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.

Surprising Radiolytic Stability of 8-Thiomethyladenine in an Aqueous Solution.

8-Thiomethyladenine (ASCH3), a potentially radiosensitizing modified nucleobase, has been synthesized in a reaction between 8-thioadenine and methyl iodide. Despite favorable dissociative electron attachment (DEA) characteristics, the radiolysis of an aqueous solution of ASCH3 with a dose of X-ray amounting to as much as 300 Gy leads to no effects. Nevertheless, crossed electron-molecule beam experiments in the gas phase on ASCH3 confirm the theoretical findings regarding the stability of its radical anion, namely, the most abundant reaction channel is related to the dissociation of the S-CH3 bond in the respective anion. Furthermore, electron-induced degradation of ASCH3 has been observed in aprotic acetonitrile, which is strong evidence for the involvement of proton transfer (PT) in stabilizing the radical anion in an aqueous solution. These findings demonstrate that PT in water can be the main player in deciding the radiosensitizing properties of modified nucleobases/nucleosides.

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

In the search for effective radiosensitizers for tumor cells, halogenated uracils have attracted more attention due to their large cross section for dissociation upon the attachment of low-energy electrons. In this study, we investigated dissociative electron attachment (DEA) to 5-iodo-4-thio-2'-deoxyuridine, a potential radiosensitizer using a crossed electron-molecule beam experiment coupled with quadrupole mass spectrometry. The experimental results were supported by calculations on the threshold energies of formed anions and transition state calculations. We show that low-energy electrons with kinetic energies near 0 eV may effectively decompose the molecule upon DEA. The by far most abundant anion observed corresponds to the iodine anion (I-). Due to the associated bond cleavage, a radical site is formed at the C5 position, which may initiate strand break formation if the molecule is incorporated into a DNA strand. Our results reflect the conclusion from previous radiolysis studies with the title compound, suggesting its potential as a radiosensitizer.

Electron-Induced Decomposition of 5-Bromo-4-thiouracil and 5-Bromo-4-thio-2'-deoxyuridine: The Effect of the Deoxyribose Moiety on Dissociative Electron Attachment.

When modified uridine derivatives are incorporated into DNA, radical species may form that cause DNA damage. This category of molecules has been proposed as radiosensitizers and is currently being researched. Here, we study electron attachment to 5-bromo-4-thiouracil (BrSU), a uracil derivative, and 5-bromo-4-thio-2'-deoxyuridine (BrSdU), with an attached deoxyribose moiety via the N-glycosidic (N1-C) bond. Quadrupole mass spectrometry was used to detect the anionic products of dissociative electron attachment (DEA), and the experimental results were supported by quantum chemical calculations performed at the M062X/aug-cc-pVTZ level of theory. Experimentally, we found that BrSU predominantly captures low-energy electrons with kinetic energies near 0 eV, though the abundance of bromine anions was rather low compared to a similar experiment with bromouracil. We suggest that, for this reaction channel, proton-transfer reactions in the transient negative ions limit the release of bromine anions.

Decomposition of triazole and 3-nitrotriazole upon low-energy electron attachment.

Compounds based on nitrotriazole have been studied for their application as potential radiosensitizers for the treatment of tumors and as energetic materials. In the former application, the initial reduction of the compounds may serve as a mechanism which leads to the formation of tumor-active species. In this study, we investigated the fundamental properties of anion formation in isolated 3-nitro-1,2,4-triazole (3NTR) molecules upon attachment of low-energy electrons. The resulting product anions formed were detected via mass spectrometry. Quantum chemical calculations were performed to study the dissociation pathways and to derive the threshold energies. We also studied the attachment of electrons to the native 1H-1,2,4-triazole (TR) molecule, revealing the influence of the nitro group on anion formation. Comparing the results for these two systems, we computationally observed a considerable more stable parent anion for 3NTR, which results in significantly more effective degradation of the molecule at lower electron energies. Although characteristic fragmentation reactions in the presence of the nitro group were observed (like formation of NO2- or the release of an OH radical), the main dissociation channel for the 3NTR anion turned out to be the direct dissociation of a hydrogen radical by a single bond cleavage, which we also observed for TR as the main channel. Thus, the triazole ring shows a pronounced stability against electron attachment-induced cleavage compared, for example, to the imidazole ring, which is found in common nitroimidazolic radiosensitizers.

Intramolecular Proton Transfer in the Radical Anion of Cytidine Monophosphate Sheds Light on the Sensitivities of Dry vs Wet DNA to Electron Attachment-Induced Damage.

