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Neurofibromin loss drives neoplastic growth and a rewiring of mitochondrial metabolism. Here we report that neurofibromin ablation dampens expression and activity of NADH dehydrogenase, the respiratory chain complex I, in an ERK-dependent fashion, decreasing both respiration and intracellular NAD+. Expression of the alternative NADH dehydrogenase NDI1 raises NAD+/NADH ratio, enhances the activity of the NAD+-dependent deacetylase SIRT3 and interferes with tumorigenicity in neurofibromin-deficient cells. The antineoplastic effect of NDI1 is mimicked by administration of NAD+ precursors or by rising expression of the NAD+ deacetylase SIRT3 and is synergistic with ablation of the mitochondrial chaperone TRAP1, which augments succinate dehydrogenase activity further contributing to block pro-neoplastic metabolic changes. These findings shed light on bioenergetic adaptations of tumors lacking neurofibromin, linking complex I inhibition to mitochondrial NAD+/NADH unbalance and SIRT3 inhibition, as well as to down-regulation of succinate dehydrogenase. This metabolic rewiring could unveil attractive therapeutic targets for neoplasms related to neurofibromin loss.

Neurofibromin loss drives neoplastic growth and a rewiring of mitochondrial metabolism. Here we report that neurofibromin ablation dampens expression and activity of NADH dehydrogenase, the respiratory chain complex I, in an ERK-dependent fashion, decreasing both respiration and intracellular NAD

This work is focused on the synthesis, characterization, and preliminary biological evaluation of bio-conjugated Au-III and Cu-II 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.

This paper deals with the combination of a proline-based moiety with biologically active gold centers in the oxidation states +1 and +3. In particular, six Au(i)/(iii)-proline dithiocarbamato (DTC) complexes with general formulae [Au(DTC)2] and [AuIIIX2(DTC)] (X = Cl, Br) are reported here. After the synthesis of the ligand and the complexes, all derivatives were characterized via several techniques and tested for their stability in DMSO/water media. This study was focused on the demonstration of a peculiar behavior of Au(iii)-DTC species in solution. Finally, the complexes were screened for their antiproliferative activity against 2 human cancer cell lines, namely HepG2 and HepG2/SB3, taken as models of hepatocellular carcinoma. The latter, chosen for its aggressiveness due to the upregulation of the anti-apoptotic protein SerpinB3, was selectively inhibited in terms of growth by some Au(iii)-DTC complexes.

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 (β-[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.

Five new Au-III-peptidodithiocarbamato complexes of the type [(AuBr2)-Br-III(dtc-AA(1)-AA(2)-OR] (in which AA(1)=N-methylglycine (Sar), l/d-Pro; AA(2)=l/d-Ala, -aminoisobutyric acid (Aib); R=OtBu, triethylene glycol methyl ether), differing with regard to the amino acid sequence and/or the chiral amino acid configuration, were designed to enhance tumor selectivity and bioavailability. The gold(III)-based moiety was functionalized to exploit the targeting properties of the peptidomimetic ligand toward two peptide transporters (namely PEPT1 and PEPT2), which are upregulated in several tumor cells. The compounds were synthesized and fully characterized, mainly by means of elemental analysis, one- and two-dimensional NMR spectroscopy, FT-IR, and UV/Vis spectrophotometry. 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 [non-small-cell lung carcinoma], MCF-7 [breast cancer], A2780 [ovarian carcinoma], H1975 [non-small-cell lung carcinoma], H460 [large-cell lung carcinoma], and A431 [human epidermoid carcinoma]) showed the dtc-Pro-Aib-OtBu derivative to be very effective, with GI(50) values much lower than those of cisplatin. This complex was thus selected for evaluating stability under physiological conditions and possible interactions with serum albumin, as well in PARP-1 enzyme inhibition assays and preliminary ex vivo toxicity experiments on healthy rat tissues.

Since the discovery of cisplatin in the 1960s, other metal complexes have been investigated as potential antitumor agents to overcome the side-effects associated with the administration of the Pt-based drug. In line with our previous research, in this work we report the synthesis and characterization of mono- and dinuclear Ru(III) complexes with the pyrrolidinedithiocarbamate (PDT) ligand and the more sterically-hindered carbazole-dithiocarbamato ligand (CDT), to compare their properties (both at the chemical and antiproliferative level), in an attempt to assess a structure-activity rationale. Moreover, to overcome the scarce solubility under physiological conditions of the Ru(III)-dithiocarbamato compounds, the biocompatible copolymer Pluronic® F127 has been used, to encapsulate the metal derivatives in water-soluble micellar carriers. Finally, preliminary biological evaluations on CDT and PDT compounds along with their nanoformulations, open intriguing perspectives in anticancer chemotherapy. In particular, comparing the structure of the Ru(III) derivatives, the ionic dinuclear PDT complex shows an important cytotoxic action in comparison to its neutral counterparts. Moreover, the micellar carrier improves the overall activity of the encapsulated Ru(III)-PDT chemotherapeutics. On the other hand, the nanoformulation of the CDT derivatives allows us to solubilize both the 1:3 and the 2:5 complexes and to state their inactivity.

