MAGNETIC RESONANCE IN CHEMISTRY Magn. Reson. Chem. 2005; 43: 139–146 Published online 23 November 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1514 Probing NMR parameters, structure and dynamics of 5-nitroimidazole derivatives. Density functional study of prototypical radiosensitizers Teodorico C. Ramalho 1 and Michael B ¨ uhl 2 * 1 Departamento de Qu´ ımica, Instituto Militar de Engenharia, 22290-270 Rio de Janeiro, RJ, Brazil 2 Max-Planck-Institut f ¨ ur Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 M ¨ ulheim an der Ruhr, Germany Received 2 August 2004; Revised 17 September 2004; Accepted 20 September 2004 The 15 N chemical shifts of metronidazole (1), secnidazole (2), nimorazole (3) and tinidazole (4), radiosensitizers based on the 5-nitroimidazole motif, are reported. A detailed computational study of 1 is presented, calling special attention to the performance of various theoretical methods in reproducing the 13 C and 15 N data observed in solution. The most sophisticated approach involves density functional- based Car–Parrinello molecular dynamics simulations (CPMD) of 1 in aqueous solution (BP86 level) and averaging chemical shifts over snapshots from the trajectory. In the NMR calculations for these snapshots (performed at the B3LYP level), a small number of discrete water molecules are retained, and the remaining bulk solution effects are included via a polarizable continuum model (PCM). A similarly good accord with experiment is obtained from much less involved, static geometry optimization and NMR computation of pristine 1 employing a PCM approach. Solvent effects on d( 15 N), which are of the order of up to 20 ppm, are not due to changes in geometric parameters upon solvation, but arise from the direct response of the electronic wavefunction to the presence of the solvent, which can be represented by discrete molecules and/or the dielectric bulk. Copyright  2004 John Wiley & Sons, Ltd. KEYWORDS: NMR; 15 N NMR; radiosensitizers; molecular dynamics simulations; solvent effects; spin–spin coupling constants INTRODUCTION In spite of early progress, cancer 1,2 is still one of the most serious problems of humanity, causing many deaths and having a great and limiting influence on life quality and development of many countries. Nowadays, it is well known that the high rate of tumor cell proliferation increases oxygen consumption in tumor tissue. 2 Furthermore, structural and functional abnormalities and function in tumor vessels lead to decreased oxygen delivery to tumor tissue, 3 because of poor vascularization and potentially high oxygen demand. These hypoxic cells are resistant to radiation therapy and to some kinds of chemotherapy. 4,5 Therefore, tumor hypoxia can be exploited for selective anticancer drug treatment using hypoxic cell cytoxins or hypoxic cell radiosensitizers. 6 Hypoxic cell radiosensitizers, such as electron-affinic compounds, behave as oxygen- mimicking compounds, affecting tumor hypoxic cells, thus leading to radiation-induced damage to DNA and to other molecules. 7 Thus, normally inert compounds, which are activated by enzymes or by radiation under hypoxic L Correspondence to: Michael B ¨ uhl, Max-Planck-Institut f ¨ ur Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 M ¨ ulheim an der Ruhr, Germany. E-mail: buel@mpi-muelheim.mpg.de Contract/grant sponsor: CAPES. Contract/grant sponsor: DAAD. conditions, will behave selectively toward tumors. Ideally, the compound is reduced reversibly so that, in normal cells, it can readily revert to its inactive form. 8 The most commonly used radiosensitizers are 5- nitroimidazole derivatives. 9,10 Because the first nitroimi- dazole drugs such as metronidazole (Fig. 1, compound 1) exhibit many undesirable side-effects, research efforts are being concentrated on finding suitable alternatives, either based on the same nitroimidazole motif or with bioreducible groups other than nitro. 11 In our previous work, we stud- ied the physical chemistry properties associated with the biological activity of radiosensitizers in aqueous and carbon tetrachloride solution. 12 – 14 Recently, 1 H, 31 P and 19 F NMR/MRI (magnetic resonance imaging) 15 of nitroimidazoles (Fig. 1) has been applied for measuring tumor and tissue oxygenation. 16 In spite of the great importance of such radiosensitizers, the solvent and dynamic effects on their NMR parameters have not yet been investigated. Furthermore, surprisingly little detailed computational work on this subject has appeared. Ab initio computation of NMR parameters, such as chem- ical shifts or coupling constants, can be very useful to support recorded spectra and investigate structure – property relationships. 17,18 In fact, calculations based on density func- tional theory (DFT) with a suitable choice of functionals are able to provide accurate values for many NMR properties. 19 Copyright  2004 John Wiley & Sons, Ltd.