- . NegomKouodom, L. Ronconi, M. Celegato, C. Nardon, L. Marchiò, P.Q. Dou, D. Aldinucci, F. Formaggio, D. Fregona, “Toward the Selective Delivery of Chemotherapeutics into Tumor Cells by Targeting Peptide Transporters: Tailored Gold-Based Anticancer Peptidomimetics” J. Med. Chem, 55(5), 2212-2226 (2012)DOI: 10.1021/jm201480u.
Complexes [Au(III)X(2)(dtc-Sar-AA-O(t-Bu))] (AA = Gly, X = Br (1)/Cl (2); AA = Aib, X = Br (3)/Cl (4); AA = l-Phe, X = Br (5)/Cl (6)) were designed on purpose in order to obtain gold(III)-based anticancer peptidomimetics that might specifically target two peptide transporters (namely, PEPT1 and PEPT2) upregulated in several tumor cells. All the compounds were characterized by means of FT-IR and mono- and multidimensional NMR spectroscopy, and the crystal structure of [Au(III)Br(2)(dtc-Sar-Aib-O(t-Bu))] (3) was solved and refined. According to in vitro cytotoxicity studies, the Aib-containing complexes 3 and 4 turned out to be the most effective toward all the human tumor cell lines evaluated (PC3, DU145, 2008, C13, and L540), reporting IC(50) values much lower than that of cisplatin. Remarkably, they showed no cross-resistance with cisplatin itself and were proved to inhibit tumor cell proliferation by inducing either apoptosis or late apoptosis/necrosis depending on the cell lines. Biological results are here reported and discussed in terms of the structure-activity relationship.
- L.Dalla Via, C. Nardon, D. Fregona, “Targeting the proteasome-ubiquitin pathway with inorganic compounds to fight cancer: a challenge for the future.” Fut. Med Chem.Special Focus: Targeted Oncology4(4), 525–543 (2012);DOI: 10.4155/FMC.11.187.
Proteasomes are large multicatalytic complexes endowed with proteinase activity, located both in the cytosol and in the nucleus of eukaryotic cells. The ubiquitin–proteasome system is responsible for selective degradation of most intracellular proteins and therefore plays an essential regulatory role in many critical cellular processes. The proteasomal activity can also contribute to the pathological states of many diseases, including inflammation, neurodegeneration and cancer, through a disregulation in the level of regulatory proteins. These diseases may be targeted by modulating components of the ubiquitin–proteasome pathway, using small molecules as inhibitors. Bortezomib (Velcade®), used for the treatment of relapsed multiple myeloma, is the first and, up to now, the only proteasome inhibitor approved by the US FDA. Nowadays, the discovery that some metal-based complexes exert their antiproliferative action by affecting proteasomal activities provides the possibility of developing new opportunities in cancer therapy.
- E. M. Nagy, A. Pettenuzzo, G. Boscutti, L. Marchiò, L. Dalla Via and D. Fregona “Ruthenium(II/III)-based Compounds with Encouraging Antiproliferative Activity against Non-Small Cell Lung Cancer” Chemistry – A European Journal (Wiley), 18(45), 14464–14472,(2012)DOI: 10.1002/chem.201202171.
Hereby we present the synthesis of several ruthenium(II) and ruthenium(III) dithiocarbamato complexes. Proceeding from the Na[trans-RuIII(dmso)2Cl4] (2) and cis-[RuII(dmso)4Cl2] (3) precursors, the diamagnetic, mixed-ligand [RuIIL2(dmso)2] complexes 4 and 5, the paramagnetic, neutral [RuIIIL3] monomers 6 and 7, the antiferromagnetically coupled ionic α-[RuIII2L5]Cl complexes 8 and 9 as well as the β-[RuIII2L5]Cl dinuclear species 10 and 11 (L=dimethyl- (DMDT) and pyrrolidinedithiocarbamate (PDT)) were obtained. All the compounds were fully characterised by elemental analysis as well as 1H-NMR and FTIR spectroscopy. Moreover, for the first time the crystal structures of the dinuclear β-[RuIII2(dmdt)5]BF4-CHCl3- CH3CN and of the novel [RuIIL2(dmso)2] complexes were also determined and discussed. For both the mono- and dinuclear RuII and RuIII complexes the central metal atoms assume a distorted octahedral geometry. Furthermore, in vitro cytotoxicity of the complexes has been evaluated on non-small-cell lung cancer (NSCLC) NCI-H1975 cells. All the mono- and dinuclear RuIII dithiocarbamato compounds (i.e., complexes 6–10) show interesting cytotoxic activity, up to one order of magnitude higher with respect to cisplatin. Otherwise, no significant antiproliferative effect for either the precursors 2 and 3 or the RuIIcomplexes 4 and 5 has been observed.
