We study the reactivity of misonidazole with low-energy electrons in a water environment combining experiment and theoretical modelling. The environment is modelled by sequential hydration of misonidazole clusters in vacuum. The well-defined experimental conditions enable computational modeling of the observed reactions. While the NO 2 - dissociative electron attachment channel is suppressed, as also observed previously for other molecules, the OH - channel remains open. Such behavior is enabled by the high hydration energy of OH - and ring formation in the neutral radical co-fragment. These observations help to understand the mechanism of bio-reductive drug action. Electron-induced formation of covalent bonds is then important not only for biological processes but may find applications also in technology.

Atomic and Molecular Collisions Laboratory CEFITEC Department of Physics Universidade Nova de Lisboa 2829 516 Caparica Portugal

Center for Biomolecular Sciences Innsbruck Leopold Franzens Universität Innsbruck Technikerstrasse 25 Innsbruck A 6020 Austria

Institut für Ionenphysik und Angewandte Physik Leopold Franzens Universität Innsbruck Technikerstrasse 25 Innsbruck A 6020 Austria

J Heyrovský Institute of Physical Chemistry v v i The Czech Academy of Sciences Dolejškova 3 18223 Prague Czech Republic

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Alizadeh E., Orlando T.M., Sanche L. Biomolecular Damage Induced by Ionizing Radiation: The Direct and Indirect Effects of Low-Energy Electrons on DNA. Annu. Rev. Phys. Chem. 2015;66:379–398. doi: 10.1146/annurev-physchem-040513-103605. PubMed DOI

Gomez-Tejedor G.G., Fuss M.C. Radiation Damage in Biomolecular Systems. Springer; Dordrecht, The Netherlands: 2012.

Alizadeh E., Sanche L. Precursors of Solvated Electrons in Radiobiological Physics and Chemistry. Chem. Rev. 2012;112:5578–5602. doi: 10.1021/cr300063r. PubMed DOI

Mucke M., Braune M., Barth S., Förstel M., Lischke T., Ulrich V., Arion T., Becker U., Bradshaw A., Hergenhahn U. A hitherto unrecognized source of low-energy electrons in water. Nat. Phys. 2010;6:143. doi: 10.1038/nphys1500. DOI

Kumar A., Walker J.A., Bartels D.M., Sevilla M.D. A Simple ab Initio Model for the Hydrated Electron That Matches Experiment. J. Phys. Chem. 2015;119:9148–9159. doi: 10.1021/acs.jpca.5b04721. PubMed DOI PMC

Chomicz L., Zdrowowicz M., Kasprzykowski F., Rak J., Buonaugurio A., Wang Y., Bowen K.H. How to Find Out Whether a 5-Substituted Uracil Could Be a Potential DNA Radiosensitizer. J. Phys. Chem. Lett. 2013;4:2853–2857. doi: 10.1021/jz401358w. DOI

Meißner R., Kočišek J., Feketeová L., Fedor J., Fárník M., Limao-Vieira P., Illenberger E., Denifl S. Low-energy electrons transform the nimorazole molecule into a radiosensitiser. Nat. Commun. 2019;10:2388. doi: 10.1038/s41467-019-10340-8. PubMed DOI PMC

Poštulka J., Slavíček P., Fedor J., Fárník M., Kočišek J. Energy Transfer in Microhydrated Uracil, 5-Fluorouracil, and 5-Bromouracil. J. Phys. Chem. 2017;121:8965–8974. doi: 10.1021/acs.jpcb.7b07390. PubMed DOI

Workman P., Strafford I.J. The experimental development of bioreductive drugs and their role in cancer therapy. Cancer Metastasis Rev. 1993;12:73–82. doi: 10.1007/BF00689802. PubMed DOI

Liu J.n., Bu W., Shi J. Chemical Design and Synthesis of Functionalized Probes for Imaging and Treating Tumor Hypoxia. Chem. Rev. 2017;117:6160–6224. doi: 10.1021/acs.chemrev.6b00525. PubMed DOI

Lopci E., Grassi I., Chiti A., Nanni C., Cicoria G., Toschi L., Fonti C., Lodi F., Mattioli S., Fanti S. PET radiopharmaceuticals for imaging of tumor hypoxia: A review of the evidence. Am. J. Nucl. Med. Mol. Imaging. 2014;4:365–384. PubMed PMC

