Dissociative Electron Attachment Dynamics of a Promising Cancer Drug Indicates Its Radiosensitizing Potential.

2-Bromo-1-(3,3-dinitroazetidin-1-yl)ethan-1-one (RRx-001) is a hypoxic cell chemotherapeutics with already demonstrated synergism in combined chemo-radiation therapy. The interaction of the compound with secondary low-energy electrons formed in large amounts during the physico-chemical phase of the irradiation may lead to these synergistic effects. The present study focuses on the first step of RRx-001 interaction with low-energy electrons in which a transient anion is formed and fragmented. Combination of two experiments allows us to disentangle the decay of the RRx-001 anion on different timescales. Sole presence of the electron initiates rapid dissociation of NO2 and HNO2 neutrals while NO2- and Br- anions are produced both directly and via intermediate complexes. Based on our quantum chemical calculations, we propose that bidirectional intersystem crossing between π*(NO2) and σ*(C-Br) states explains the experimental spectra. The fast dynamics monitored will impact the condensed phase chemistry of the anion as well.

Interaction of low-energy electrons with radiosensitizers.

We provide an experimentalist's perspective on the present state-of-the-art in the studies of low-energy electron interactions with common radiosensitizers, including compounds used in combined chemo-radiation therapy and their model systems. Low-energy electrons are important secondary species formed during the interaction of ionizing radiation with matter. Their role in the radiation chemistry of living organisms has become an important topic for more than 20 years. With the increasing number of works and reviews in the field, we would like to focus here on a very narrow area of compounds that have been shown to have radio-sensitizing properties on the one hand, and high reactivity towards low-energy electrons on the other hand. Gas phase experiments studying electron attachment to isolated molecules and environmental effects on reaction dynamics are reviewed for modified DNA components, nitroimidazoles, and organometallics. In the end, we provide a perspective on the future directions that may be important for transferring the fundamental knowledge about the processes induced by low-energy electrons into practice in the field of rational design of agents for concomitant chemo-radiation therapy.

Electron attachment to microhydrated 4-nitro- and 4-bromo-thiophenol.

We investigate the effect of microhydration on electron attachment to thiophenols with halogen (Br) and nitro (NO2) functional groups in the para position. We focus on the formation of anions upon the attachment of low-energy electrons with energies below 8 eV to heterogeneous clusters of the thiophenols with water. For nitro-thiophenol (NTP), the primary reaction channel observed is the associative electron attachment, irrespective of the microhydration. On the other hand, bromothiophenol (BTP) fragments significantly upon the electron attachment, producing Br- and (BTP-H)- anions. Microhydration suppresses fragmentation of both molecules, however in bromothiophenol, the Br- channel remains intense and Br(H2O)n- hydrated fragment clusters are observed. The results are supported by the reaction energetics obtained from ab initio calculations. Different dissociation dynamics of NTP and BTP can be related to different products of their plasmon induced reactions on Au nanoparticles. Computational modeling of the simplified BTP(H2O) system indicates that the electron attachment products reflect the structure of neutral precursor clusters - the anion dissociation dynamics is controlled by the hydration site.

Electron attachment to isolated and microhydrated favipiravir.

Electron attachment and its equivalent in complex environments, single-electron reduction, are important in many biological processes. Here, we experimentally study the electron attachment to favipiravir, a well-known antiviral agent. Electron attachment spectroscopy is used to explore the energetics of associative (AEA) and dissociative (DEA) electron attachment to isolated favipiravir. AEA dominates the interaction and the yields of the fragment anions after DEA are an order of magnitude lower than that of the parent anion. DEA primary proceeds via decomposition of the CONH2 functional group, which is supported by reaction threshold calculations using ab initio methods. Mass spectrometry of small favipiravir-water clusters demonstrates that a lot of energy is transferred to the solvent upon electron attachment. The energy gained upon electron attachment, and the high stability of the parent anion were previously suggested as important properties for the action of several electron-affinic radiosensitizers. If any of these mechanisms cause synergism in chemo-radiation therapy, favipiravir could be repurposed as a radiosensitizer.

Electron Attachment to Microhydrated Deoxycytidine Monophosphate.

DNA constituents are effectively decomposed via dissociative electron attachment (DEA). However, the DEA contribution to radiation damage in living tissues is a subject of ongoing discussion. We address an essential question, how aqueous environment influences the DEA to DNA. In particular, we report experimental fragmentation patterns for DEA to microhydrated 2-deoxycytidine 5-monophosphate (dCMP). Isolated dCMP was previously set as a model to describe mechanisms of DNA-strand breaks induced by secondary electrons and decomposes primarily by dissociation of the C-O phosphoester bond. We show that hydrated molecules decompose via dissociation of the C-N glycosidic bond followed by dissociation of the P-O bond. This significant change of the proposed mechanism can be interpreted by a reactive role of water in the postattachment dynamics. Comparison of the fragmentation with previous macroscopic irradiation studies suggests that the actual contribution of DEA to DNA radiation damage in living tissue is rather small.