Controlling NO Production Upon Valence Ionization of Nitroimidazoles

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Controlling NO Production Upon Valence Ionization of Nitroimidazoles Eero Itälä, Hanna Myllynen, Johannes Niskanen, Jesús GonzálezVázquez, Yang Wang, Dang Trinh Ha, Stephan Paul Denifl, and Edwin Kukk J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b11342 • Publication Date (Web): 26 Feb 2019 Downloaded from http://pubs.acs.org on March 5, 2019

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The Journal of Physical Chemistry

Controlling NO Production Upon Valence Ionization of Nitroimidazoles Eero Itälä,∗,† Hanna Myllynen,† Johannes Niskanen,† Jesús González-Vázquez,‡ Yang Wang,‡ Dang Trinh Ha,† Stephan Denifl,¶ and Edwin Kukk† †Department of Physics and Astronomy, University of Turku, FI-20014, Finland ‡Departamento de Qu´ımica, Módulo 13, Universidad Autónoma de Madrid, 28049 Madrid, Spain ¶Institut f¨ ur Ionenphysik und Angewandte Physik and Center of Molecular Biosciences, Leopold Franzens Universität Innsbruck, Technikerstrasse 25, 6020 Innsbruck (Austria) E-mail: ersita.utu.fi

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Abstract Nitroimidazole exhibits a remarkable regio-selective fragmentation subsequent to valence ionization, which is characterized by ejection of NO. As NO is also considered to be an effective radiosensitizer, we investigated its production efficiency as a function of isomeric composition (the site of the NO2 nitro group). We observe strong dependence in the 8.6–15 eV binding energy range, and moreover, that the production of NO can be effectively suppressed by methylation of nitroimidazole. This behaviour can be understood by modification of the valence electronic structure with respect to the dissociation threshold, which gives rise to varying effective density of dissociative states. We find the NO yield to follow the efficiency of the nitroimidazole dervivatives as radiosensitizers, found in pre-clinical studies.

Introduction Nitroimidazoles (NIZs) have recently attracted keen attention from several research groups focusing on molecular fragmentation induced by ionizing radiation. 1–5 The main reason for such attention is the clinical success in using nitroimidazoles to improve the effects of radiation therapy. 6–8 The major contribution of the damage inflicted by ionizing radiation is caused indirectly by reactive species such as (OH·) formed via the radiolysis of water molecules. These species form radicals when reacting with DNA; in an environment where free oxygen is present (aerobic environment), the oxygen falsely repairs the damaged DNA, making the repaired DNA function improperly (oxygen fixation hypothesis 9,10 ). Under hypoxia (oxygen depletion), this radical formation is suppressed and DNA crosslink-repair is possible – thus the survival rate of the tumor cells is increased. To increase the oxygen levels using pure oxygen has proven to be very problematic. Actively respiring cells constantly consume oxygen and the distance to the malignant tumors significantly limit the oxygen diffusion. This has led to the development of oxygen mimics, compounds that match the chemical characteristics of molecular oxygen but are better trans2


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ported to the tumors. A rule of thumb for a potential oxygen mimetic is that it is sufficiently non-toxic and electron-affinic (so that they pair efficiently with damaged DNA). Probably the most common and well-studied oxygen mimetics are nitroimidazoles. In addition to the high electron affinity, nitroimidazoles also contain nitric oxide (NO), a compound that has been estimated to be an even more effective radiosensitizer than oxygen. 11 Despite promising results on nitroimidazolic compounds in radiosensitization, the exact mechanisms of how nitroimidazoles act as radiosensitizers is not fully understood. It has been suggested thahen subjected to ionizing radiation, nitroimidazoles generate radicals such as OH that react with their surroundings (DNA), damaging it and thus enhancing the damaging effect of the ionizing radiation. This hypothesis is supported by the electron attachment studies on several nitroimidazoles by Tanzer et al. 1 Another hypothesis, on which the development of nitroimidazole-based radiosensitizers has largely been based, is that (under hypoxic conditions) nitroimidazoles mimic the action of oxygen, falsely repairing the DNA damage inflicted by the ionizing radiation (cf. the oxygen fixation hypothesis). However, several recent studies on isolated nitroimidazoles suggest that the enhancement would rather be due to the fragments of nitroimidazoles, such as NO, formed during the irradiation. 2,4,12,13 We present here a combined experimental and theoretical study of three valence-ionized