Paterson I., Dawes P., Henk J., Moore J. Pilot study of radiotherapy with misonidazole in head and neck cancer. Clin. Radiol. 1981;32:225–229. doi: 10.1016/S0009-9260(81)80166-3. PubMed DOI

Fu K.K., Cooper J.S., Marcial V.A., Laramore G.E., Pajak T.F., Jacobs J., Al-Sarraf M., Forastiere A.A., Cox J.D. Evolution of the radiation therapy oncology group clinical trials for head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 1996;35:425–438. doi: 10.1016/S0360-3016(96)80003-4. PubMed DOI

Mason R.P., Holtzman J.L. Mechanism of microsomal and mitochondrial nitroreductase. Electron spin resonance evidence for nitroaromatic free radical intermediates. Biochemistry. 1975;14:1626–1632. doi: 10.1021/bi00679a013. PubMed DOI

Knox R.J., Knight R.C., Edwards D.I. Studies on the action of nitroimidazole drugs: The products of nitroimidazole reduction. Biochem. Pharmacol. 1983;32:2149–2156. doi: 10.1016/0006-2952(83)90220-4. PubMed DOI

Wardman P. The mechanism of radiosensitization by electron-affinic compounds. Int. J. Radiat. Appl. Instrum. Part Radiat. Phys. Chem. 1987;30:423–432. doi: 10.1016/1359-0197(87)90111-1. DOI

Varghese A.J., Whitmore G.F. Modification of Guanine Derivatives by Reduced 2-Nitroimidazoles. Cancer Res. 1983;43:78–82. PubMed

Edwards D.I. Reduction of nitroimidazoles in vitro and DNA damage. In: Alexander P., Gielen J., Sartorelli A.C., editors. Bioreduction in the Activation of Drugs. Pergamon Press Ltd.; Oxford, UK: 1986. p. 53. PubMed

Tanzer K., Feketeová L., Puschnigg B., Scheier P., Illenberger E., Denifl S. Reactions in Nitroimidazole Triggered by Low-Energy (0–2 eV) Electrons: Methylation at N1-H Completely Blocks Reactivity. Angew. Chem. Int. Ed. 2014;53:12240–12243. doi: 10.1002/anie.201407452. PubMed DOI PMC

Ribar A., Fink K., Probst M., Huber S.E., Feketeová L., Denifl S. Isomer Selectivity in Low-Energy Electron Attachment to Nitroimidazoles. Chem. Eur. J. 2017;23:12892–12899. doi: 10.1002/chem.201702644. PubMed DOI

Meißner R., Feketeová L., Illenberger E., Denifl S. Reactions in the Radiosensitiser Misonidazole Induced by Low-Energy (0–10 eV) Electrons. Int. J. Mol. Sci. 2019;20:3496. doi: 10.3390/ijms20143496. PubMed DOI PMC

Böhler E., Warneke J., Swiderek P. Control of chemical reactions and synthesis by low-energy electrons. Chem. Soc. Rev. 2013;42:9219–9231. doi: 10.1039/c3cs60180c. PubMed DOI

Lafosse A., Bertin M., Azria R. Electron driven processes in ices: Surface functionalization and synthesis reactions. Prog. Surf. Sci. 2009;84:177–198. doi: 10.1016/j.progsurf.2009.03.001. DOI

Sajeev Y. Cycloaddition of molecular dinitrogens: formation of tetrazete anion (N4-; D2h) through associative electron attachment. Mol. Phys. 2019;117:2162–2166. doi: 10.1080/00268976.2019.1607599. DOI

Davis D., Sajeev Y. Low energy electron catalyst: the electronic origin of catalytic strategies. Phys. Chem. Chem. Phys. 2016;18:27715–27720. doi: 10.1039/C6CP05480C. PubMed DOI

Lee S.H., Kim N., Ha D.G., Kim S.K. “Associative” Electron Attachment to Azabenzene-(CO2)n van der Waals Complexes: Stepwise Formation of Covalent Bonds with Additive Electron Affinities. J. Am. Chem. Soc. 2008;130:16241–16244. doi: 10.1021/ja8039103. PubMed DOI

Kočišek J., Pysanenko A., Fárník M., Fedor J. Microhydration Prevents Fragmentation of Uracil and Thymine by Low-Energy Electrons. J. Phys. Chem. Lett. 2016;7:3401–3405. doi: 10.1021/acs.jpclett.6b01601. PubMed DOI

