A Synchrotron Radiation Study of Nitroimidazoles and their Derivatives

Nitroimidazole derived 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. Inthis work we present the results of a bottom-up approach, which goes from the model molecule to the real drugs used in therapy. Mass spectrometry and several spectroscopic techniques (XPS, PES, NEXAFS, PEPICO) basedon the use of synchrotron radiation have been combined with computational methods to link the electronic and geometric structure of the molecule to their functions.The investigation of the fragmentation patterns of the nitroimidazole isomers [1,2] has allowed to understand their capacity to produce reactive molecular species like nitric oxide, carbon monoxide or hydrogencyanide and their potential impact on the biological system. Guided by these results, the fragmentation mechanisms of metronidazole and misonidazole, the two radiosensitisers built on the 5-nitroimidazole and 2-nitroimidazole compounds used in therapy, as well as the 1-Methyl-5-nitroimidazole have been investigated. The results on these more complex systems suggest that different mechanisms are active. The release of nitric oxideis hampered by the efficient formation of nitrous acid or nitrogen dioxide and the long and branched tails attached to the imidazole ring increase the ring stability, providing an efficient channel for excess energy dissipation.