Reactions in Tirapazamine Induced by the Attachment of Low‐Energy Electrons: Dissociation Versus Roaming of OH

Abstract

Tirapazamine (TPZ) has been tested in clinical trials on radio‐chemotherapy due to its potential highly selective toxicity towards hypoxic tumor cells. It was suggested that either the hydroxyl radical or benzotriazinyl radical may form as bioactive radical after the initial reduction of TPZ in solution. In the present work, we studied low‐energy electron attachment to TPZ in the gas phase and investigated the decomposition of the formed TPZ− anion by mass spectrometry. We observed the formation of the (TPZ–OH)− anion accompanied by the dissociation of the hydroxyl radical as by far the most abundant reaction pathway upon attachment of a low‐energy electron. Quantum chemical calculations suggest that NH2 pyramidalization is the key reaction coordinate for the reaction dynamics upon electron attachment. We propose an OH roaming mechanism for other reaction channels observed, in competition with the OH dissociation.

Ring-Selective Fragmentation in the Tirapazamine Molecule upon Low-Energy Electron Attachment

“…Calculations at the MRCI and EOM-CCSD levels are very close to each other in the FC point and at the beginning of the interpolation pathway; when D 0 and D 1 electronic states approach each other, the single-reference EOM-CCSD method is unable to retrieve the potential energy surface of D 1 reliably. Within the single-reference TD–BMK method, a D 1 minimum of a similar structure but with a considerable D 0 /D 1 gap is thus obtained [ 26 ]. Finally, the shift from the 6–31g* basis set to aug–cc–pVDZ within the TD–BMK approach has a very limited effect on the position of valence states included in Figure 1 in the FC point (with a difference in energy below 0.04 eV).…”

“…Further, we focus on the fragmentation mechanisms, resonances positions for the detected anions, experimental onsets of the various anions and quantitatively determined thermodynamic thresholds, as presented in Table 1 . The mechanisms leading to the formation of the fragment anions (TPZ–H) − , (TPZ–NH 2 ) − and (TPZ–OH) − included in Table 1 were analyzed previously [ 26 ]. The suggested reaction pathways for ions resulting from initial OH predissociation are shown in Figure 2 .…”

“…Low-energy electron attachment to TPZ has been studied recently [ 26 ]. In summary, this study showed the formation of the intact parent anion (TPZ) − , the dehydrogenated parent anion (TPZ–H) − , the fragment anion due to loss of NH 2 forming (TPZ–NH 2 ) − via single bond cleavage and the loss of the hydroxyl radical to form the most abundant fragment anion (TPZ–OH) − with mass of 161 u.…”

Electron Attachment Studies with the Potential Radiosensitizer 2-Nitrofuran

“…For the nitroimidazolic compound nimorazole, it was proposed that its action is based on the initial reduction by low-energy electrons in tumor cells leading to an intact parent radical anion which (after protonation) represents the damaging species itself [ 18 ]. Such a mode of action is distinctly different from other radiosensitisers such as tirapazamine, which efficiently breaks up upon low-energy electron attachment at ≈0 eV and forms damaging neutral radical species such as the hydroxyl radical [ 53 ]. The present results show that dissociation reactions leading to the formation of neutral radicals are minor upon electron attachment to 2-NIF, and thus, the properties are more similar to nimorazole.…”

Electron-Induced Decomposition of Uracil-5-yl O-(N,N-dimethylsulfamate): Role of Methylation in Molecular Stability

“…Nitroimidazoles such as nimorazole, are one class of such substances that have demonstrated their radiosensitization potential as oxygen mimetics [ 5 ]. Other derivatives such as fluorinated pyrimidines and heterocyclic- N -oxides are being exploited to counter the setbacks of hypoxia and improve the treatment [ 6 , 7 , 8 , 9 ].…”