Single-strand breaks (SSBs) induced via electron attachment were previously observed in dry DNA under ultrahigh vacuum (UHV), while hydrated electrons were found not able to induce this DNA damage in an aqueous solution. To explain these findings, crossed electron-molecular beam (CEMB) and anion photoelectron spectroscopy (aPES) experiments coupled to density functional theory (DFT) modeling were used to demonstrate the fundamental importance of proton transfer (PT) in radical anions formed via electron attachment. Three molecular systems were investigated: 5'-monophosphate of 2'-deoxycytidine (dCMPH), where PT in the electron adduct is feasible, and two ethylated derivatives, 5'-diethylphosphate and 3',5'-tetraethyldiphosphate of 2'-deoxycytidine, where PT is blocked due to substitution of labile protons with the ethyl residues. CEMB and aPES experiments confirmed the cleavage of the C3'/C5'-O bond as the main dissociation channel related to electron attachment in the ethylated derivatives. In the case of dCMPH, however, electron attachment (in the aPES experiments) yielded its parent (intact) radical anion, dCMPH-, suggesting that its dissociation was inhibited. The aPES-measured vertical detachment energy of the dCMPH- was found to be 3.27 eV, which agreed with its B3LYP/6-31++G(d,p)-calculated value and implied that electron-induced proton transfer (EIPT) had occurred during electron attachment to the dCMPH model nucleotide. In other words, EIPT, subduing dissociation, appeared to be somewhat protective against SSB. While EIPT is facilitated in solution compared to the dry environment, the above findings are consistent with the stability of DNA against hydrated electron-induced SSB in solution versus free electron-induced SSB formation in dry DNA.

Electron attachment to fluorodeoxyglucose: Dissociation dynamics in a molecule of near-zero electron affinity.

Fluorodeoxyglucose (FDG) is a glucose derivative with fluorine at the C2 position. The molecule containing the radioactive F-18 isotope is well known from its application in positron emission tomography as a radiotracer in tumor examination. In the stable form with the F-19 isotope, FDG was proposed as a potential radiosensitizer. Since reduction processes may be relevant in radiosensitization, we investigated low-energy electron attachment to FDG with a crossed electron-molecule beam experiment and with quantum chemical calculations as well as molecular dynamics at elevated temperatures to reveal statistical dissociation. We experimentally find that the susceptibility of FDG to low-energy electrons is relatively low. The calculations indicate that upon attachment of an electron with a kinetic energy of ∼0 eV, only dipole-bound states are accessible, which agrees with the weak ion yields observed in the experiment. The temporary negative ions formed upon electron attachment to FDG may decay by a large variety of dissociation reactions. The major fragmentation channels include H2O, HF, and H2 dissociation, accompanied by ring opening.

Electron Attachment to 5-Fluorouracil: The Role of Hydrogen Fluoride in Dissociation Chemistry.

We investigate dissociative electron attachment to 5-fluorouracil (5-FU) employing a crossed electron-molecular beam experiment and quantum chemical calculations. Upon the formation of the 5-FU- anion, 12 different fragmentation products are observed, the most probable dissociation channel being H loss. The parent anion, 5-FU-, is not stable on the experimental timescale (~140 µs), most probably due to the low electron affinity of FU; simple HF loss and F- formation are seen only with a rather weak abundance. The initial dynamics upon electron attachment seems to be governed by hydrogen atom pre-dissociation followed by either its full dissociation or roaming in the vicinity of the molecule, recombining eventually into the HF molecule. When the HF molecule is formed, the released energy might be used for various ring cleavage reactions. Our results show that higher yields of the fluorine anion are most probably prevented through both faster dissociation of an H atom and recombination of F- with a proton to form HF. Resonance calculations indicate that F- is formed upon shape as well as core-excited resonances.

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

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.

Stabilization of phenanthrene anions in helium nanodroplets.

It has been debated for years if the polycyclic aromatic hydrocarbon phenanthrene exists in its anionic form, or, in other words, if its electron affinity (EA) is positive or negative. In this contribution we confirm that the bare phenanthrene anion Ph- created in a binary collision with an electron at room temperature has a lifetime shorter than microseconds. However, the embedding of neutral phenanthrene molecules in negatively charged helium nanodroplets enables the formation of phenanthrene anions by charge transfer processes and the stabilization of the latter in the ultracold environment. Gentle shrinking of the helium matrix of phenanthrene-doped HNDs by collisions with helium gas makes the bare Ph- visible by high-resolution mass spectrometry. From these and previous measurements we conclude, that the EA of phenanthrene is positive and smaller than 24.55 meV.