Figure 1: The skeletal formulas of the studied samples, 2-nitroimidazole (a), 4-nitroimidazole (b), 5-nitroimidazole (c) and 1-methyl-5-nitroimidazole (d). The 4-nitroimidazole isomerizes to its 5-nitroimidazole form upon sublimation, which leads to the mixture of the two isomers with the ratio of 1:0.70 for 4-nitroimidazole and 5-nitroimidazole vapors respectively. 3 3



nitroimidazole isomers and a methylated nitroimidazole (MeNIZ), shown in Figure 1. Although only 2- and 4-NIZ appear in the condensed form, 4-NIZ isomerizes to the 5-NIZ form upon evaporation. 3 There are several previous studies of these compounds connected to the subject; regarding the ionization of nitroimidazle by electron or ion collision, Feketeova et al. reported that the fragmentation following the collision characteristically involves the formation of NO. 2 Similarly, Bolognesi et al. suggested that the fragmentation of nitroimidazole following valence photoionization universally involves the ejection of NO (or NO+ ). 4,5 NO production (as neutral or cation) has also been found to govern the fragmentation of nitroimidazole following core ionization by X-rays. 12 In addition, the same study revealed that methylation efficiently quenches the NO production. Thus, we set out to investigate how methylation alters the NO production following valence ionization of nitroimidazole and what is the role of the initial site of the nitro (NO2 ) group. This information is also useful from the viewpoint of radiation therapy due to the radiosensitizing properties of nitric oxide. The ability to control the NO concentration within tumour cells could therefore be very beneficial. Although valence ionization by electrons is more relevant in the context of radiation damage (secondary electrons capable of valence ionization are created in large numbers e.g. during medical X-ray irradiation), we have utilized 21.2 eV photons to induce the valence ionization. This much more selective process makes it possible to conduct photoelectronphotoion coincidence (PEPICO) measurements. In PEPICO, 14–18 the sample is irradiated with ionizing radiation and the resulting photoelectrons and photoions originating from the same ionization event are detected. The detected electrons and ions carry information about the electronic structure and the fragmentation of the studied sample. In a sense, when using PEPICO, one records an electron spectrum for each fragmentation process. As the electron spectrum represents the electronic structure of a compound, PEPICO technique allows one to connect individual cationic states with specific ion fragments and to study the effects (such as fragmentation) of certain changes in the studied compounds electronic structure. This

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is not possible with electron ionization, due to the indeterminate energy sharing in electron scattering. However, the intramolecular processes following valence ionization induced by electrons or photons are the same, so the results obtained using photons are as relevant as those obtained with electrons.

Methods Experiment The measurements were carried out using a PEPICO setup described in detail elsewhere. 19,20 Briefly, the setup consists of a Wiley-McLaren type linear ion time of flight (TOF) spectrometer and a hemispherical electron energy analyzer. The ion TOF spectrometer was operated under Wiley-McLaren conditions, applying -727 V potential to the drift tube and ±100 V to the ion extraction grids. The electron analyzer was operated at 50 eV pass energy using 1 mm entrance slit (which corresponds to a resolution of approximately 200 meV) and tuned to capture the kinetic energy window from 5 to 13 eV. The electron energy scale was calibrated using the Ar 3p photoline as in Ref. 21 The 21.2 eV photons used to ionize the sample were created with a gas discharge lamp using helium. The samples (purchased from Sigma Aldrich, stated purity ≥99%) were introduce into the ionization chamber using an effusion cell. The heating temperature was kept at around 90◦ C for 2-NIZ and 120◦ C for 4-NIZ (keep in mind that 4-NIZ isomerizes to 5-NIZ during evaporation resulting in a mixture of 4-NIZ and 5-NIZ gases 3 ). MeNIZ sublimated sufficiently without any further heating.

