Cell uptake and processing of metalated purines: a new possible path to antitumor and antiviral drugs

Cisplatin, cis-diamminedichloroplatinum(II), is one of the most widely used antitumor drugs in clinical therapy, as a critical component against a broad range of malignancies. Platinum anticancer compounds are known to target DNA where they can bind the N7 of a purine base. Cisplatin, as other bifunctional agents, is also able to bind to adjacent G/A residues, resulting in the cross-link lesions believed to be responsible for the observed antitumor activity. N7-metalated purines, in some cases, seem to be characterized by a relevant antitumor activity. This has led us to hypothesize a cisplatin parallel mechanism of action: based on free platinated purines formation, directly in tissues, after drug administration, see Figure. In order to evaluate this possible mechanism as a key path to develop new drugs, we performed a series of experiments focused on platinated nucleobases cell uptake and processing. In particular our researches were focused on the possible insertion of metalated nucleobases into nuclear and/or mitochondrial DNA/RNA synthesis, operated by DNA/RNA polymerases. Model metalated nucleosides/nucleotides with nitrogen carrier ligands have been synthesized, isolated and characterized. For the first time cell uptake and mobility mechanism, related to plasmatic cell and/or mitochondrial membrane crossing, has been studied. The possible development of new drugs based on this new rational base will be discussed.