Nitroimidazolic radiosensitizers investigated by electrospray ionization time-of-flight mass spectrometry and density functional theory

Pandeti, Sukanya; Feketeová, Linda; Reddy, T. Jagadeshwar; Abdoul‐Carime, H.; Farizon, B.; Farizon, M.; Märk, T.D.

doi:10.1039/c7ra08312b

Cited by 14 publications

(26 citation statements)

References 27 publications

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“…Although the detailed mechanisms by which radiosensitisation operates are still unknown, it is believed that radiosensitisers are chemical compounds subject to redox reactions inside the hypoxic cells [4], and in case of nitroimidazoles, the ring facilitates reduction through reactive anion radicals' formation [5][6][7]. Nitroimidazole radiosensitisers have been thoroughly investigated by experimental methods on low-energy electron interactions [8][9][10][11][12] and together with nimorazole probed by electrospray ionization mass spectrometry [13][14][15]. While associative electron attachment may contribute to NIMO's radiosensitising effect, within the biological environment, electron transfer processes (redox reactions) may prevail and so these may seem more appropriate to describe the underlying molecular mechanisms of such chemical compounds and their role as radiosensitisers.…”

Section: Introductionmentioning

confidence: 99%

Bound Electron Enhanced Radiosensitisation of Nimorazole upon Charge Transfer

et al. 2022

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This novel work reports nimorazole (NIMO) radiosensitizer reduction upon electron transfer in collisions with neutral potassium (K) atoms in the lab frame energy range of 10–400 eV. The negative ions formed in this energy range were time-of-flight mass analyzed and branching ratios were obtained. Assignment of different anions showed that more than 80% was due to the formation of the non-dissociated parent anion NIMO•− at 226 u and nitrogen dioxide anion NO2− at 46 u. The rich fragmentation pattern revealed that significant collision induced the decomposition of the 4-nitroimidazole ring, as well as other complex internal reactions within the temporary negative ion formed after electron transfer to neutral NIMO. Other fragment anions were only responsible for less than 20% of the total ion yield. Additional information on the electronic state spectroscopy of nimorazole was obtained by recording a K+ energy loss spectrum in the forward scattering direction (θ ≈ 0°), allowing us to determine the most accessible electronic states within the temporary negative ion. Quantum chemical calculations on the electronic structure of NIMO in the presence of a potassium atom were performed to help assign the most significant lowest unoccupied molecular orbitals participating in the collision process. Electron transfer was shown to be a relevant process for nimorazole radiosensitisation through efficient and prevalent non-dissociated parent anion formation.

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Section: Introductionmentioning

confidence: 99%

Bound Electron Enhanced Radiosensitisation of Nimorazole upon Charge Transfer

et al. 2022

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“…17,28 Similarly to nimorazole, the fragmentation of metronidazole also changes because of protonation. According to the study of Pandeti et al, 5 protonated metronidazole most likely ejects a vinyl alcohol (C 2 H 3 OH tail), subsequently followed by NO 2 release. Also NO 2 release accompanied by the ejection of methyl group is possible, but less probable.…”

Section: ■ Discussionmentioning

confidence: 99%

“…A number of recent studies of nitroimidazoles using mass and electron spectroscopic techniques − have been motivated by the success in using some nitroimidazoles in combination with radiation therapy to increase its effect. − Nimorazole in particular has proven to be a useful radiosensitizer and is being used in the treatment of certain head and neck cancers in Denmark . The benefit of using nitroimidazoles as radiosensitizers arises mostly in the case of hypoxic tumors (low oxygen concentration), which are more resistant to ionizing radiation than well-oxygenated tumors …”

Section: Introductionmentioning

confidence: 99%

Fragmentation Patterns of Radiosensitizers Metronidazole and Nimorazole upon Valence Ionization

et al. 2020

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We study gas-phase photodissociation of radiosensitizer molecules nimorazole and metronidazole with the focus on the yield of the oxygen mimics nitrogen oxides and nitrous acid. Regardless of photon energy, we find the nimorazole cation to split the intramolecular bridge with little NO2 or NO production, which makes the molecule a precursor of dehydrogenated methylnitroimidazole. Metronidazole cation, on the contrary, has numerous fragmentation pathways with strong energy dependence. Most notably, ejection of NOOH and NO2 takes place within 4 eV from the valence ionization energy. Whereas the NO2 ejection is followed by further fragmentation steps when energy so allows, we find emission of NOOH takes place in microsecond time-scales and as a slow process that is relevant only when no other competing reaction is feasible. These primary dissociation characteristics of the molecules are understood by applying the long-known principle of rapid internal conversion of the initial electronic excitation energy and by studying the energy minima and the saddle points on the potential energy surface of the electronic ground state of the molecular cation.

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“…At 9.5 eV only the parent ion is produced in the photoionization event, while at 11 eV fragments corresponding to the NO2 and HONO losses at m/z 124 and 125 are observed as well as at the highest photon energy used (13 eV) also the fragments corresponding to m/z = 126 and 127. Pandeti et al (2017) observed the loss of C2H4O (44 Da) at position N1 followed by the NO2 loss as the dominant fragmentation channels in a collision induced dissociation experiment of protonated metronidazole. Such a process in the present case would lead to prominent features at m/z 127 and 81, respectively.…”

Section: Discussionmentioning

confidence: 99%

Radiation Damage Mechanisms of Chemotherapeutically Active Nitroimidazole Derived Compounds

et al. 2019

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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.

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Nitroimidazolic radiosensitizers investigated by electrospray ionization time-of-flight mass spectrometry and density functional theory

Abstract: Formation of positive and negative ions and radical anions of 5-nitroimidazolic radiosensitizers and their ability to form these ions.

Cited by 14 publications

References 27 publications

Bound Electron Enhanced Radiosensitisation of Nimorazole upon Charge Transfer

Bound Electron Enhanced Radiosensitisation of Nimorazole upon Charge Transfer

Fragmentation Patterns of Radiosensitizers Metronidazole and Nimorazole upon Valence Ionization

Radiation Damage Mechanisms of Chemotherapeutically Active Nitroimidazole Derived Compounds

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