Gold(III) to Ruthenium(III) Metal Exchange in Dithiocarbamato Complexes Tunes Their Biological Mode of Action for Cytotoxicity in Cancer Cells.

Malignant tumors have affected the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors, including deleterious lifestyle habits (i.e., smoking) and the higher longevity. Many efforts have been spent in the last decades on achieving an early stage diagnosis of cancer, and more effective cures, leading to a decline in age-standardized cancer mortality rates. In the last years, our research groups have developed new metal-based complexes, with the aim to obtain a better selectivity for cancer cells and less side effects than the clinically established reference drug cisplatin. This work is focused on four novel Au(III) and Ru(III) complexes that share the piperidine dithiocarbamato (pipe-DTC) as the ligand, in a different molar ratio. The compounds [AuCl2(pipeDTC)], [Au(pipeDTC)2]Cl, [Ru(pipeDTC)3] and ß-[Ru2(pipeDTC)5] have been synthesized and fully characterized by several chemical analyses. We have then investigated their biological properties in two different cell lines, namely, AGS (gastric adenocarcinoma) and HCT116 (colon carcinomas), showing significant differences among the four compounds. First, the two gold-based compounds and ß-[Ru2(pipeDTC)5] display IC50 in the µM range, significantly lower than cisplatin. Second, we showed that [AuCl2(pipeDTC)] and ß-[Ru2(pipeDTC)5]Cl drive different molecular mechanisms. The first was able to induce the protein level of the DNA damage response factor p53 and the autophagy protein p62, in contrast to the second that induced the ATF4 protein level, but repressed p62 expression. This study highlights that the biological activity of different complexes bringing the same organic ligand depends on the electronic and structural properties of the metal, which are able to fine tune the biological properties, giving us precious information that can help to design more selective anticancer drugs.

Labelled micelles for the delivery of cytotoxic Cu(II) and Ru(III) compounds in the treatment of aggressive orphan cancers: Design and biological in vitro data.

A recent study on our metal-dithiocarbamato complexes pointed out the antiproliferative properties and the druglikeness of some new patented derivatives. In this work, the best compounds have been encapsulated in micellar nanocarriers, being also carbohydrate-functionalized on their hydrophilic surface to investigate the possibility of a cancer-selective delivery. In particular, the nonionic block copolymer Pluronic® F127 (PF127) has been chemically modified with sugars and the derivatives characterized by means of NMR spectroscopy and FT-IR spectrophotometry. Then, the two selected complexes (ß-[Ru2(PipeDTC)5]Cl (PipeDTC = piperidine dithiocarbamate) and [Cu(ProOMeDTC)2] (ProOMeDTC = L-proline methyl ester dithiocarbamate)), have been loaded into the hydrophobic core of PF127 micelles and cancer-targeting counterparts. These nanoformulations have been studied for their dimensions (DLS, TEM) and stability, and tested for their cytotoxicity against aggressive human cancer cell lines. The in vitro results were paralleled with mechanistic studies through Confocal Laser Scanning Microscopy and xCELLigence analysis.

CuII and AuIII Complexes with Glycoconjugated Dithiocarbamato Ligands for Potential Applications in Targeted Chemotherapy.

This work is focused on the synthesis, characterization, and preliminary biological evaluation of bio-conjugated AuIII and CuII complexes with the aim of overcoming the well-known side effects of chemotherapy by improving the selective accumulation of an anticancer metal payload in malignant cells. For this purpose, carbohydrates were chosen as targeting agents, exploiting the Warburg effect that accounts for the overexpression of glucose-transporter proteins (in particular GLUTs) in the phospholipid bilayer of most neoplastic cells. We linked the dithiocarbamato moiety to the C1 position of three different monosaccharides: d-glucose, d-galactose, and d-mannose. Altogether, six complexes with a 1:2 metal-to-ligand stoichiometry were synthesized and in vitro tested as anticancer agents. One of them showed high cytotoxic activity toward the HCT116 colorectal human carcinoma cell line, paving the way to future in vivo studies aimed at evaluating the role of carbohydrates in the selective delivery of whole molecules into cancerous cells.

Is matching ruthenium with dithiocarbamato ligands a potent chemotherapeutic weapon in oncology?

In the last years, several metal-based compounds have been designed and biologically investigated worldwide in order to obtain chemotherapeutics with a better toxicological profile and comparable or higher antiblastic activity than the clinically-established platinum-based drugs. In this context, researchers have addressed their attention to alternative nonplatinum derivatives able to maximize the anticancer activity of the new drugs and to minimize the side effects. Among them, a number of ruthenium complexes have been developed, including the compounds NAMI-A and KP1019, now in clinical trials. Here, we report the results collected so far for a particular class of ruthenium complexes - the ruthenium(II/III)-dithiocarbamates - which proved more potent than cisplatin in vitro, even at nanomolar concentrations, against a wide panel of human tumor cell lines.

Gold(III)-pyrrolidinedithiocarbamato Derivatives as Antineoplastic Agents.

Transition metals offer many possibilities in developing potent chemotherapeutic agents. They are endowed with a variety of oxidation states, allowing for the selection of their coordination numbers and geometries via the choice of proper ligands, leading to the tuning of their final biological properties. We report here on the synthesis, physico-chemical characterization, and solution behavior of two gold(III) pyrrolidinedithiocarbamates (PDT), namely [Au(III)Br2(PDT)] and [Au(III)Cl2(PDT)]. We found that the bromide derivative was more effective than the chloride one in inducing cell death for several cancer cell lines. [Au(III)Br2(PDT)] elicited oxidative stress with effects on the permeability transition pore, a mitochondrial channel whose opening leads to cell death. More efficient antineoplastic strategies are required for the widespread burden that is cancer. In line with this, our results indicate that [Au(III)Br2(PDT)] is a promising antineoplastic agent that targets cellular components with crucial functions for the survival of tumor cells.