Low-Energy Electron Induced Reactions in Metronidazole at Different Solvation Conditions

Abstract

Metronidazole belongs to the class of nitroimidazole molecules and has been considered as a potential radiosensitizer for radiation therapy. During the irradiation of biological tissue, secondary electrons are released that may interact with molecules of the surrounding environment. Here, we present a study of electron attachment to metronidazole that aims to investigate possible reactions in the molecule upon anion formation. Another purpose is to elucidate the effect of microhydration on electron-induced reactions in metronidazole. We use two crossed electron/molecular beam devices with the mass-spectrometric analysis of formed anions. The experiments are supported by quantum chemical calculations on thermodynamic properties such as electron affinities and thresholds of anion formation. For the single molecule, as well as the microhydrated condition, we observe the parent radical anion as the most abundant product anion upon electron attachment. A variety of fragment anions are observed for the isolated molecule, with NO2− as the most abundant fragment species. NO2− and all other fragment anions except weakly abundant OH− are quenched upon microhydration. The relative abundances suggest the parent radical anion of metronidazole as a biologically relevant species after the physicochemical stage of radiation damage. We also conclude from the present results that metronidazole is highly susceptible to low-energy electrons.

Observation of Transient Anions That Do Not Decay through Dissociative Electron Attachment: New Pathways for Radiosensitization

“…The level of agreement between the experiment and the IAM-SCAR+I calculations is excellent at higher energies but no longer holds below ∼15 eV (not shown), where the IAM-SCAR+I method cannot provide reliable cross sections. ,, Even so, it is worth mentioning the good matching at around 15 eV between the SMC and the (elastic) IAM-SCAR+I results. Finally, the TCS for 1M5NI lies around 10 –18 m 2 at the lower energies (∼1 eV), which is on the same order of magnitude as the associative electron attachment cross sections reported for metronidazole (3.6 × 10 –18 m 2 ) and nimorazole (2.8 × 10 –18 m 2 ) close to 0 eV. Despite the different impact energies, systems, and processes, this comparison helps to put the latter cross sections in perspective, highlighting the relevance of associative attachment for metronidazole and nimorazole.…”

“…While DEA is believed to make a major contribution to the understanding of radiosensitivity, − our results point out neutral dissociation through catalytic electrons as a new pathway for radiosensitization. In particular, this pathway represents an alternative radiosensitizing mechanism for nitroimidazolic radiosensitizers, which could play a role similarly important to that of the previously proposed associative attachment (for nimorazole and metronidazole) and DEA (for smaller NIs − ) electron-induced processes. Detection of neutral fragments remains one of the main experimental challenges in the field of electron–molecule interactions, and we expect our contribution will further encourage the community into looking at this missing puzzle. , Our results also shed new light on the transient anions and dissociation pathways of 1M5NI below 4 eV and on the effect of methylation in suppressing DEA reactions between 4 and 6 eV.…”

“…Nitroimidazoles (NIs) comprise one of the main classes of candidate radiosensitizers under investigation, in view of their high electron affinities. , The most studied NIs are nimorazole, metronidazole, and misonidazole, the first one being currently employed to treat some types of carcinomas in Denmark . Their radiosensitizing effect is believed to stem from the action of low-energy electrons, which would produce reactive species when interacting with the NIs. − Specifically, DEA reactions have been suggested to be the most relevant underlying process for smaller NIs. − More recently, however, the radiosensitivity of nimorazole and metronidazole has been linked to the formation of the nondecomposed anion via associative electron attachment. Here we put forward a new route for the radiosensitization of NIs, based on the production of neutral fragments via the action of catalytic electrons.…”

“…It is also worth mentioning that NIs have been proposed as potential candidates for high-energy materials − due to their high heats of formation . These aspects have motivated several studies on the decomposition of NIs upon collisions with different projectiles. − ,− Of major relevance to the study presented here, Tanzer et al , carried out two experimental investigations of DEA to 4(5)-nitroimidazole [4(5)­NI] and its methylated derivatives, 1-methyl-5-nitroimidazole (1M5NI) and 1-methyl-4-nitroimidazole (1M4NI), and obtained the ion yields as a function of the electron impact energy. Several fragment anions were detected between 2 and 6 eV, for the three molecules, despite some differences in their fragmentation pattern.…”

Dissociative Electron Attachment to 5-Iodo-4-thio-2′-deoxyuridine: A Potential Radiosensitizer of Hypoxic Cells

“…In recent years, investigations with isolated or microhydrated DNA constituents in the gas phase substantially contributed to the understanding of the dynamics of electron attachment to biomolecular systems. − This knowledge is also essential in the search for new molecules, which should enhance the effects of ionizing radiation in tumor cells. − Such so-called radiosensitizers may be designed so that they are particularly prone to low-energy electron attachment. , DEA could be then a mechanism that is exploited for the generation of species (like free radicals) damaging the DNA in tumor cells. − To study the basic electron attachment properties of potential radiosensitizers, crossed electron-molecule beam (CEMB) experiments were carried out. − There was early interest in DEA to halogenated uracils . The incorporation of these modified uracils into native DNA should enhance radiation-induced cell killing due to their strong electrophilic properties and low cytotoxicity toward cancer and normal cells …”