Kočišek J., Lengyel J., Fárník M. Ionization of large homogeneous and heterogeneous clusters generated in acetylene–Ar expansions: Cluster ion polymerization. J. Chem. Phys. 2013;138:124306. doi: 10.1063/1.4796262. PubMed DOI

Fárník M., Lengyel J. Mass spectrometry of aerosol particle analogues in molecular beam experiments. Mass Spectrom. Rev. 2018;37:630–651. doi: 10.1002/mas.21554. PubMed DOI

Grimme S. Semiempirical GGA-type Density Functional Constructed with a Long-Range Dispersion Correction. J. Comput. Chem. 2006;27:1787–1799. doi: 10.1002/jcc.20495. PubMed DOI

Frisch M.J., Trucks G.W., Schlegel H.B., Scuseria G.E., Robb M.A., Cheeseman J.R., Scalmani G., Barone V., Petersson G.A., Nakatsuji H., et al. Gaussian 16 Revision A.03, 2016. Gaussian Inc.; Wallingford, CT, USA: 2016.

Hollas D., Svoboda O., Ončák M., Slavíček P. ABIN, Source Code. [(accessed on 1 September 2019)]; Available online: https://github.com/PHOTOX/ABIN.

Kočišek J., Grygoryeva K., Lengyel J., Fárník M., Fedor J. Effect of Cluster Environment on the Electron Attachment to 2-Nitrophenol. Eur. Phys. J. 2016;70:98. doi: 10.1140/epjd/e2016-70074-0. DOI

Smiglak M., Hines C.C., Reichert W.M., Vincek A.S., Katritzky A.R., Thrasher J.S., Sun L., McCrary P.D., Beasley P.A., Kelley S.P., et al. Synthesis, limitations, and thermal properties of energetically-substituted, protonated imidazolium picrate and nitrate salts and further comparison with their methylated analogs. New J. Chem. 2012;36:702–722. doi: 10.1039/C1NJ20677J. DOI

Solov’yov A.V., Surdutovich E., Scifoni E., Mishustin I., Greiner W. Physics of ion beam cancer therapy: A multiscale approach. Phys. Rev. E. 2009;79:011909. doi: 10.1103/PhysRevE.79.011909. PubMed DOI

Zou L., Wang H., He B., Zeng L., Tan T., Cao H., He X., Zhang Z., Guo S., Li Y. Current Approaches of Photothermal Therapy in Treating Cancer Metastasis with Nanotherapeutics. Theranostics. 2016;6:762–772. doi: 10.7150/thno.14988. PubMed DOI PMC

Feketeová L., Albright A.L., Sørensen B.S., Horsman M.R., White J., O’Hair R.A., Bassler N. Formation of radical anions of radiosensitizers and related model compounds via electrospray ionization. Int. J. Mass Spectrom. 2014;365–366:56–63. doi: 10.1016/j.ijms.2013.12.014. DOI

Overgaard J., Overgaard M., Nielsen O.S., Pedersen A.K., Timothy A.R. A comparative investigation of nimorazole and misonidazole as hypoxic radiosensitizers in a C3H mammary carcinoma in vivo. Br. J. Cancer. 1982;46:904–911. doi: 10.1038/bjc.1982.300. PubMed DOI PMC

Pshenichnyuk S.A., Modelli A., Komolov A.S. Interconnections between dissociative electron attachment and electron-driven biological processes. Int. Rev. Phys. Chem. 2018;37:125–170. doi: 10.1080/0144235X.2018.1461347. DOI

Fedor J., Cicman P., Coupier B., Feil S., Winkler M., Głuch K., Husarik J., Jaksch D., Farizon B., Mason N.J., et al. Fragmentation of Transient Water Anions Following Low-Energy Electron Capture by H2O/D2O. J. Phys. At. Mol. Opt. Phys. 2006;39:3935. doi: 10.1088/0953-4075/39/18/022. DOI

Kočišek J., Sedmidubská B., Indrajith S., Fárník M., Fedor J. Electron Attachment to Microhydrated Deoxycytidine Monophosphate. J. Phys. Chem. 2018;122:5212–5217. doi: 10.1021/acs.jpcb.8b03033. PubMed DOI

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