- V. Milacic, D. Chen, L. Ronconi, K. R. Landis-Piwowar, D. Fregona, and Q. P. Dou,“A Novel Anticancer Gold(III) Dithiocarbamate Complex Inhibits the Activity of a Purified 20S Proteasome and 26S Proteasome in Human Breast Cancer Cell Cultures and Xenografts”. Cancer Res. 66, 10478-10486 (2006).DOI: 10.1158/0008-5472.CAN-06-3017.
Although cisplatin has been used for decades to treat human cancer, some toxic side effects and resistance are observed. It has been suggested that gold(III) complexes, containing metal centers isoelectronic and isostructural to cisplatin, are promising anticancer drugs. Gold(III) dithiocarbamate complexes were shown to exhibit in vitro cytotoxicity, comparable with and even greater than cisplatin; however, the involved mechanism of action remained unknown. Because we previously reported that copper(II) dithiocarbamates are potent proteasome inhibitors, we hypothesized that gold(III) dithiocarbamate complexes could suppress tumor growth via direct inhibition of the proteasome activity. Here, for the first time, we report that a synthetic gold(III) dithiocarbamate (compound 2) potently inhibits the activity of a purified rabbit 20S proteasome and 26S proteasome in intact highly metastatic MDA-MB-231 breast cancer cells, resulting in the accumulation of ubiquitinated proteins and the proteasome target protein p27 and induction of apoptosis. The compound 2-mediated proteasome inhibition and apoptosis induction were completely blocked by addition of a reducing agent DTT or N-acetyl-L-cysteine, showing that process of oxidation is required for proteasome inhibition by compound 2. Treatment of MDA-MB-231 breast tumor-bearing nude mice with compound 2 resulted in significant inhibition of tumor growth, associated with proteasome inhibition and massive apoptosis induction in vivo. Our findings reveal the proteasome as a primary target for gold(III) dithiocarbamates and support the idea for their potential use as anticancer therapeutics.
- G.Boscutti,L.Marchiò, L.Ronconi, and D. Fregona, “Insights into the Reactivity of Gold-Dithiocarbamato Anticancer Agents toward Model Biomolecules from Multinuclear NMR Spectroscopy”. Chem. Eur. J. (accepted).
Some gold(III)-dithiocarbamato derivatives of either single amino acids or oligopeptides have been showing promising as potential anticancer agents, but their capability to interact with biologically-relevant macromolecules is still poorly understood. We investigated the affinity of the representative complex [AuIIIBr2(dtc-Sar-OCH3)] with selected model molecules of histidine-, methionine- and cysteine-rich proteins (i.e. 1-methylimidazole, dimethylsulfide and N-acetyl-L-cysteine, respectively). In particular, detailed mono- and multinuclear NMR studies,in combination with multiple 13C/15N-enrichment, allowed interactions to be followed over time, indicating somewhat unexpected reaction pathways. Whereas dimethylsulfide was proved unreactive, a sudden multi-step redox reaction occurred in presence of the other potential sulfur-donor N-acetyl-L-cysteine (confirmed when glutathione was used instead). On the other hand, the gold(III) complex underwent an unprecedented acid-base reaction with 1-methylimidazole, rather than the expected coordination to the metal center by replacing, for instance,a bromide. Our findings are here discussed and compared with the data available in the literature on related complexes, confirming that the peculiar reactivity of gold(III)-dithiocarbamato complexes can lead to novel reaction pathways and, therefore, to new cytotoxic mechanisms in cancer cells.
- D. Fregona, L. Ronconi, F. Formaggio, Q.P. Dou, D. Aldinucci, “Gold(III) complexes with oligopeptides functionalized with sulfur donors and use thereof as antitumor agents”, PCT Int. Appl. 2009, PCT/EP2009/053296.