Synthesis, Characterization, and Comparative in Vitro Cytotoxicity Studies of Platinum(II), Palladium(II), and Gold(III) Methylsarcosinedithiocarbamate Complexes

This work reports on the synthesis, characterization, and in vitro cytotoxic activity of some new platinum(II), palladium(II), and gold(III) derivatives of methylsarcosinedithiocarbamate and its S-methyl ester, to study their behavior as potential antitumor agents. The biological activity of these compounds, as determined by growth inhibition and apoptosis induction, has been investigated in both human leukemic promyelocites HL60 and human squamous cervical adenocarcinoma HeLa cell lines, and their activity has been compared to the well-known platinum-based anticancer agent cisplatin. On the basis of these experimental results, [Pd(MSDT)X]n (MSDT = methylsarcosinedithiocarbamate; X = Cl, Br) complexes show a strong dose-dependent growth inhibition of both HL60 and HeLa cells, with IC50 values slightly higher than those recorded for cisplatin; moreover, [Au(MSDT)X2] activity appears significantly higher or, at least, comparable to that of the reference drug. Exposure of both cell lines to [Pd(MSDT)X]n and [Au(MSDT)X2] complexes induces apoptosis, as determined by an Apo2.7 assay

Chimeric siRNA-DNA Surfactants for the Enhanced Delivery and Sustained Cytotoxicity of a Gold(III) Metallodrug

Using a recently developed nucleic acid delivery platform, we demonstrate the effective delivery of metallodrug [AuIIIBr2(SSC-Inp-OEt)] (AP228; Inp = isonipecotic moiety), a hydrophobic, low solubility gold complex cytotoxic to cancer cells. It is shown that AP228 is delivered more effectively into HeLa cells using micellular surfactant assemblies compared to that of a more polar derivative [AuIIIBr2(SSC-Inp-GlcN1)] (AP209; GlcN1 = (α,β)-d-glucosamino moiety). When AP228 is codelivered with siRNA targeting Bcl-2, a key regulator of apoptosis, the overall cytotoxic therapeutic effects of the drug are maximized. The optimized delivery and distribution of the compound is monitored by both fluorescence microscopy and inductively coupled plasma mass spectrometry. We show that codelivery of the AP228 and Bcl-2 targeting siRNA results in a substantial increase in drug efficacy, wherein the cytotoxic therapeutic effects of the drug are maximized, reducing the IC50 from 760 nM to 11 nM. This hybrid small molecule drug and therapeutic nucleic acid delivery vehicle is shown to enable both the improved solubility and uptake of the gold­(III) metallodrugs and the delivery of chemically unmodified siRNA, resulting in enhanced cytotoxic effects

Gold Dithiocarbamate Derivatives as Potential Antineoplastic Agents: Design, Spectroscopic Properties, and in Vitro Antitumor Activity

At present, cisplatin (cis-diamminodichloroplatinum(II)) is one of the most largely employed anticancer drugs as it is effective in the treatment of 70−90% of testicular and, in combination with other drugs, of ovarian, small cell lung, bladder, brain, and breast tumors. Anyway, despite its high effectiveness, it exhibits some clinical problems related to its use in the curative therapy, such as a severe normal tissue toxicity (in particular, nephrotoxicity) and the frequent occurrence of initial and acquired resistance to the treatment. To obtain compounds with superior chemotherapeutic index in terms of increased bioavailability, higher cytotoxicity, and lower side effects than cisplatin, we report here on some gold(I) and gold(III) complexes with dithiocarbamate ligands (DMDT = N,N-dimethyldithiocarbamate; DMDTM = S-methyl-N,N-dimethyldithiocarbamate; ESDT = ethylsarcosinedithiocarbamate), which have been synthesized, purified, and characterized by means of elemental analyses, conductivity measurements, mono- and bidimensional NMR, FT-IR, and UV−vis spectroscopy, and thermal analyses. Moreover, the electrochemical properties of the designed compounds have been studied through cyclic voltammetry. All the synthesized gold complexes have been tested for their in vitro cytotoxic activity. Remarkably, most of them, in particular gold(III) derivatives of N,N-dimethyldithiocarbamate and ethylsarcosinedithiocarbamate, have been proved to be much more cytotoxic in vitro than cisplatin, with IC50 values about 1- to 4-fold lower than that of the reference drug, even toward human tumor cell lines intrinsically resistant to cisplatin itself. Moreover, they appeared to be much more cytotoxic also on the cisplatin-resistant cell lines, with activity levels comparable to those on the corresponding cisplatin-sensitive cell lines, ruling out the occurrence of cross-resistance phenomena and supporting the hypothesis of a different antitumor activity mechanism of action

Design and results of the Coherent Dot Motion (CDM) task.

<p>Panel A: Schematic representation of central and peripheral condition of the CDM task used in the present study. Panel B: Graph shows mean threshold as a function of group (ASD and TD) and condition (central and peripheral CDM). Error bars represent the standard error of the mean. * represents a significant difference revealed by planned comparisons (p<.05).</p

Partial correlation plot showing the relationship between central (Panel A) and peripheral (Panel B) CDM threshold and attentional gradient in large cue condition (i.e. zoom-out attentional index), controlled for age and performance IQ.

<p>Values on the x-axis represent the residuals of attentional zoom-out index. Values on the y-axis represent the residuals of threshold in the central CDM task.</p

Partial correlation plots showing the relationship between the following: A) the threshold in the central CDM task and ADOS total interaction score; B) the threshold in the peripheral CDM task and ADOS total interaction score; C) the attentional zoom-out index and ADOS total interaction score.

<p>Values on the x-axis represent the residuals of central CDM threshold (Panel A), of peripheral CDM threshold (Panel B) and of attentional zoom-out index (Panel C). Values on the y-axis represent the residuals of ADOS total interaction score.</p

Descriptive statistics for autism spectrum disorder (ASD) and typically developing (TD) groups.

<p>PIQ = performance intelligence quotient, VIQ = verbal intelligence quotient, TIQ = total intelligence quotient. Vocabulary, similarities, Picture completion, and block design are subtests from WISC-R <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049019#pone.0049019-Wechsler1" target="_blank">[34]</a>.</p

Design of the attentional zooming task.

<p>Panel A (large cue condition) and B (small cue condition) show the two types of trials in the attentional zooming task employed in Ronconi and colleagues. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049019#pone.0049019-Ronconi2" target="_blank">[30]</a>. Panel C and D reported a schematic illustration of how the attentional gradient was computed (i.e., a measure of the zoom-in/zoom-out mechanism). The gradient effect in the large cue represents a measure of the ability to enlarge the attentional focus (zoom-out), whereas the gradient effect in the small cue represents a measure of the ability to narrow the attentional focus (zoom-in).</p

Results of the attentional zooming task showing: A) the mean reaction times as a function of cue size, eccentricity and group; B) the mean attentional gradient for ASD and TD groups as a function of cue size (large vs. small).

<p>Error bars represent the standard error of the mean and * indicates a significant difference revealed by planned comparisons.</p

Gold(III) Dithiocarbamate Derivatives for the Treatment of Cancer: Solution Chemistry, DNA Binding, and Hemolytic Properties

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