Radiation Damage Mechanisms of Chemotherapeutically Active Nitroimidazole Derived Compounds

Photoionization mass spectrometry, photoelectron-photoion coincidence spectroscopic technique, and computational methods have been combined to investigate the fragmentation of two nitroimidazole derived compounds: the metronidazole and misonidazole. These molecules are used in radiotherapy thanks to their capability to sensitize hypoxic tumor cells to radiation by “mimicking” the effects of the presence of oxygen as a damaging agent. Previous investigations of the fragmentation patterns of the nitroimidazole isomers (Bolognesi et al., 2016; Cartoni et al., 2018) have shown their capacity to produce reactive molecular species such as nitric oxide, carbon monoxide or hydrogen cyanide, and their potential impact on the biological system. The results of the present work suggest that different mechanisms are active for the more complex metronidazole and misonidazole molecules. The release of nitric oxide is hampered by the efficient formation of nitrous acid or nitrogen dioxide. Although both metronidazole and misonidazole contain imidazole ring in the backbone, the side branches of these molecules lead to very different bonding mechanisms and properties

Smart decomposition of cyclic alanine-alanine dipeptide by VUV radiation: a seed for the synthesis of biologically relevant species

A combined experimental and theoretical study shows how the interaction of VUV radiation with cyclo-(alanine-alanine), one of the 2,5-diketopiperazines (DKPs), produces reactive oxazolidinone intermediates. The theoretical simulations reveal that the interaction of these intermediates with other neutral and charged fragments, released in the molecular decomposition, leads either to the reconstruction of the cyclic dipeptide or to the formation of longer linear peptide chains. These results may explain how DKPs could have, on one hand, survived hostile chemical environments and, on the other, provided the seed for amino acid polymerization. Shedding light on the mechanisms of production of such prebiotic building blocks is of paramount importance to understanding the abiotic synthesis of relevant biologically active compoundsThis article is based upon work from COST action CA18212 - Molecular Dynamics in the GAS phase (MD-GAS), supported by COST (European Cooperation in Science and Technology). The authors acknowledge the generous allocation of computer time at the Centro de Computación Cientıfí ca at the Universidad Autonoma de Madrid (CCC-UAM). This work ́ was partially supported by MICINN (Spanish Ministry of Science and Innovation) project PID2019-110091GB-I00, the “Marıa de Maeztu ́ ” (CEX2018-000805-M) Program for Centers of Excellence in R&D, MAECI Italy-Sweden project “Novel molecular tools for the exploration of the nanoworld”, and PRIN 20173B72NB project “Predicting and controlling the fate of biomolecules driven by extreme-ultraviolet radiation”. D.B.-L. acknowledges the FPI grant associated with MICINN project CTQ2016-76061-P. H.Z. acknowledges the Swedish Research Council for the individual project grant with contract no. 2020- 0343

Photofragmentation specificity of photoionized cyclic amino acids (diketopiperazines) as precursors of peptide building blocks

The photoionisation and photofragmentation of the two cyclic dipetides cyclo(alanyl-glycine) cGA and cyclo(glycyl-glycine) cGG, have been studied combining experiments and simulations. State selected fragments from the ionized molecules are detected using photo-electron photo-ion coincidence (PEPICO) measurements and specific fragmentation paths are identified and characterized via the use of ion-neutral coincidence maps. The simulations, performed using Quantum Chemistry methods, allow us to infer the fragmentation mechanisms of the ionized and excited molecules. We show that ring opening is followed by emission of the neutral fragments CO and HNCO. In the case of cGG the emission of neutral CO leads to a metastable structure that breaks producing small cationic fragments. The studied cyclic dipeptides evolve under ionizing radiation generating different small aziridin moieties and oxazolidinones. These two species are key reactants to elongate producing peptide chains. The corresponding mechanisms have been computed and show that the reaction requires very low energy and may occur in the presence of ionizing radiationThis article is based upon work from COST action CA18212 –Molecular Dynamics in the GAS phase (MD-GAS), supported by COST (European Cooperation in Science and Technology). The authors acknowledge the generous allocation of computer time at the Centro de Computación Científica at the Universidad Autónoma de Madrid (CCC-UAM). This work was partially supported by MICINN (Spanish Ministry of Science and Innovation) project PID2019-110091GB-I00 funded by MCIN/AEI/10.13039/ 501100011033, the ‘‘María de Maeztu’’ (CEX2018-000805-M) Program for Centers of Excellence in RD, MAECI Italy-Sweden project ‘‘Novel molecular tools for the exploration of the nanoworld’’, and PRIN 20173B72NB project ‘‘Predicting and controlling the fate of bio-molecules driven by extreme-ultraviolet radiation’’. D. B.-L. acknowledges the FPI grant associated with MICINN project CTQ2016-76061-P. H. Z. acknowledges the Swedish Research Council for the individual project grant with contract no. 2020-03437. M. H. S. acknowledges the Swedish Research council (Grant no. 2016-03675) and the Carl Trygger Foundation (Grant no. 17:436