This work is focused on the synthesis, characterization, and preliminary biological evaluation of bio-conjugated Au

The medicinal gold(III) dithiocarbamato complex AuL12 forms a stable adduct with bovine serum albumin. The crystal structure reveals that a single gold(I) center is bound to Cys34, with the dithiocarbamato ligand being released. To the best of our knowledge, this is the first structure for a gold adduct of serum albumin.

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 action

In this paper, we focused on the analysis of the effects mediated by different cyclic dithiocarbamic ligands (DTC) on three classes of antiproliferative coordination compounds, namely, Ru(III) complexes with the general formulae [Ru(DTC)3] and [Ru2(DTC)5]Cl, and the neutral Cu(II) derivatives of the type [Cu(DTC)2]. In particular, we present the synthesis and characterization of a library of total 23 coordination compounds containing Ru(III) or Cu(II) as the biologically-active metal center and two or more dithiocarbamato (DTC) ligands derived from cyclic amines (aliphatic or aromatic). Several techniques including elemental analysis, X-ray crystallography, ESI-MS, 1H-NMR spectroscopy, FT-IR and UV-Vis spectrophotometry were used to characterize the compounds, which highlighted the different electronic behaviors generated by the substituents within the DTC moiety. Moreover, the synthesized compounds were tested for their stability in order to investigate their antiproliferative activity against 3 human cancer cell lines, namely, HeLa, HepG2 and HepG2/SB3. In particular, HepG2/SB3 was chosen for its aggressiveness due to upregulation of the anti-apoptotic protein SerpinB3. Finally, the most promising compounds are studied in terms of log P. Overall, the results reveal the drug-likeness of some of the derivatives of copper(II) and ruthenium(III).

AuL10 [AuIIICl2DMDT] (DMDT: N,N-dimethyldithiocarbamate) and AuL12 [AuIIIBr2ESDT] (ESDT: ethylsarcosine dithiocarbamate) are two extremely promising gold-based anticancer compounds. Their mechanisms of action are still largely unknown although some specific hypotheses were put forward. To shed light on reactivity with probable biological targets we report here on their interactions with serum albuminand with calf thymus DNA taken as model biomolecules. Quite unexpectedly, spectrophotometric investigations revealed substantially different patterns of interaction for these two gold complexes with the mentioned biomolecules, probably arising from differences in redox chemistry. Afterwards, AuL12 was tested against A549 human non-small-cell lung carcinoma cells, evaluating its real-time profile of cell-growth inhibition by the xCELLigence Real-Time Cell Analysis (RTCA) system. Measures of the impedance at the base of each well by non-invasive gold microelectrodes point out that this gold complex inhibits cell proliferation after only 4 hours of treatment, producing its cytotoxic effects probably at the membrane level.

The gold(III)-dithiocarbamate complex AuL12 (dibromo [ethyl-N-(dithiocarboxy-kS,kS')-N-methylglycinate] gold(III)), is endowed with promising in vitro/in vivo antitumor activity and toxicological profile. Here, we report our recent strategies to improve its water solubility and stability under physiological conditions along with our efforts for unravelling its tangled mechanism of action. We used three types of alpha-cyclodextrins (CDs), namely beta-CD, Me-beta-CD and HP-beta-CD to prepare aqueous solutions of AuL12. The ability of these natural oligosaccharide carriers to enhance water solubility of hydrophobic compounds, allowed drug stability of AuL12 to be investigated. Moreover, pharmacokinetic experiments were first carried out for a gold(III) coordination compound, after i.v. injection of the nanoformulation AuL12/HP-beta-CD to female mice. The gold content in the blood samples was detected at scheduled times by AAS (atomic absorption spectrometry) analysis, highlighting a fast biodistribution with a t beta 1/2 of few minutes and a slow escretion (t alpha(1/2) of 14.3 h). The in vitro cytotoxic activity of AuL12 was compared with the AuL12/HP-beta-CD mixture against a panel of three human tumor cell lines (i.e., HeLa, KB and MCF7). Concerning the mechanism of action, we previously reported the proteasome-inhibitory activity of some our gold(III)-based compounds. In this work, we moved from the proteasome target to upstream of the important ubiquitin-proteasome pathway, testing the effects of AuL12 on the polyubiquitination reactions involving the Ub-activating (E1) and -conjugating (E2) enzymes. (C) 2017 Elsevier Masson SAS. All rights reserved.

