A series of novel (C^N) cyclometallated Au(III) complexes of general formula Au(py(b)-H)L(1)L(2)(n+) (py(b)-H = C^N cyclometallated 2-benzylpyridine, L(1) and L(2) being chlorido, phosphane or ...glucosethiolato ligands, n = 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested in vitro in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time C^N cyclometallated gold(III) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance.
A series of novel (C^N) cyclometallated Au(
iii
) complexes of general formula Au(py
b
-H)L
1
L
2
n
+
(py
b
-H = C^N cyclometallated 2-benzylpyridine, L
1
and L
2
being chlorido, phosphane or ...glucosethiolato ligands,
n
= 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested
in vitro
in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our
in vitro
screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time C^N cyclometallated gold(
iii
) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance.
New (C^N) cyclometallated Au(
iii
) complexes with cytotoxic properties shown to be potent inhibitors of the zinc finger protein PARP-1.
A series of novel (C perpendicular ) cyclometallated Au(iii) complexes of general formula Au(py super(b)-H)L super(1)L super(2) super(n+) (py super(b)-H = C perpendicular cyclometallated ...2-benzylpyridine, L super(1) and L super(2) being chlorido, phosphane or glucosethiolato ligands, n= 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested in vitro in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time C perpendicular cyclometallated gold(iii) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance.
Abstract The neuropeptide oxytocin has become a subject of great interest in studies investigating human social cognition. Single intranasal administration of the hormone has been reported to have ...positive behavioral effects, such as increasing trust or facilitating social approach, 45–80 min after administration. However, little is still known about the long-term pharmacokinetics of oxytocin nasal spray application in humans. This study addressed the question how long oxytocin plasma levels remain elevated following nasal spray administration. Another goal was to examine the influence of oxytocin administration on endogenous steroid hormones since such alterations might modulate social behavior via an indirect way. Eight healthy Caucasian men were challenged with a single intranasal application of 26 international units of oxytocin. Changes in oxytocin blood plasma levels, as well as steroid hormone levels of progesterone, testosterone and estradiol were assessed at 5 consecutive time points over a period of 3.5 h (−5, +30, +90, +150, +210 min relative to oxytocin administration). Results gave evidence for a substantial rise of oxytocin plasma levels 30 min after intranasal administration, observed in 7 of 8 participants. Group mean oxytocin plasma level was found to have returned to baseline already 90 min post administration, though in some individuals the plasma levels was still elevated relative to sampling at post 150 min. Steroid hormone analyses yielded a slight augmentation of endogenous testosterone levels 210 min after oxytocin administration. Our data confirms previous findings that oxytocin administered as a nasal spray enters the blood circulation, elevating oxytocin plasma levels for a limited time. Our findings suggest that this time window differs between individuals, but that, for the used dose, it does not extend beyond 150 min post administration. The data further provides preliminary evidence that intranasal oxytocin has an enhancing effect on testosterone in healthy men.
Background Evidence accumulates that the neuropeptide oxytocin plays an important role in mediating social interaction among humans and that a dysfunction in oxytocin-modulated brain mechanisms might ...lie at the core of disturbed social behavior in neuropsychiatric disease. Explanatory models suggest that oxytocin guides social approach and avoidance by modulating the perceived salience of socially meaningful cues. Animal data point toward the ventral tegmental area (VTA) as the brain site where this modulation takes place. Methods We used functional magnetic resonance imaging and a social incentive delay task to test the hypothesis that oxytocin modulates the neural processing of socially relevant cues in the VTA, hereby facilitating behavioral response. Twenty-eight nulliparous women (not taking any hormones) received intranasal oxytocin or placebo in a double-blind randomized clinical trial with a parallel-group design. Results Oxytocin significantly enhanced VTA activation in response to cues signaling social reward (friendly face) or social punishment (angry face). Oxytocin effects on behavioral performance were modulated by individual differences in sociability with enhanced performance in women scoring low but decreased performance in women scoring high on self-reported measures of agreeableness. Conclusions Our data provide evidence that the VTA is the human brain site where oxytocin attaches salience to socially relevant cues. This mechanism might play an important role in triggering motivation to react at the prospect of social reward or punishment.
The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on ...the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.
Human behaviour is generally guided by the anticipation of potential outcomes that are considered to be rewarding. Reward processing can thus be dissected into a phase of reward anticipation and a ...phase of reward consumption. A number of brain structures have been suggested to be involved in reward processing. However, it is unclear whether anticipation and consumption are mediated by the same or different neural networks. We examined the neural basis of these processes using functional magnetic resonance imaging (fMRI) in an incentive delay task offering either money or social approval. In both conditions participants (N=28) were given a cue indicating potential reward. In order to receive reward a target button had to be pushed within a certain time window (adapted for individual reaction time). Cues triggering either monetary or social reward anticipation were presented sessionwise. Imaging was performed on a 1.5-Tesla Philips scanner in an event-related design. Anticipation of both reward types activated brain structures constituting the brain reward system including the ventral striatum. In contrast to the task independent activity in the anticipation phase, reward consumption evoked different patterns of activation for money and social approval, respectively. While social stimuli were mainly associated with amygdala activation, the thalamus was more strongly activated by the presentation of monetary rewards. Our results identify dissociable neural networks for the anticipation and consumption of reward. The findings implicate that the neural mechanisms underlying reward consumption are more modality-specific than those for reward anticipation, and that they are mediated by subjective reward value.
Motivation for goal-directed behaviour largely depends on the expected value of the anticipated reward. The aim of the present study was to examine how different levels of reward value are coded in ...the brain for two common forms of human reward: money and social approval. To account for gender differences 16 male and 16 female participants performed an incentive delay task expecting to win either money or positive social feedback. fMRI recording during the anticipation phase revealed proportional activation of neural structures constituting the human reward system for increasing levels of reward, independent of incentive type. However, in men activation in the prospect of monetary rewards encompassed a wide network of mesolimbic brain regions compared to only limited activation for social rewards. In contrast, in women, anticipation of either incentive type activated identical brain regions. Our findings represent an important step towards a better understanding of motivated behaviour by taking into account individual differences in reward valuation.
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