In search of universalities in the dissociative photoionization of PANHs via isomerizations

In search of the cause behind the similarities often seen in the fragmentation of PANHs, vacuum ultraviolet (VUV) photodissociation of two pairs of isomers quinoline-isoquinoline and 2-naphthylamine-3-methyl-quinoline are studied using the velocity map imaging technique. The internal energy dependence of all primary fragmentation channels is obtained for all four target molecules. The decay dynamics of the four molecules is studied by comparing their various experimental signatures. The dominant channel for the first pair of isomers is found to be hydrogen cyanide (HCN) neutral loss, while the second pair of isomers lose HCNH neutral as its dominant channel. Despite this difference in their primary decay products and the differences in the structures of the four targets, various similarities in their experimental signatures are found, which could be explained by isomerization mechanisms to common structures. The fundamental role of these isomerization in controlling different dissociative channels is explored via a detailed analysis of the experimental photoelectron-photoion coincidences and the investigation of the theoretical potential energy surface. These results add to the notion of a universal PANH fragmentation mechanism and suggests the seven member isomerization as a key candidate for this universal mechanism. The balance between isomerization, dissociation, and other key mechanistic processes in the reaction pathways, such as hydrogen migrations, is also highlighted for the four molecules

Competitive dehydrogenation and backbone fragmentation of superhydrogenated PAHs: A laboratory study

Superhydrogenated polycyclic aromatic hydrocarbons (PAHs) have been suggested to catalyze the formation of H2 in certain regions of space, but it remains unclear under which circumstances this mechanism is viable given the reduced carbon backbone stability of superhydrogenated PAHs. We report a laboratory study on the stability of the smallest pericondensed PAH, pyrene (C16H10+N , with N = 4, 6, and 16 additional H atoms), against photodestruction by single vacuum ultraviolet photons using the photoelectron-photoion coincidence technique. For N = 4, we observe a protective effect of hydrogenation against the loss of native hydrogens, in the form of an increase in the appearance energies of the and C16H8+ daughter ions compared to those reported for pristine pyrene (C16H10). No such effect is seen for N = 6 or 16, where the weakening effect of replacing aromatic bonds with aliphatic ones outweighs the buffering effect of the additional hydrogen atoms. The onset of fragmentation occurs at similar internal energies for N = 4 and 6, but is significantly lower for N = 16. In all three cases, H-loss and C m H n -loss (m ≥ 1, carbon backbone fragmentation) channels open at approximately the same energy. The branching fractions of the primary channels favor H-loss for N = 4, C m H n -loss for N = 16, and are roughly equal for the intermediate N = 6. We conclude that superhydrogenated pyrene is probably too small to support catalytic H2-formation, while trends in the current and previously reported data suggest that larger PAHs may serve as catalysts up to a certain level of hydrogenation

Electron and ion spectroscopy of Azobenzene in the valence and core shells

Azobenzene is a prototype and building block of a class of molecules of extreme technological interest as molecularphoto-switches. We present a joint experimental and theoretical study of its response to irradiation with light across theUV to X-ray spectrum. The study of valence and inner shell photo-ionization and excitation processes, combined withmeasurement of valence photoelectron-photoion coincidence (PEPICO) and of mass spectra across the core thresholdsprovides a detailed insight onto the site- and state-selected photo-induced processes. Photo-ionization and excita-tion measurements are interpreted via the multi-configurational restricted active space self-consistent field (RASSCF)method corrected by second order perturbation theory (RASPT2). Using static modelling, we demonstrate that thecarbon and nitrogen K edges of Azobenzene are suitable candidates for exploring its photoinduced dynamics thanks tothe transient signals appearing in background-free regions of the NEXAFS and XP

