Cisplatin, cis-diamminedichloroplatinum(II), is one of the most widely used antitumor drugs in cancer chemotherapy, as a critical component against a broad range of malignancies. Platinum anticancer drugs are generally known to target DNA, where they can bind to the N7 of purine bases. Cisplatin, as other bifunctional agents, is able to bind to adjacent purines, resulting in crosslink 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. 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 and mitochondrial uptake and processing. For the first time cell uptake and mobility mechanisms, related to plasmatic cell and/or mitochondrial membrane crossing, has been studied. Moreover the possible insertion of metalated nucleobases into nuclear and/or mitochondrial new synthesized DNA/RNA, operated by DNA/RNA polymerases was evaluated. At this scope model metalated nucleosides/nucleotides, with nitrogen carrier ligands, have been synthesized, isolated and characterized. The possible development of new drugs based on this new rational drug design will be discussed.
METALATED PURINES AS A NEW POSSIBLE PATH TO ANTITUMOR AND ANTIVIRAL DRUGS
BENEDETTI, MICHELE;C. Girelli;P. Lunetti;MIGONI, DANILO;VERRI, Tiziano;CAPOBIANCO, Loredana;FANIZZI, Francesco Paolo
2012-01-01
Abstract
Cisplatin, cis-diamminedichloroplatinum(II), is one of the most widely used antitumor drugs in cancer chemotherapy, as a critical component against a broad range of malignancies. Platinum anticancer drugs are generally known to target DNA, where they can bind to the N7 of purine bases. Cisplatin, as other bifunctional agents, is able to bind to adjacent purines, resulting in crosslink 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. 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 and mitochondrial uptake and processing. For the first time cell uptake and mobility mechanisms, related to plasmatic cell and/or mitochondrial membrane crossing, has been studied. Moreover the possible insertion of metalated nucleobases into nuclear and/or mitochondrial new synthesized DNA/RNA, operated by DNA/RNA polymerases was evaluated. At this scope model metalated nucleosides/nucleotides, with nitrogen carrier ligands, have been synthesized, isolated and characterized. The possible development of new drugs based on this new rational drug design will be discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