Theory To understand the fragmentation of NIZ and MeNIZ upon single-photon ionization, we performed calculations for the three NIZ isomers and MeNIZ using the GAMESS program 22 with the 6-311++G** basis set. 23 First, we focused on dissociation energetics by using geometry optimization to locate the most relevant stationary points (and their energies) of the 5



neutral and cationic ground states. The implicit assumption made here is that rapid conversion to the cationic ground state takes place after ionization. For these calculations we used mono-referencial perturbation theory: MP2 for the neutral species and restricted-open-shell MP2 for the cationic ones. Next, we turned to the cationic states that form the photoelectron spectrum by calculating electronic Density of States (DOS) in the ground state using density functional theory (DFT) and the M06-2X 24 functional. For easier comparison with the experiment, the obtained delta-peak spectra were convoluted with a Gaussian lineshape of 0.5 eV full-width-at-half-maximum (FWHM). This procedure accounts for the vibrational lineshape in an ad hoc fashion.

Results and discussion The mass spectra of 2-NIZ, 4(5)-NIZ, including both 4-NIZ and 5-NIZ isomers, and MeNIZ are presented in Figure 2. One should note that as the mass spectra correspond the binding energy (BE) range of 8.6-15 eV, the spectra also contain background signal from e.g. H2 O (M=18 amu) and N2 (M=28 amu). As the fragmentation of different NIZ isomers following valence photoionization and the dependence of the fragmentation on the isomeric composition of NIZ have been studied in detail earlier, 4,5 we concentrate here on neutral and charged NO release. We focus on the dependence on the isomeric composition of NIZ and furthermore, on methylation. The fragmentation of NIZ is characterized by neutral or cationic NO ejection (processes (1) and (2)) that begins to take place when a valence hole is created in the 11–12 eV BE regime. 3 Depending on the initial site of the nitro group, NO release is followed by further dissociation either very rapidly or in a longer timescale comparable to (M-NO)+ ion’s flight time. This further fragmentation (theoretical basis of which has been studied in detail e.g. in Refs 2,4 )

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Figure 2: Mass spectra of 2-NIZ (black), 4(5)-NIZ (red) and MeNIZ (blue) measured in coincidence with 8.6-15 eV BE photoelectrons. The parent ion (referred as M+ ) mass peaks at 113 u and 127 u are normalized to equal intensity. Those ionic fragments not involving the NO release are labeled in gray and those presented in brackets originate from residual gas. produces the light fragments labeled in black in Figure 2.

M + hν → e− + M+ → (M − NO)+ + NO

(1)

M + hν → e− + M+ → (M − NO) + NO+

(2)

The (M-NO)+ cation has different survival time depending on the initial site of the nitro group Let us assume that NO ejection from MeNIZ also follows the processes (1) and (2) and results from a valence hole in the 11-12 eV BE regime. This assumption is supported by the calculations (further discussion of which is given later in text and e.g. in Fig. 5) which place the NO ejection from MeNIZ within 11-12 eV regime. Now we can identify those fragments of MeNIZ that involve NO ejection. For example, the 42 u fragment would follow a fragmentation pathway

M+ → NO + (M−NO)+ → NO + C2 HNO + C2 H4 N+ 7



if the 42 u fragment appeared when the valence hole is created within the 11-12 eV regime. As (see Figure 3) this is the case, we conclude that C2 H4 N+ really follows the suggested pathway.

Figure 3: Yield curves of the ion fragments following the ionization of MeNIZ as a function of BE. The curves are labeled with mass numbers that correspond to the mass peaks of MeNIZ in Fig. 1. Correspondingly, 54 u fragment (C3 H4 N+ ) could follow a fragmentation pathway M+ → NO + (M−NO)+ → NO + CHNO + C3 H4 N+ .

