Binuclear Heteroleptic Ru(III) Dithiocarbamate Complexes: A Step towards Tunable Antiproliferative Agents

Binuclear dithiocarbamate complexes of Ru(III) are promising candidates in the search for outstanding metal-based anticancer agents. While different dithiocarbamates have shown ligand-dependent cytotoxicity in homoleptic binuclear Ru(III) complexes, the properties of heteroleptic analogues with different dithiocarbamate (DTC) ligands have yet to be explored. We herein propose the introduction of heteroleptic ligands as tunable features for the development of improved ruthenium-based antiproliferative agents and report a synthetic strategy for their synthesis as well as the evaluation of the cytotoxic activity of a selection of binuclear heteroleptic Ru(III) compounds towards MDA-MB-231 and PC3 cells

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 [AuIIIBr2(PDT)] and [AuIIICl2(PDT)]. We found that the bromide derivative was more effective than the chloride one in inducing cell death for several cancer cell lines. [AuIIIBr2(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 [AuIIIBr2(PDT)] is a promising antineoplastic agent that targets cellular components with crucial functions for the survival of tumor cells

Chemistry, antiproliferative properties, tumor selectivity, and molecular mechanisms of novel gold(III) compounds for cancer treatment: a systematic study

The antiproliferative properties of a group of 13 structurally diverse gold(III) compounds, including six mononuclear gold(III) complexes, five dinuclear oxo-bridged gold(III) complexes, and two organogold(III) compounds, toward several human tumor cell lines were evaluated in vitro using a systematic screening strategy. Initially all compounds were tested against a panel of 12 human tumor cell lines, and the best performers were tested against a larger 36-cell-line panel. Very pronounced antiproliferative properties were highlighted in most cases, with cytotoxic potencies commonly falling in the low micromolar—and even nanomolar—range. Overall, good-to-excellent tumor selectivity was established for at least seven compounds, making them particularly attractive for further pharmacological evaluation. Compare analysis suggested that the observed antiproliferative effects are caused by a variety of molecular mechanisms, in most cases "DNA-independent,” and completely different from those of platinum drugs. Remarkably, some new biomolecular systems such as histone deacetylase, protein kinase C/staurosporine, mammalian target of rapamycin/rapamycin, and cyclin-dependent kinases were proposed for the first time as likely biochemical targets for the gold(III) species investigated. The results conclusively qualify gold(III) compounds as a promising class of cytotoxic agents, of outstanding interest for cancer treatment, while providing initial insight into their modes of action. Graphical Abstract: A series of gold(III) compounds showed cytotoxic properties and tumor selectivity toward a panel of cancer cell lines. Compare analysis provided insight into their possible mechanisms of actio

Chemistry, antiproliferative properties, tumor selectivity, and molecular mechanisms of novel gold(III) compounds for cancer treatment: a systematic study

The antiproliferative properties of a group of 13 structurally diverse gold(III) compounds, including six mononuclear gold(III) complexes, five dinuclear oxo-bridged gold(III) complexes, and two organogold(III) compounds, toward several human tumor cell lines were evaluated in vitro using a systematic screening strategy. Initially all compounds were tested against a panel of 12 human tumor cell lines, and the best performers were tested against a larger 36-cell-line panel. Very pronounced antiproliferative properties were highlighted in most cases, with cytotoxic potencies commonly falling in the low micromolar-and even nanomolar-range. Overall, good-to-excellent tumor selectivity was established for at least seven compounds, making them particularly attractive for further pharmacological evaluation. Compare analysis suggested that the observed antiproliferative effects are caused by a variety of molecular mechanisms, in most cases "DNA-independent,'' and completely different from those of platinum drugs. Remarkably, some new biomolecular systems such as histone deacetylase, protein kinase C/staurosporine, mammalian target of rapamycin/rapamycin, and cyclin-dependent kinases were proposed for the first time as likely biochemical targets for the gold(III) species investigated. The results conclusively qualify gold(III) compounds as a promising class of cytotoxic agents, of outstanding interest for cancer treatment, while providing initial insight into their modes of action

Anticancer gold(III) peptidomimetics: from synthesis to in vitro and ex vivo biological evaluation

Five new Au(III)‐peptidodithiocarbamato complexes of the type [AuIIIBr2(dtc‐AA1‐AA2‐OR] (AA1=Sar, L/D‐Pro; AA2=L/D‐Ala, Aib; R=OtBu, TEG), differing in the amino acidic sequence and/or the chiral amino acid configuration, were designed to enhance the tumor selectivity and bioavailability. The gold(III)‐based moiety was functionalized to exploit the targeting properties of the peptidomimetic ligand towards two peptide transporters (namely, PEPT1 and PEPT2), up‐regulated in several tumor cells. The compounds were synthesized and fully characterized, mainly by means of elemental analysis, mono‐ and bidimensional NMR spectroscopy, FT‐IR and UV‐Vis spectrophotometries. The crystal structures of three compounds were also solved by X‐ray diffraction. In vitro cytotoxicity studies using a panel of human tumor cell lines (A549, MCF‐7, A2780, H1975, H460 and A431) showed that the dtc‐Pro‐Aib‐OtBu derivative is very effective, with GI50 values much lower than those of Cisplatin. It was thus selected for evaluating the stability under physiological conditions and possible interaction with serum albumin as well as for PARP‐1 enzyme inhibition assays and preliminary ex vivo toxicity experiments on healthy rat tissues