Exploring the C^N^C theme: Synthesis and biological properties of tridentate cyclometalated gold(III) complexes

A family of cyclometalated Au(III) complexes featuring a tridentate CNC scaffold has been synthesized and characterized. Microwave assisted synthesis of the ligands has also been exploited and optimized. The biological properties of the thus formed compounds have been studied in cancer cells and demonstrate generally moderate antiproliferative effects. Initial mechanistic insights have also been gained on the gold complex [Au(CNC)(GluS)] (3), and support the idea that the thioredoxin system may be a target for this family of compounds together with other relevant intracellular thiol-containing molecules. (C) 2017 Elsevier Ltd. All rights reserved

Exploring the Anticancer Activity of Tamoxifen-Based Metal Complexes Targeting Mitochondria

Two new 'hybrid' metallodrugs of Au(III)(AuTAML)and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophoreto ideally synergize the anticancer activity of both the metal centerand the organic ligand. The compounds have antiproliferative effectsagainst human MCF-7 and MDA-MB 231 breast cancer cells. Moleculardynamics studies suggest that the compounds retain the binding activityto estrogen receptor (ER & alpha;). In vitro and in silico studies showed that the Au(III) derivative isan inhibitor of the seleno-enzyme thioredoxin reductase, while theCu(II) complex may act as an oxidant of different intracellular thiols.In breast cancer cells treated with the compounds, a redox imbalancecharacterized by a decrease in total thiols and increased reactiveoxygen species production was detected. Despite their different reactivitiesand cytotoxic potencies, a great capacity of the metal complexes toinduce mitochondrial damage was observed as shown by their effectson mitochondrial respiration, membrane potential, and morphology

Pediatric Mania: The Controversy between Euphoria and Irritability

Abstract: Pediatric Bipolar Disorder (BD) is a highly morbid pediatric psychiatric disease, consistently associated with family psychiatric history of mood disorders and associated with high levels of morbidity and disability and with a great risk of suicide. While there is a general consensus on the symptomatology of depression in childhood, the phenomenology of pediatric mania is still highly debated and the course and long-term outcome of pediatric BD still need to be clarified. We reviewed the available studies on the phenomenology of pediatric mania with the aim of summarizing the prevalence, demographics, clinical correlates and course of these two types of pediatric mania. Eighteen studies reported the number of subjects presenting with either irritable or elated mood during mania. Irritability has been reported to be the most frequent clinical feature of pediatric mania reaching a sensitivity of 95–100% in several samples. Only half the studies reviewed reported on number of episodes or cycling patterns and the described course was mostly chronic and ultra-rapid whereas the classical episodic presentation was less common. Few long-term outcome studies have reported a diagnostic stability of mania from childhood to young adult age. Future research should focus on the heterogeneity of irritability aiming at differentiating distinct subtypes of pediatric psychiatric disorders with distinct phenomenology, course, outcome and biomarkers. Longitudinal studies of samples attending to mood presentation, irritable versus elated, and course, chronic versus episodic, may help clarify whether these are meaningful distinctions in the course, treatment and outcome of pediatric onset bipolar disorder

The Road from Pathological Narcissism to Suicidality in Adolescence: An Empirical Study

Background: Clinical and empirical research evidenced a complex link between pathological narcissism and the suicidal process in adulthood. Given the relevance of suicidality and the peculiar narcissistic vicissitudes of adolescence, the proposed research investigated the relationship between pathological narcissism analyzed from the multi-dimensional perspective of the Diagnostic Interview for Narcissism (DIN) and suicidal ideation conducted in a sample of Italian Adolescents. Methods: One hundred and three Italian male and female adolescents between 12 and 18 were administered the DIN, SCIDII, CSSRS, and Kiddie-SADS with six months follow-up. Results: The correlation, t-test, multiple regression analyses evidenced the association of narcissistic affective states and mood with both suicidal ideation and lethality of conduct. The increase in the dimension of grandiosity is associated with the passage to potentially highly lethal suicidal gestures. Conclusions: Suicidal ideation and conduct seem to serve the function of restoring a sense of control and self-esteem in narcissistic individuals experiencing a state of affective dysregulation. Narcissistic pathological functioning seems to play an important role in the adolescent suicidal process, quite like adulthood. Assessing an adolescent’s narcissistic functioning may provide useful clinical information in understanding and managing the suicidal risk in this phase of life

Thioredoxin reductase: a target for gold compounds acting as a potential anticancer drugs.

The thioredoxin system plays a key role in regulating the overall intracellular redox balance. It basically comprises the small redox protein thioredoxin (Trx), nicotinamide adenine dinucleotide phosphate, in its reduced form (NADPH), and thioredoxin reductase (TrxR), a large homodimeric selenzoenzyme controlling the redox state of thioredoxin. Details of the thioredoxin system are provided herein, particular emphasis being given to the protein chemistry of thioredoxin reductases. Several lines of evidence point out today that the thioredoxin system represents an effective "druggable" target for the development of new anticancer agents. Accordingly, a number of established anticancer agents were retrospectively found to be potent inhibitors of thioredoxin reductases and to induce severe oxidative stress. During the last decade a variety of gold compounds, either gold(I) or gold(III), were reported to manifest outstanding antitumor properties, forming a promising class of experimental anticancer agents. In turn, recent studies have revealed that several cytotoxic gold Compounds, either gold(I) or gold(III), are potent TrxR inhibitors. Details of their mechanism of selenoenzyme inhibition are currently under investigation, in our laboratory, and some new results will be anticipated here; notably, preferential gold targeting of active site selenolate could be experimentally supported. Based on the numerous experimental evidences now available, both at the molecular and cellular level, we propose that the relevant cytotoxic actions produced by gold compounds are mainly the result of potent inhibition of thioredoxin reductase; the alterations of mitochondrial functions, elicited by profound TrxR inhibition, would eventually lead to cell apoptosis. A general and unitary framework is thus offered to interpret the mode of action of cytotoxic gold compounds, according to which they should be primarily considered as antimitochondrial drugs. The peculiar properties of gold compounds highlighted in this review might be further exploited for the obtainment of newer and selective anticancer agents