Autoionization from the plasmon resonance in isolated 1-cyanonaphthalene

Polycyclic aromatic hydrocarbons have widely been conjectured to be ubiquitous in space, as supported by the recent discovery of two isomers of cyanonaphthalene, indene, and 2-cyanoindene in the Taurus molecular cloud-1 using radioastronomy. Here, the photoionization dynamics of 1-cyanonaphthalene (1-CNN) are investigated using synchrotron radiation over the hν = 9.0–19.5 eV range, revealing that prompt autoionization from the plasmon resonance dominates the photophysics for hν = 11.5–16.0 eV. Minimal photo-induced dissociation, whether originating from an excited state impulsive bond rupture or through internal conversion followed by a statistical bond cleavage process, occurs over the microsecond timescale (as limited by the experimental setup). The direct photoionization cross section and photoelectron angular distributions are simulated using an ezDyson model combining Dyson orbitals with Coulomb wave photoejection. When considering these data in conjunction with recent radiative cooling measurements on 1-CNN+, which showed that cations formed with up to 5 eV of internal energy efficiently stabilize through recurrent fluorescence, we conclude that the organic backbone of 1-CNN is resilient to photodestruction by VUV and soft XUV radiation. These dynamics may prove to be a common feature for the survival of small polycyclic aromatic hydrocarbons in space, provided that the cations have a suitable electronic structure to support recurrent fluorescence

A Synchrotron Radiation Study of Nitroimidazoles and their Derivatives

Nitroimidazole derived molecules are used in radiotherapy thanks to their capability to sensitize hypoxic tumor cells to radiation by ‘mimicking’ the effects of the presence of oxygen as a damaging agent. Inthis work we present the results of a bottom-up approach, which goes from the model molecule to the real drugs used in therapy. Mass spectrometry and several spectroscopic techniques (XPS, PES, NEXAFS, PEPICO) basedon the use of synchrotron radiation have been combined with computational methods to link the electronic and geometric structure of the molecule to their functions.The investigation of the fragmentation patterns of the nitroimidazole isomers [1,2] has allowed to understand their capacity to produce reactive molecular species like nitric oxide, carbon monoxide or hydrogencyanide and their potential impact on the biological system. Guided by these results, the fragmentation mechanisms of metronidazole and misonidazole, the two radiosensitisers built on the 5-nitroimidazole and 2-nitroimidazole compounds used in therapy, as well as the 1-Methyl-5-nitroimidazole have been investigated. The results on these more complex systems suggest that different mechanisms are active. The release of nitric oxideis hampered by the efficient formation of nitrous acid or nitrogen dioxide and the long and branched tails attached to the imidazole ring increase the ring stability, providing an efficient channel for excess energy dissipation

Core shell investigation of 2-nitroimidazole

Tunability and selectivity of synchrotron radiation have been used to study the excitation and ionization of 2-nitroimidazole at the C, N, and O K-edges. The combination of a set of different measurements (X-ray photoelectron spectroscopy, near-edge photoabsorption spectroscopy, Resonant Auger electron spectroscopy, and mass spectrometry) and computational modeling have successfully disclosed local effects due to the chemical environment on both excitation/ionization and fragmentation of the molecule

VUV Photofragmentation of Chloroiodomethane: The Iso-CH2I–Cl and Iso-CH2Cl–I Radical Cation Formation

Dihalomethanes XCH2Y (X and Y= F, Cl, Br and I) are a class of compounds involved in several processes leading to the release of halogen atoms, ozone consumption and aerosol particle formation. Neutral dihalomethanes have been largely studied, but chemical physics properties and processes involving their radical ions, like the pathways of their decomposition, have not been completely investigated. In this work the photodissociation dynamics of the ClCH2I molecule has been explored in the photon energy range 9-21 eV using both VUV rare gas discharge lamps and synchrotron radiation. The experiments show that among the different fragment ions, CH2I+ and CH2Cl+, which correspond to the Cl- and I-losses, respectively, play a dominant role. The experimental ionization energy of ClCH2I and the appearance energies of the CH2I+ and CH2Cl+ ions are in agreement with the theoretical results obtained at the MP2/CCSD(T) level of theory. Computational investigations have been also performed to study the isomerization of geminal [ClCH2I].+ into the iso-chloroiodomethane isomers: [CH2I-Cl].+ and [CH2Cl-I].+