Gold compounds form a new class of promising metal-based drugs with a number of potential therapeutic applications, particularly in the fields of anticancer and antimicrobial treatments. Previous research revealed that a group of structurally diverse gold compounds cause conspicuous inhibition of the protease activities of the human proteasome. Given the pharmacological importance of protease inhibition, the present study further explored whether these gold compounds might inhibit a few other proteases that are accepted druggable targets for disease treatment. In particular, four distinct cysteine proteases were considered here: cathepsin B and L that play a primary role in tumor-cell invasion and metastasis; rhodesain, the major cathepsin L-like cysteine protease of Trypanosoma brucei rhodesiense and CPB2.8 Delta CTE, a Leishmania mexicana mature cysteine protease. Based on the encouraging results obtained for some of the tested gold compounds on the two parasitic cysteine proteases, especially against CPB2.8 Delta CTE, with IC50s in the micromolar range, we next evaluated whether those gold compounds might contrast effectively the growth of the respective protozoa and indeed important antiprotozoal properties were disclosed; on the other hand a certain lack of selectivity was highlighted. Also, no direct or clear correlation could be established between the in vitro antiprotozoal properties and the level of protease inhibition. The implications of these results are discussed in relation to possible pharmaceutical applications.

Pure sterically stabilized micelles (SSM) of DSPE-PEG2000, and sterically stabilized mixed micelles (SSMM) containing PC or DOPC phospholipids (5, 10 or 20% mol/mol with respect to DSPE-PEG2000) are developed as delivery systems for the gold based cytotoxic drug Au(III)-dithiocarbamato complex AuL12. In particular, SSMM containing 5% of PC at 5 mM of lipid concentration encapsulates 61.0 ?g of AuL12 with a DL% of 1.13. The gold complex remains stable up to 72 h when incorporated in the aggregate, as indicated by UV-vis measurements. Incorporation in micelle composition of a low amount of the peptide derivative MonY-BN-AA1, containing a bombesin peptide analogue does not influence structural parameters of the micelles (diameter around 20 nm) neither the AuL12 loading parameters. Target selective properties of the peptide containing full aggregate on PC-3 cells overexpressing the GRP/bombesin receptors are observed by in vitro cytotoxic studies: a decrease of cell viability, ~50%, is obtained in cells treated with AuL12-targeted micelles at 10 ?M drug concentration for 48 h with respect to untargeted micelles. © 2014 Elsevier B.V.

In the last decade, we have been developing some gold(III) derivatives showing interesting antitumor properties and reduced systemic and renal toxicity, compared to the clinically-established reference drug cisplatin. Starting from the rationale at the base of our investigations, this review has been divided into two sections, with respect to our patented first- (aminoderivatives) and secondgeneration (peptidomimetics) potential drugs. Every section describes the in vitro and in vivo anticancer activity of the compounds, chosen as models, towards different types of tumor. In particular, we summarize the results achieved so far, in particular taking into account the latest in-depth studies related to their activity, mechanism of action and toxicological profile. Taken together, our data could open up new prospects for further advanced preclinical pharmacological testing.

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.

Gold(III)-dithiocarbamato complexes have recently gained increasing attention as potential anticancer agents because of their strong tumor cell growth--inhibitory effects, generally achieved by exploiting non-cisplatin-like mechanisms of action. The rationale of our research work is to combine the antitumor properties of the gold(III) metal center with the potential chemoprotective function of coordinated dithiocarbamates in order to reduce toxic side effects (in particular nephrotoxicity) induced by clinically established platinum-based drugs. In this context, [Au(III) Br(2) (ESDT)] (AUL12) was proved to exert promising and outstanding antitumor activity in vitro and to overcome both acquired and intrinsic resistance showed by some types of tumors toward cisplatin. As a subsequent extension of our previous work, we here report on detailed in vivo studies in rodents, including antitumor activity toward three transplantable murine tumor models, toxicity, nephrotoxicity and histopathological investigations. Remarkably, the gold(III) complex AUL12 stands out for higher anticancer activity than cisplatin toward all the murine tumor models examined, inducing up to 80% inhibition of tumor growth. In addition, it shows low acute toxicity levels (lethal dose, LD(50) = 30 mg kg(-1) ) and reduced nephrotoxicity. Altogether, these results confirm the reliability of our drug design strategy and support the validation of this gold(III)-dithiocarbamato derivative as a suitable candidate for clinical trials.

