Treating cancer without harming healthy tissue is an important goal in modern medicine. Our research group has developed a series of novel, relatively non-toxic glycosidic prodrugs that are activated to give the corresponding highly cytotoxic drugs selectively in the tumour tissue. Our first investigations have shown a high duplex DNA alkylation efficiency of the drugs, whereas the prodrugs showed almost no tendency for alkylation of duplex DNA. Herein we report on novel investigations of the mode of action of the anti-cancer drugs on a molecular level. Using high-resolution mass spectrometry, we determined the reactivity of these drugs as well as of other drugs of similar structure against different nucleophiles such as RNA and the tripeptide glutathione. In addition, the new drugs were also tested for their interaction with duplex DNA. All compounds show a high reactivity against duplex DNA, whereas the alkylation efficiency regarding RNA and glutathione is only poor. Furthermore, the alkylation of duplex DNA correlates qualitatively but not quantitatively with the cytotoxicity of the drugs. Consequently, other factors besides the alkylation efficiency such as the stability of the drugs seem to influence their biological activity. Altogether the results show that high-resolution mass spectrometry constitutes a powerful method for studying the mode of action of drugs on a molecular level.
4-Methoxy-α-PVP: in silico prediction, metabolic stability, and metabolite identification by human hepatocyte incubation and high-resolution mass spectrometry
