dominant channels were assigned to the Br‾ + PtBr dissociation limit reached at ∼1 eV and the higher energy channel to Br‾ + Pt + Br [74].

The observation that all these radiosenisitizers exhibit DEA with high effciency, even close to 0 eV, may have significant implications for the development and use of these drugs in tumor radiation therapy. Considering their use as radiosensitizers, their fragmentation and the resulting generation of radicals at very low electron energies may be a key in understanding their action and the molecular mechanisms necessary to improve radiotherapy.