We have previously reported on a gold(III) complex, namely [AuBr(2)(DMDT)] (N,N-dimethyldithiocarbamate) showing potent in vitro and in vivo growth inhibitory activities toward human cancer cells and identifying the cellular proteasome as one of the major targets. However, the importance of the oxidation state of the gold center and the involved mechanism of action has yet to be established. Here we show that both gold(III)- and gold(I)-dithiocarbamato species, namely [AuBr(2)(ESDT)] (AUL12) and [Au(ESDT)](2) (AUL15), could inhibit the chymotrypsin-like activity of purified 20S proteasome and 26S proteasome in human breast cancer MDA-MB-231 cells, resulting in accumulation of ubiquitinated proteins and proteasome target proteins, and induction of cell death, but at significantly different levels. Gold(I)- and gold(III)-compound-mediated proteasome inhibition and cell death induction were completely reversed by the addition of a reducing agent, dithiothreitol or N-acetyl-L-cysteine, suggesting the involvement of redox processes. Furthermore, treatment of MDA-MB-231 cells with gold(III) compound (AUL12), but not the gold(I) analog (AUL15), resulted in the production of significant levels of reactive oxygen species. Our study provides strong evidence that the cellular proteasome is an important target of both gold(I) and gold(III)-dithiocarbamates, but distinct cellular mechanisms of action are responsible for their different overall effect.

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.

The bioavailability and target selectivity of chemotherapeutics are significant issues in drug development. Here, we report the loading of the antiproliferative gold(III) complex, dibromo[ethyl-N-(dithiocarboxy-kS,kS′)-N-methylglycinato] gold(III) (AuL12), into the lipophilic core of micelles produced from the surfactant Pluronic® F127 (PF127). When AuL12 is encapsulated in PF127-based micelles it remains stable in saline solution up to 72 h with the gold center in the +3 oxidation state. PF127-based aggregates are efficient carriers as they enhance the water solubility of the gold complex. In vitro studies indicate that after micelle encapsulation, AuL12 gold complex preserves its antiproliferative efficacy. Moreover, by labeling the hydrophilic shell of micelles with the bioactive CCK8 peptide, the aggregates act as target-selective vehicles. In fact, cytotoxic activity towards the A431 cells overexpressing the CCK2 receptors is 10-fold higher than that towards the control cells.

Gold(III) compounds are emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. We report here on the solution and electrochemical properties, and the biological behavior of some gold(III) dithiocarbamate derivatives which have been recently proved to be one to 4 orders of magnitude more cytotoxic in vitro than the reference drug (cisplatin) and to be able to overcome to a large extent both intrinsic and acquired resistance to cisplatin itself. Their solution properties have been monitored in order to study their stability under physiological conditions; remarkably, they have shown to undergo complete hydrolysis within 1 h, the metal center remaining in the +3 oxidation state. Their DNA binding properties and ability in hemolyzing red blood cells have been also evaluated. These gold(III) complexes show high reactivity toward some biologically important isolated macromolecules, resulting in a dramatic inhibition of both DNA and RNA synthesis and inducing DNA lesions with a faster kinetics than cisplatin. Nevertheless, they also induce a strong and fast hemolytic effect (compared to cisplatin), suggesting that intracellular DNA might not represent their primary or exclusive biological target.

The synthesis and characterization of new coordination compounds of some organotin(IV) chlorides with ethylsarcosine hydrochloride (N-methylglycine ethyl ester hydrochloride) is reported; the ligand molecules appear to be bound to the tin atoms through the carbonyl oxygen atoms by means of dative bonds. As single crystals were not obtained, a number of experimental techniques were used to accomplish a definitive characterization and determination of their structure. The results obtained by 1H, 13C, 119Sn NMR, FT-IR and 119mSn Mossbauer spectroscopy and thermogravimetric analysis suggested pentacoordination for the 1:1 (Sn:ligand (ESH)) derivatives, [R2SnCl2(ESH)]+Cl−, in a trigonal bipyramidal (TBP) structure, and hexacoordination for the 1:2 complexes, [R2SnCl2(ESH)2]2+2Cl−, in an octahedral structure (R = Me, n-Bu, Ph; ESH = protonated ethylsarcosine, CH3CH2O(O)CCH2N(CH3)H2+). The triphenyltin(IV) chloride ethylsarcosine hydrochloride derivative exists only as a 1:1 pentacoordinated adduct in a strongly distorted TBP structure. Finally, the compounds have been tested for in vitro cytotoxic activity against human adenocarcinoma HeLa cells, showing, in some cases, a high potency, even at low concentration. Copyright © 2002 John Wiley & Sons, Ltd.