Thioredoxin reductase: A target for gold compounds acting as potential anticancer drugs

The thioredoxin system plays a key role in regulating the overall intracellular redox balance. It basically comprises the small redox protein thioredoxin (Trx), nicotinamide adenine dinucleotide phosphate, in its reduced form (NADPH), and thioredoxin reductase (TrxR), a large homodimeric selenzoenzyme controlling the redox state of thioredoxin. Details of the thioredoxin system are provided herein, particular emphasis being given to the protein chemistry of thioredoxin reductases. Several lines of evidence point out today that the thioredoxin system represents an effective "druggable" target for the development of new anticancer agents. Accordingly, a number of established anticancer agents were retrospectively found to be potent inhibitors of thioredoxin reductases and to induce severe oxidative stress. During the last decade a variety of gold compounds, either gold(I) or gold(III), were reported to manifest outstanding antitumor properties, forming a promising class of experimental anticancer agents. In turn, recent studies have revealed that several cytotoxic gold Compounds, either gold(I) or gold(III), are potent TrxR inhibitors. Details of their mechanism of selenoenzyme inhibition are currently under investigation, in our laboratory, and some new results will be anticipated here; notably, preferential gold targeting of active site selenolate could be experimentally supported. Based on the numerous experimental evidences now available, both at the molecular and cellular level, we propose that the relevant cytotoxic actions produced by gold compounds are mainly the result of potent inhibition of thioredoxin reductase; the alterations of mitochondrial functions, elicited by profound TrxR inhibition, would eventually lead to cell apoptosis. A general and unitary framework is thus offered to interpret the mode of action of cytotoxic gold compounds, according to which they should be primarily considered as antimitochondrial drugs. The peculiar properties of gold compounds highlighted in this review might be further exploited for the obtainment of newer and selective anticancer agents. (c) 2009 Elsevier B.V. All rights reserved

Predicting suicide in adolescence: Mood disorders, personality pathology and narcissistic functioning

Predicting suicide in adolescence: Mood disorders, personality pathology and narcissistic functioning Riccardo Williams (Dynamic & Clinical Psychology, Rome, Italy) M. P. Casini, G. Serra, C. Frattini, S. Vicari, E. Ronningstam Objective This study has 4 objectives: a) To verify whether the mood disorders/traits have a differential predictive role with respect to three clinical groups of adolescents: Suicidal Ideation, NSSI with suicidal ideation, Suicidal attempts. b) To verify whether the categorical and dimensional traits of personality pathology have a differential predictive role with respect to three clinical groups of adolescents: Suicidal Ideation, NSSI with suicidal ideation, Suicidal attempts. c) To verify whether the dinensions of pathological narcissism have a differential predictive role with respect to three clinical groups of adolescents: Suicidal Ideation, NSSI with suicidal ideation, suicidal attempts. d) To verify whether mood conditions, personality pathology, narcissistic functioning discriminate between the motivations sustaining sucidal ideations and behaviors. Methods Sample A sample of 40 adolescents referred at the Adolescent Psychiatric In-Patient and Mood Disorders Units of the Pediatric Hospital Bambino Gesù of Rome have been recruited with the method of subsequent admissions. Adolescents presenting a QI below 90, a generalized developmental disorder have been excluded from the study. Instruments a) Assessment of suicidal ideation and conducts: - Columbia Suicide Severity Rating Scale (CSSRS): - The Deliberate Self-Harm Inventory (DSHI); b) Assessment of the presence of categorical and dimensional symptoms of mood disorders (and other relevant psychopathological conditions): - Kiddie-SADS PL: clinician’s assessment of diagnosis for Axis I Disorders - Kiddie SADS Mania Rating Scale (K-SADS-MRS): - Child Depression Rating Scale Revised (CDRS-R): c) Categorical and dimensional Assessment of Personality Pathology - SCID II (DSM5-version): questionnaire and interview for personality disorders diagnosis (both categorical and dimensional- number of symptoms measures will be considered). - Diagnostic Interview for Narcissism (DIN) Results Borderline Personality Disorder presents a significant association with suicidal attempts. The narcissistic dimension presented significant associations with suicidal ideation and conducts. Conclusion In order to predict suicidal conducts in adolescence, several factors should be taken into consideration with a specific role to be attributed to narcissistic functioning typical of this developmental stag

Fluorescent silver(I) and gold(I)-N-heterocyclic carbene complexes with cytotoxic properties:mechanistic insights

<p>Silver(I) and gold(I)-N-heterocyclic carbene (NHC) complexes bearing a fluorescent anthracenyl ligand were examined for cytotoxicity in normal and tumor cells. The silver(I) complex exhibits greater cytotoxicity in tumor cells compared with normal cells. Notably, in cell extracts, this complex determines a more pronounced inhibition of thioredoxin reductase (TrxR), but it is ineffective towards glutathione reductase (GR). Both gold and silver complexes lead to oxidation of the thioredoxin system, the silver(I) derivative being particularly effective. In addition, the dimerization of peroxiredoxin 3 (Prx3) was also observed, demonstrating the ability of these compounds to reach the mitochondrial target. The fluorescence microscopy visualization of the subcellular distribution of the complexes shows a larger diffusion of these molecules in tumor cells with respect to normal cells.</p>