Now, as the 54 u fragment only appears when the valence hole is created clearly above the 13 eV, we conclude that the fragmentation does not involve NO ejection and cannot follow the suggested pathway. In fact, we believe that it is more likely that 54 u fragment involves NO2 ejection and follows a similar fragmentation pathway than NIZ’s C2 H2 N+ . 5 This kind of reasoning leads to a conclusion that in addition to the obvious (M−NO)+ , the only fragment of MeNIZ involving NO ejection is C2 H4 N+ . However, there is also a very weak fragmentation channel producing (M−OH)+ (at 110 u), which is connected to the same BE regime as NO release (11-12 eV). Thus, it is possible that the 42 u fragment of MeNIZ is not solely C2 H4 N+ , but can correspond also to CNO+ for example. Regardless of this, 8


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if one now looks at the spectra of Figure 2, it is evident that the NO (or NO+ ) release rate depends on the initial site of the nitro group and methylation; the key difference is the combined intensity of the black-labeled fragments. To get a clear picture of the NO and (NO+ ) production in the studied samples, we look at the electronic-state-dependence shown in Figure 4. The Figure presents the NO and NO+ yields (random background subtracted) from the three sample gases as a function of the BE of the coincident electrons. The yield curves are produced by summing the coincident ion yields of those fragments involving NO ejection (those fragments labeled black in Fig. 2) and then normalized with respect to the parent ion yield (M+ in the spectrum of Fig. 2). The normalization removes the possible intensity variations caused eg. by different ionization cross-sections, beam density of the effusive beam or the light intensity. One should note that + although HNCH+ and N+ 2 have the same mass (28 u), N2 peaks around 15.6 eV, which is

clearly beyond the 11–12 eV range.

Figure 4: Yields of NO and NO+ following the ionization of 2-NIZ, 4(5)-NIZ and 1Me5NIZ as function of electron binding energy. The yield curves have been normalized with respect to the parent ion yield. Thus the intensity scale is given with respect to the parent ion yield. The most obvious observation from the Figure 4 is that methylation suppresses the NO production very efficiently while the NO+ yield is inhibited altogether. In addition 9



to methylation, also the initial site of the nitro group has a notable effect: in 2-NIZ the NO yield is about 50% higher than in 4(5)-NIZ whereas the NO+ yield is about three times higher in 2-NIZ than in 4(5)-NIZ. Next, we turn to systematic explanation of the observed phenomena. Figure 5 presents the energy level diagrams of the processes (1) and (2) with energy values relative to the neutral ground state. On left, the diagrams show the cationic state in the neutral ground state geometry, which relaxes to the charged ground state geometry. From this geometry, the fragmentation of the parent ion then proceeds via the transition state (TS) and intermediate state (IM) to the neutral or cationic NO release. As NO release is the first step of the fragmentation (virtually all ion fragments in the spectra of Figure 2 result from NO ejection), the TS of the parent ion also determines the theoretical dissociation threshold (DT). One should note that in this model, the DTs for the different NIZ isomers are slightly lower (0.19 eV, 0.14 eV and 0.16 eV for 2NIZ, 4NIZ and 5NIZ respectively) compared to those of Bolognesi et al. 4 who applied DFT instead of MP2 which was applied here. Also, the DTs given here concern ionization and the production of one positively charged ion fragment, not the dissociation of a neutral molecule. Because the TSs for the NIZ isomers are very close to each other, one could expect the NO release not to depend on the isomeric composition (cf. Ref 4 ). As this is not the case, we calculated the ground state density-of-states (DOS) with DFT, which we take as an approximation of the photoelectron spectrum. This approximation is based on on Koopmans theorem which strictly speaking applies for the Hartree-Fock model without relaxation. The use of DOS can be intuitively understood when thinking the photoelectron spectrum as a collection of orbitals, ionized at different energies with equal probability each. We assume internal conversion to the cationic ground state to be quick with respect to the dissociation time scale. Then, the process can be thought to take place on the cationic ground state, with the additional energy from the ionized state. In this thinking we evaluated vertical ionization energies, the relation to the TS then dictates whether energy is sufficient for the

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Figure 5: Energy level diagrams for the NO and NO+ release in the three isomers of nitroimidazole and in 1Me5NIZ. The energies are given with respect to the neutral ground 11 state. ACS Paragon Plus Environment


process. The DOS plots with 6 lowest states are presented in Figure 6 (broadened by 0.5 eV Gaussian profile and aligned by the experimental HOMO orbital energies as in Ref. 25 ). The figure depicts also the simulated DT as dashed line. Whereas the BE of the HOMO orbital remains almost constant in the set of NIZ-dervivatives, the DOS of HOMO-1 to HOMO-5 show variation, especially with respect to the DT.