This work reports on the synthesis, characterization and biological activity of new coordination compounds of the type [M(TSDTM)X 2 ] (M=Pt(II), Pd(II); X=Cl, Br; TSDTM= ter -butylsarcosine( S -methyl)dithiocarbamate) and [Pd(TSDT)X] n (TSDT= ter -butylsarcosinedithiocarbamate) in order to study their behavior as potential antitumor agents. All the synthesized compounds were characterized by means of elemental analysis, FT-IR, 1 H and 13 C-NMR spectroscopy and thermogravimetric analysis, suggesting a chelate S , S ′ structure of the TSDTM/TSDT ligand in a square-planar geometry. Finally, the synthesized complexes have been tested for in vitro cytotoxic activity against human leukemic HL60 and adenocarcinoma HeLa cells; the most active compound [Pt(TSDTM)Br 2 ], characterized by IC 50 values very similar to those of the reference compound (cisplatin), was also tested for in vitro nephrotoxicity showing a very low renal cytotoxicity as compared to cisplatin itself.

Background: Recently, novel gold(III)-dithiocarbamato peptidomimetics, designed to target peptide transporters upregulated in several tumor cells have shown promise as anticancer agents. Results: The biological behavior of the most promising derivatives AuD8 and AuD9 was studied in PC3 and DU145 prostate cancer cells. They exert higher cytotoxicity in vitro than the reference drug cisplatin and induce apoptosis, promoting mitochondrial membrane permeabilization and stimulating reactive oxygen species generation. Moreover, they inhibit both selenoenzyme thioredoxin reductase and proteasome activity. Additionally, AuD8 effectively reduces tumor growth in prostate tumor-bearing nude mice with minimal systemic toxicity. Conclusion: Altogether, our results provide insights into the anticancer activity of these gold(III)-dithiocarbamato peptidomimetics and support their potential as new agents for prostate cancer treatment.

Palladium and platinum dihalides react with dl-selenomethionine (sem), yielding the complexes [M(sem)X2](M=Pd,X=Cl or Br;M=Pt,X=Cl) and, in the presence of N,N-dimethylformamide (dmf), the species [M(sem)X2]·dmf (M=Pd, X=I; M=Pt, X=Cl, Br or I). The complexes were characterized by i.r. and proton n.m.r. spectroscopy and by thermogravimetric analysis, and their properties were compared with those of the dl-methionine analogues [M(Met)Cl2] and [Pt(Met)Cl2]·dmf. On the basis of n.m.r. data in deuteriated dimethyl sulfoxide, the platinum complexes undergo ligand rearrangement to form [Pt(sem)2]2+ moieties whereas the solvent does not seem to interact with the palladium coordination sphere, which contains the chelated N, Se ligand.

Some gold(III)-dithiocarbamato derivatives of either single amino acids or oligopeptides have shown promise 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 [Au(III)Br2(dtc-Sar-OCH3)] (dtc: dithiocarbamate; Sar: sarcosine (N-methylglycine)) with selected model molecules for histidine-, methionine-, and cysteine-rich proteins (that is, 1-methylimidazole, dimethylsulfide, and N-acetyl-L-cysteine, respectively). In particular, detailed mono- and multinuclear NMR studies, in combination with multiple (13)C/(15)N enrichments, allowed interactions to be followed over time and indicated somewhat unexpected reaction pathways. Whereas dimethylsulfide proved to be unreactive, a sudden multistep redox reaction occurred in the presence of the other potential sulfur donor, N-acetyl-L-cysteine (confirmed if glutathione was used instead). On the other hand, 1-methylimidazole underwent an unprecedented acid-base reaction with the gold(III) complex, rather than the expected coordination to the metal center by replacing, for instance, a bromide. Our results are discussed herein and compared with the data available in the literature on related complexes; our findings confirm that the peculiar reactivity of gold(III)-dithiocarbamato complexes can lead to novel reaction pathways and, therefore, to new cytotoxic mechanisms in cancer cells.

Palladium and platinum dihalides reacted with N,N-dimethylselenourea (dmsu) yielding complexes of the general formulae [M(dmsu) 4 ]X 2 , [M(dmsu) 3 X]X, [Pd(dmsu) 2 X 2 ] and Pt(dmsu) 1.5 X 2 , (M = Pd or Pt; X = Cl or Br); which were characterized by IR and proton NMR spectroscopy and thermogravimetric analysis (TD, DTG and DTA). The 1:4 adducts can be obtained in two crystalline forms, depending on the crystallization medium. In particular, [Pd(dmsu) 4 ]Cl 2 crystals have been obtained in deuterated chloroform, which differ from those of [Pd(dmsu) 4 ]Cl 2 · 0.5EtOH samples obtained in ethanol/ n -pentane. In the latter case a solvent molecule is interspersed in the crystal packing. The crystal structures of both modifications have been determined by X-ray crystallography and refined to R = 0.042 and R = 0.062, respectively. In both structures the Pd(dmsu) 4 2+ complex cation is approximately square planar with Pd-Se bonds ranging from 2.43 to 2.46 A. An extensive net of NH···Cl bonds is present in the crystal packing of the compounds.

