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We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.

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After the discovery of the anticancer activity of cisplatin many studies have focused on elucidating its mechanism of action. The antitumor effects of platinum complexes originate from their interaction with DNA, which causes interference with normal transcription or DNA replication. Pt-DNA adducts produced by cisplatin and many of its analogues are almost identical, and would explain their similar patterns of tumor sensitivity and susceptibility to resistance. However, platinum compounds bearing trans-amine (ammine) ligands, and those of multinuclear Pt complexes give rise to radically different DNA-Pt adducts. Platinum-sulfur interactions are associated with undesired phenomena such as resistance and toxicity. Modern multinuclear n.m.r. approaches are very powerful for the investigation of thermodynamics and kinetics of the reactions of metal compounds with biomolecules, and it is possible to study the coordination chemistry of platinum drugs under physiological relevant conditions. In this review biocoordination chemistry of platinum anticancer drugs and various mechanistic aspects related to the antitumor effects of platinum complexes have been explained.

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