Figure 6: DOS of the four studied samples. The solid vertical lines denote individual electronic states and the dashed lines the DTs of each molecule. We find that the detected dependency of the NO (and NO+ ) production on methylation and the initial site of the nitro (NO2 ) group can be explained by this model. As seen in Figure

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6, the number of states below the DT is 1 in 2-NIZ, 2 in 4-NIZ and 5-NIZ, and 5 in MeNIZ. This explains largely the effects of the initial site of the nitro group and methylation on the neutral or cationic NO production. Compared to 2-NIZ, there is a larger number of electronic states in 4(5)-NIZ (keep in mind the ratio of 1.0:0.7 for 4-NIZ and 5-NIZ respectively in the 4(5)-NIZ gas mixture) that can be ionized without fragmenting the molecule, which naturally leads to lower degree of fragmentation and NO production. Furthermore, as there are even more states in MeNIZ that can be ionized without dissociation, the degree of fragmentation and NO production is clearly the lowest in MeNIZ. To visualize the effect of the ”density of effective fragmentation states”, we plotted those states above the DT and combined the curves of 4-NIZ and 5-NIZ (and made the normalization so that the ratio for 4-NIZ and 5-NIZ would be 1.0:0.7)). The resulting curves are presented in Figure 7 together with the experimental NO and NO+ yields (added together unlike in Fig. 2). As seen, the model describes the combined NO and NO+ yields very well for the nitroimidazoles, while for MeNIZ the yield is slightly exaggerated. This slight mismatch would be explained if part of the 42 u mass peak is due to CNO+ . In such case, the plot in Figure 7 would indeed overestimate the NO yield from MeNIZ. Although the samples studied here have not to our knowledge been clinically tested as radiosensitizers, our finding is potentially useful from the viewpoint of radiosensitization. As it has been suggested that NO would be even more potent hypoxic radiosensitizer than oxygen, 11 the ability to deliver NO to the hypoxic tumors e.g. using a suitable form of nitroimidazole could be very beneficial. Regarding the working mechanisms of nitroimidazole radiosensitizers, our results show that the fragmentation of NIZ is easily affected by altering the initial site of the nitro group and by different functional groups. Thus, to be able to take a stand on whether it is the nitroimidazole molecule itself or one of its fragments that make certain nitroimidazoles potent hypoxic radiosensitizers, further studies on e.g. hydrated nitroimidazoles are needeed.

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Figure 7: Experimental (NO + NO+ ) yields (bottom) and the modeled DOS of those states above the DT (top). The intensity scale is given with respect to the parent ion yield

Conclusions The fragmentation of NIZ is strongly characterized by the production of NO and NO+ , the rate of which can be controlled by altering the attachment site of the nitro group to the imidazole ring. Adding a methyl group to the N1 site of 5-NIZ suppresses the NO production even further and totally inhibits the NO+ production. These findings can be understood based on density of effective dissociative states, that accounts for only ionization of electronic orbitals above the threshold as potential first step of dissociation. Because the density of efective dissociative states alone explains the relative yields, we deduce that the means of ionization is not crucial for the NO-ejection process. Thus, the same reasoning

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should hold for photon ionization done here and electron ionization, the true mechanism of e.g. photosensitization in radiotherapy. Regarding radiotherapy, this study assumes that the ionization cross sections for the studied samples are equal, which in reality may not be precisely true. Alteration in ionization cross sections could either compensate or further enhance e.g. the total yield of NO between different samples.

Acknowledgements Work was supported by the Academy of Finland, the Spanish MINECO projects FIS201677889-R, the CAM project NANOFRONTMAG-CM ref S2013/MIT-2850, and the European COST Action CM1204 XLIC. S.D. acknowledges support from FWF, Vienna (P30332). The authors acknowledge computational resources from the FGI project (Finland). Also the computer time at the Centro de Computación Cientifica of the Universidad Autónoma de Madrid (CCC-UAM) and the Red Espa˜ nola de Supercomputación is acknowledged.

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Controlling NO Production Upon Valence Ionization of Nitroimidazoles

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