As a further extension of our research work focusing on the development of gold(III)-dithiocarbamato dtc derivatives of oligopeptides as potential anticancer agents, complexes [Au III X 2 (dtc-Sar- l -Ser( t -Bu)-O( t -Bu))] (X = Br ( 1a )/Cl ( 1b )), [Au III X 2 (dtc-AA-Aib 2 -O( t -Bu))] (AA = Sar (sarcosine, N -methylglycine), X = Br ( 2a )/Cl ( 2b ); AA = d,l -Pro, X = Br ( 3a )/Cl ( 3b )), [Au III X 2 (dtc-Sar-Aib 3 -O( t -Bu))] (X = Br ( 4a )/Cl ( 4b )), and [Au III X 2 (dtc-Sar-Aib 3 -Gly-OEt)] (X = Br ( 5a )/Cl ( 5b )) (Aib = “alpha”-aminoisobutyric acid, 2-methylalanine) were designed to obtain metal-based peptidomimetics that may specifically target two peptide transporters (namely, PEPT1 and PEPT2) upregulated in several human tumor cells. All the compounds were characterized by means of FT-IR and mono- and multidimensional NMR spectroscopy. According to in vitro cytotoxicity studies, complex [Au III Cl 2 (dtc- d,l -Pro-Aib 2 -O( t -Bu))] ( 3b ) turned out to be the most effective toward the four human tumor cell lines evaluated (PC3, 2008, C13, and L540), for which the IC 50 values were lower than cisplatin. Remarkably, it showed no cross-resistance with cisplatin itself and was proved to inhibit tumor cell proliferation by inducing almost exclusively late apoptosis/necrosis. Biological results are here reported and discussed in terms of the structure–activity relationship.

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.

Cytotoxic gold compounds hold today great promise as new pharmacological agents for treatment of human ovarian carcinoma; yet, their mode of action is still largely unknown. To shed light on the underlying molecular mechanisms, we performed 2D-DIGE analysis to identify differential protein expression in a cisplatin-sensitive human ovarian cancer cell line (A2780/S) following treatment with two representative gold(iii) complexes that are known to be potent antiproliferative agents, namely AuL12 and Au(2)Phen. Software analysis using DeCyder was performed and few differentially expressed protein spots were visualized between the three examined settings after 24 h exposure to the cytotoxic compounds, implying that cellular damage at least during the early phases of exposure is quite limited and selective, reflecting the attempts of the cell to repair damage and to survive the insult. The potential of novel proteomic methods to disclose mechanistic details of cytotoxic metallodrugs is herein further highlighted. Different patterns of proteomic changes were highlighted for the two metallodrugs with only a few perturbed protein spots in common. Using MALDI-TOF MS and ESI-Ion trap MS/MS, several differentially expressed proteins were identified. Two of these were validated by western blotting: Ubiquilin-1, responsible for inhibiting degradation of proteins such as p53 and NAP1L1, a candidate marker identified in primary tumors. Ubiquilin-1 resulted over-expressed following both treatments and NAP1L1 was down-expressed in AuL12-treated cells in comparison with control and with Au(2)Phen-treated cells. In conclusion, we performed a comprehensive analysis of proteins regulated by AuL12 and Au(2)Phen, providing a useful insight into their mechanisms of action.

To date, cisplatin and its analogs are among the most effective chemotherapeutic agents for cancer treatment. However, high systemic toxicity and the propensity for patients to develop tumor resistance remain the main challenges in the clinical application. Therefore, the discovery and development of novel active chemotherapeutic agents are largely needed and the research of new metal-based anticancer drugs continues to be a very active international field. In this review paper we aim to give a detailed overview on our research work devoted to the design of novel dithiocarbamato complexes with different noble metals (such as palladium, platinum, copper, ruthenium and gold), which have gained considerable interest in both the development and the treatment of cancer. In particular, we summarize the results of the metal complexes achieved so far, focusing on the gold(III) compounds, that show outstanding in vitro and in vivo antitumor properties and reduced, or even no, systemic and renal toxicity, compared to the reference drug cisplatin.