Formation of Temporary Negative Ions and Their Subsequent Fragmentation upon Electron Attachment to CoQ0 and CoQ0 H2.

Ubiquinone molecules have a high biological relevance due to their action as electron carriers in the mitochondrial electron transport chain. Here, we studied the dissociative interaction of free electrons with CoQ0 , the smallest ubiquinone derivative with no isoprenyl units, and its fully reduced form, 2,3-dimethoxy-5-methylhydroquinone (CoQ0 H2 ), an ubiquinol derivative. The anionic products produced upon dissociative electron attachment (DEA) were detected by quadrupole mass spectrometry and studied theoretically through quantum chemical and electron scattering calculations. Despite the structural similarity of the two studied molecules, remarkably only a few DEA reactions are present for both compounds, such as abstraction of a neutral hydrogen atom or the release of a negatively charged methyl group. While the loss of a neutral methyl group represents the most abundant reaction observed in DEA to CoQ0 , this pathway is not observed for CoQ0 H2 . Instead, the loss of a neutral OH radical from the CoQ0 H2 temporary negative ion is observed as the most abundant reaction channel. Overall, this study gives insights into electron attachment properties of simple derivatives of more complex molecules found in biochemical pathways.

Electron ionization of clusters containing the formamide molecule.

Studies on electron interactions with formamide (FA) clusters promote scientific interest as a model system to understand phenomena relevant to astrophysical, prebiotic, and radiobiological processes. In this work, mass spectrometric detection of cationic species for both small bare and microhydrated formamide clusters was performed at an electron ionization of 70 eV. Furthermore, a comparative analysis of the cluster spectra with the literature-reported gas-phase spectra is presented and discussed, revealing different reaction channels affected by the cluster environment. This study is essential in developing our understanding of both low-energy electron phenomena in clusters that can bridge the complexity gap between gas and realistic systems and the effect of hydration on electron-induced processes.

Survival of polycyclic aromatic hydrocarbon knockout fragments in the interstellar medium.

Laboratory studies play a crucial role in understanding the chemical nature of the interstellar medium (ISM), but the disconnect between experimental timescales and the timescales of reactions in space can make a direct comparison between observations, laboratory, and model results difficult. Here we study the survival of reactive fragments of the polycyclic aromatic hydrocarbon (PAH) coronene, where individual C atoms have been knocked out of the molecules in hard collisions with He atoms at stellar wind and supernova shockwave velocities. Ionic fragments are stored in the DESIREE cryogenic ion-beam storage ring where we investigate their decay for up to one second. After 10 ms the initially hot stored ions have cooled enough so that spontaneous dissociation no longer takes place at a measurable rate; a majority of the fragments remain intact and will continue to do so indefinitely in isolation. Our findings show that defective PAHs formed in energetic collisions with heavy particles may survive at thermal equilibrium in the interstellar medium indefinitely, and could play an important role in the chemistry in there, due to their increased reactivity compared to intact or photo-fragmented PAHs.

Selective Bond Cleavage in RAFT Agents Promoted by Low-Energy Electron Attachment.

Radical polymerization with reversible addition-fragmentation chain transfer (RAFT polymerization) has been successfully applied to generate polymers of well-defined architecture. For RAFT polymerization a source of radicals is required. Recent work has demonstrated that for minimal side-reactions and high spatio-temporal control these should be formed directly from the RAFT agent or macroRAFT agent (usually carbonothiosulfanyl compounds) thermally, photochemically or by electrochemical reduction. In this work, we investigated low-energy electron attachment to a common RAFT agent (cyanomethyl benzodithioate), and, for comparison, a simple carbonothioylsulfanyl compound (dimethyl trithiocarbonate, DMTTC) in the gas phase by means of mass spectrometry as well as quantum chemical calculations. We observe for both compounds that specific cleavage of the C-S bond is induced upon low-energy electron attachment at electron energies close to zero eV. This applies even in the case of a poor homolytic leaving group (. CH3 in DMTTC). All other dissociation reactions found at higher electron energies are much less abundant. The present results show a high control of the chemical reactions induced by electron attachment.

Ring-Selective Fragmentation in the Tirapazamine Molecule upon Low-Energy Electron Attachment.