Hereby we present the synthesis of several ruthenium(II) and ruthenium(III) dithiocarbamato complexes. Proceeding from the Na[trans-Ru(III)(dmso)(2)Cl(4)] (2) and cis-[Ru(II)(dmso)(4)Cl(2)] (3) precursors, the diamagnetic, mixed-ligand [Ru(II)L(2)(dmso)(2)] complexes 4 and 5, the paramagnetic, neutral [Ru(III)L(3)] monomers 6 and 7, the antiferromagnetically coupled ionic α-[Ru(III)(2)L(5)]Cl complexes 8 and 9 as well as the β-[Ru(III)(2)L(5)]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 (1)H NMR and FTIR spectroscopy. Moreover, for the first time the crystal structures of the dinuclear β-[Ru(III)(2)(dmdt)(5)]BF(4)⋅CHCl(3)⋅CH(3)CN and of the novel [Ru(II)L(2)(dmso)(2)] complexes were also determined and discussed. For both the mono- and dinuclear Ru(II) and Ru(III) 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 Ru(III) 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 Ru(II) complexes 4 and 5 has been observed.

As a further extension of our research work focusing on the development of gold(III)-dithiocarbamato derivatives as potential anticancer agents, the new complexes [AuIIIX2(dtc-Sar-O(t-Bu))] (X = Cl (1)/Br (2)) are here reported. The compounds were characterized by means of FT-IR, ESI mass, and mono- and multidimensional NMR spectroscopy. In order to get further insights into the possible behavior under physiological conditions, their affinity toward selected model biomolecules was spectroscopically investigated in detail. In this regard, they seem to react very slowly with isolated dAMP (but not dGMP), forming a species identified as [AuIII(dtc-Sar-O(t-Bu))(dAMP-N1,C6NH)]+. In presence of GSH they undergo sudden reduction to the gold(I) counterpart [AuIII2(dtc-Sar-O(t-Bu))2], whereas only secondary interactions seem to occur when reacted with BSA. According to in vitro cytotoxicity studies, both complexes turned out to be highly effective toward all the human tumor cell lines evaluated (HeLa, L540 and U937), reporting IC50 values lower than cisplatin. Apoptosis was proved a major cell death mechanism and, accordingly, DNA fragmentation was observed. Remarkably, cell cycle progression was negligibly affected, thus supporting the hypothesis of a different mechanism of action from clinically-established platinum-based drugs.

Group 3 and rare-earth triflate-complexes M(OTf)2(bdmpza) {M = Sc (1Sc ), Y (1Y ), La (1La ), Sm (1Sm ), Eu (1Eu ) OTf = SO3CF3} bearing the heteroscorpionate ligand bdmpza {bdmpza = bis(3,5-dimethyl-pyrazol-1-yl)acetate} have been synthesized and characterized, together with the yttrium and europium complexes M(OTf)(bdmpza)2 {M = Y (2Y ), Eu (2Eu )}. The photoluminescent behavior of 2Eu has been investigated. The coordination mode of the [N,N,O]-donor in these complexes has been elucidated by DFT calculations. The cytotoxic effect of selected complexes and of the free ligand toward HeLa cells has been evaluated.

During the last decade, our research group has prepared a number of metal dithiocarbamato derivatives of Pt, Pd and Au that were expected to resemble the main features of cisplatin together with higher activity, improved selectivity and bioavailability, and lower side-effects. Furthermore, we have already published the synthesis, characterization and in vitro cytotoxicity studies of novel ruthenium(III) dithiocarbamato complexes such as [RuL(3)] monomers (11) and α-[Ru(2)L(5)]Cl dimers (12) with five different dithiocarbamate ligands. As both the monomer and the dinuclear complexes have shown significant antitumor activity in different human tumor cell lines, we decided to widen the characterization studies and to analyse thoroughly their behavior in physiological-like medium by UV-visible and CD spectroscopy. In the present paper we report on the crystal structure of [Ru(DMDT)(3)], [Ru(PDT)(3)] and [Ru(ESDT)(3)] complexes and we determine the spin state of the paramagnetic Ru(III) by means of Evans' method. Then, we discuss in detail the UV-visible spectral data of the complexes in different medium. All the studied complexes are stable in dimethyl sulfoxide, and show low solubility in phosphate buffered saline solution, particularly the monomer species, even at low concentration, while increased solubility for both types of complexes have been found in the presence of bovine serum albumin (BSA). Moreover, no changes on the coordination sphere of the metal, as well as no direct interaction between the BSA protein and the complex have been identified by UV-visible spectroscopy. However, some conformational changes on the BSA structure, induced by the ruthenium(III) complexes have been confirmed by CD spectroscopy, indicating a probable secondary electrostatic interaction between the metal complex and the peptide. In addition, no significant interaction has been demonstrated with the components of Dulbecco's Modified Eagle's Medium, used for the in vitro assays.

Among the nonplatinum antitumor drugs, gold(III)-dithiocarbamato derivatives have recently attracted considerable attention due to their strong in vitro and in vivo antiproliferative activity and reduced renal toxicity. Some of them, namely [AuCl(2) (DMDT)] (compound 1) and [AuBr(2) (ESDT)] (compound 2), have shown to be highly active against the androgen-resistant prostate cancer cell lines PC3 and DU145, both inhibiting cell proliferation in a dose-dependent way, and are more active than the reference drug cisplatin (cis-[PtCl(2) (NH(3) )(2) ]). In particular, [AuCl(2) (DMDT)] was proved cytotoxic against cisplatin-resistant R-PC3 cells, with activity levels comparable to those induced on the parent cisplatin-sensitive PC3 cells, ruling out the occurrence of cross-resistance phenomena. Moreover, it causes early cell damage, slightly affecting the cell cycle, thus suggesting a different mechanism of action from clinically established platinum-based drugs. In fact, the investigated gold(III) complex alters mitochondrial functions, promoting mitochondrial membrane permeabilization and Cyt-c release, stimulating ROS generation, and strongly inhibiting the activity of the selenoenzyme TrxR, which is overexpressed in prostate cancer and associated with the onset of drug resistance. In addition, it induces apoptosis, caspase activation, Bcl-2 downregulation and Bax upregulation, reduces the expression of the phosphorylated form of the EGFR, and it inhibits PC3 cell migration. Finally, the treatment of PC3 prostate tumor-bearing nude mice with [AuCl(2) (DMDT)] significantly inhibited tumor growth in vivo, causing minimal systemic toxicity. Altogether, our results confirm that these gold(III)-dithiocarbamato derivatives have potential for the treatment of prostate cancer.

Since ancient times, many cultures worldwide found out independently that the topical administration of some photoactive natural products (mainly extracted from plants) followed by exposure to sunlight, might be an effective treatment of some skin diseases, thus accidently giving birth to the so-called photochemotherapy. In the attempt to resemble nature by exploiting its teaching, during the last two centuries, scientists tried to rationalize this knowledge in order to develop more effective therapeutic strategies and to understand in depth the mechanisms of action involved, expanding the potential application of this therapy to pathologies other than skin diseases, such as some types of tumors. In this paper we aim at giving an overview on results achieved to date on state-of-the-art photochemotherapy related to the treatment of cancer. The script is organized in three sections. Subsequent to a general introduction describing the origin and basic principles of photochemotherapy, the first section deals with the issue concerning the choice of the proper light sources for each type of therapeutic application, stressing the technological advances in the field (e.g. fiber optics). The second and the third sections provide an overview of the two clinically-established phototherapies to date, that is, PUVA photochemotherapy and PDT, respectively. Both sections are further subdivided into sub-paragraphs emphasizing specific relate topics such as principles and applications, employed light sources, and available data concerning anticancer activity. The third section also provides examples of non-conventional metal-based photosensitizers for PDT.

In this review paper we aim at giving a detailed overview on our research work devoted to the design of gold-based anticancer agents. In particular, during the last decade, we have been developing some gold(III)-dithiocarbamato derivates showing outstanding in vitro and in vivo antitumor properties and reduced, or even no, systemic and renal toxicity, compared to the reference clinically-established anticancer drug cisplatin. Starting from the rationale behind our investigations, we here summarize the results achieved so far, focusing on the latest in-depth mechanistic studies that have recently provided insights into their mechanism of action, thus opening up new prospects for further pharmacological testing and, hopefully, to enter clinical trials.

The reaction of lanthanide(III) salts with 2,6-diformylphenol derivatives in alcoholic media and in the presence of primary amines could lead to formation of different intermediates due to a formyl group — solvent interaction. In particular Schiff bases prepared in alcoholic media should result in mixtures of variously acetalated moieties, derived from acetalation of one of the formyl groups. When dehydroacetic acid reacts with amines, the phenolic moiety turns into pyrone carbonyl owing to an internal rearrangement, the whole molecule behaving preferentially as a neutral donor. Lanthanide salt complexes with condensation precursors containing either formylphenols of ketophenols is reported, along with lanthanide(III) nitrate adducts with 2,6-dimethyl-4H-pyran-4-one.

By reaction of 3-acetyl-4-hydroxy-6-raethyl-2H-pyran-2-one (HDh, dehydroacetic acid) with H2NR (R = Me, nPr or nBu) and HN(CH2CH2NH2)2 the related Schiff bases HDHR and H2Dh2T were obtained. All ligands react with uranyl nitrate yielding 1 : 2 adducts. In the uranyl acetate-HDhR systems adduct formation and ligand deprotonation should occur, depending on solvent, reaction time and hydration, whereas H2Dh2T undergoes total deprotonation in the presence of uranyl acetate to give [UO2(Dh2T)]. Ligands and complexes have been characterized by ir and nmr (1H and 13C) spectroscopy and, in some cases, by thermogravimetric measurements. The action of the amines on the preformed [UO2(Dh)2] complex is discussed.