We investigate dissociative electron attachment to tirapazamine through a crossed electron-molecule beam experiment and quantum chemical calculations. After the electron is attached and the resulting anion reaches the first excited state, D1, we suggest a fast transition into the ground electronic state through a conical intersection with a distorted triazine ring that almost coincides with the minimum in the D1 state. Through analysis of all observed dissociative pathways producing heavier ions (90-161 u), we consider the predissociation of an OH radical with possible roaming mechanism to be the common first step. This destabilizes the triazine ring and leads to dissociation of highly stable nitrogen-containing species. The benzene ring is not altered during the process. Dissociation of small anionic fragments (NO2-, CN2-, CN-, NH2-, O-) cannot be conclusively linked to the OH predissociation mechanism; however, they again do not require dissociation of the benzene ring.

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

The incorporation of modified uracil derivatives into DNA leads to the formation of radical species that induce DNA damage. Molecules of this class have been suggested as radiosensitizers and are still under investigation. In this study, we present the results of dissociative electron attachment to uracil-5-yl O-(N,N-dimethylsulfamate) in the gas phase. We observed the formation of 10 fragment anions in the studied range of electron energies from 0-12 eV. Most of the anions were predominantly formed at the electron energy of about 0 eV. The fragmentation paths were analogous to those observed in uracil-5-yl O-sulfamate, i.e., the methylation did not affect certain bond cleavages (O-C, S-O and S-N), although relative intensities differed. The experimental results are supported by quantum chemical calculations performed at the M06-2X/aug-cc-pVTZ level of theory. Furthermore, a resonance stabilization method was used to theoretically predict the resonance positions of the fragment anions O- and CH3-.

Negative ion formation and fragmentation upon dissociative electron attachment to the nicotinamide molecule.

Nicotinamide (C6H6N2O) is a biologically relevant molecule. This compound has several important roles related to the anabolic and metabolic processes that take place in living organisms. It is also used as a radiosensitizer in tumor therapy. As a result of the interaction of high-energy radiation with matter, low-energy electrons are also released, which can also interact with other molecules, forming several types of ions. In the present investigation, dissociative electron attachment to C6H6N2O has been studied in a crossed electron-molecular beams experiment in the electron energy range of about 0-15 eV. In the experiment, six anionic species were detected: C6H5N2O-, C5H4N-, NCO-, O-/NH2 -, and CN-, with NCO- being the most prominent anion. We also provide detailed computational results regarding the energetic thresholds and pathways of the respective dissociative electron attachment (DEA) channels. The experimental results are compared with the theoretical ones and on this basis, the possible DEA reactions for the formation of anions at a given resonance energy were assigned as well as the generation of neutrals fragments such as pyridine and its several derivatives and radicals are predicted. The pyridine ring seems to stay intact during the DEA process.

Electron Attachment Studies with the Potential Radiosensitizer 2-Nitrofuran.

Nitrofurans belong to the class of drugs typically used as antibiotics or antimicrobials. The defining structural component is a furan ring with a nitro group attached. In the present investigation, electron attachment to 2-nitrofuran (C4H3NO3), which is considered as a potential radiosensitizer candidate for application in radiotherapy, has been studied in a crossed electron-molecular beams experiment. The present results indicate that low-energy electrons with kinetic energies of about 0-12 eV effectively decompose the molecule. In total, twelve fragment anions were detected within the detection limit of the apparatus, as well as the parent anion of 2-nitrofuran. One major resonance region of ≈0-5 eV is observed in which the most abundant anions NO2-, C4H3O-, and C4H3NO3- are detected. The experimental results are supported by ab initio calculations of electronic states in the resulting anion, thermochemical thresholds, connectivity between electronic states of the anion, and reactivity analysis in the hot ground state.

Reactions in Tirapazamine Induced by the Attachment of Low-Energy Electrons: Dissociation Versus Roaming of OH.

Tirapazamine (TPZ) has been tested in clinical trials on radio-chemotherapy due to its potential highly selective toxicity towards hypoxic tumor cells. It was suggested that either the hydroxyl radical or benzotriazinyl radical may form as bioactive radical after the initial reduction of TPZ in solution. In the present work, we studied low-energy electron attachment to TPZ in the gas phase and investigated the decomposition of the formed TPZ- anion by mass spectrometry. We observed the formation of the (TPZ-OH)- anion accompanied by the dissociation of the hydroxyl radical as by far the most abundant reaction pathway upon attachment of a low-energy electron. Quantum chemical calculations suggest that NH2 pyramidalization is the key reaction coordinate for the reaction dynamics upon electron attachment. We propose an OH roaming mechanism for other reaction channels observed, in competition with the OH dissociation.

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

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.