Editorial: The role of platinum-based antitumor prodrugs in medicinal inorganic chemistry

Editorial on the research topic "The role of platinum-based antitumor prodrugs in medicinal inorganic chemistry

On the use of AMSU-based products for the description of soil water content at basin scale

Abstract. Characterizing the dynamics of soil moisture fields is a key issue in hydrology, offering a strategy to improve our understanding of complex climate-soil-vegetation interactions. Besides in-situ measurements and hydrological models, soil moisture dynamics can be inferred by analyzing data acquired by sensors on board of airborne and/or satellite platforms. In this work, we investigated the use of the National Oceanic and Atmospheric Administration – Advanced Microwave Sounding Unit-A (NOAA-AMSU-A) radiometer for the remote characterization of soil water content. To this aim, a field measurement campaign, lasted about three months (3 March 2010–18 May 2010), was carried out using a portable time-domain reflectometer (TDR) to get soil water content measures over five different locations within an experimental basin of 32.5 km2, located in the South of Italy. In detail, soil moisture measurements were carried out systematically at the times of satellite overpasses, over two square areas of 400 m2, a triangular area of 200 m2 and two transects of 60 and 170 m, respectively. Each monitored site is characterized by different land covers and soil textures, to account for spatial heterogeneity of land surface. Afterwards, a more extensive comparison (i.e. analyzing a 5 yr data time series) was made using soil moisture simulated by a hydrological model. Measured and modeled soil moisture data were compared with two AMSU-based indices: the Surface Wetness Index (SWI) and the Soil Wetness Variation Index (SWVI). Both time series of indices have been filtered by means of an exponential filter to account for the fact that microwave sensors only provide information at the skin surface. This allowed to understand the ability of each satellite-based index to account for soil moisture dynamics and to understand its performances under different conditions. As a general remark, the comparison shows a higher ability of the filtered SWI to describe the general trend of soil moisture, while the SWVI can capture soil moisture variations with a precision that increases at the higher values of SWVI

Platinum(IV) complexes of trans-1,2-diamino-4-cyclohexene: Prodrugs affording an oxaliplatin analogue that overcomes cancer resistance

Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo. X-ray photoelectron spectroscopy (XPS) data indicated an X-ray-induced surface reduction of the Pt(IV) substrates, which correlates with the reduction potentials measured by cyclic voltammetry. The cytotoxic activity was assessed in vitro on a panel of human cancer cell lines, also including oxaliplatin-resistant cancer cells, and compared with that of the reference compounds cisplatin and oxaliplatin; all IC50 values were remarkably lower than those elicited by cisplatin and somewhat lower than those of oxaliplatin. Compared to the other Pt(IV) compounds of the series, the bis-benzoate derivative was by far (5–8 times) the most cytotoxic showing that low reduction potential and high lipophilicity are essential for good cytotoxicity. Interestingly, all the complexes proved to be more active than cisplatin and oxaliplatin even in three-dimensional spheroids of A431 human cervical cancer cells

New oxaliplatin-pyrophosphato analogs with improved in vitro cytotoxicity

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3- diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na2[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4- diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis

Time variations in the deep underground muon flux

More than 35 million high-energy muons collected with the MACRO detector at the underground Gran Sasso Laboratory have been used to search for flux variations of different nature. Two kinds of studies were carried out: a search for the occurrence of clusters of events and a search for periodic variations. Different analysis methods, including the Scan Statistics test and the Lomb-Scargle spectral analysis have been applied to the data.Comment: 7 pages, 5 figures, accepted by EP

Search for spontaneous muon emission from lead nuclei

We describe a possible search for muonic radioactivity from lead nuclei using the base elements ("bricks" composed by lead and nuclear emulsion sheets) of the long-baseline OPERA neutrino experiment. We present the results of a Monte Carlo simulation concerning the expected event topologies and estimates of the background events. Using few bricks, we could reach a good sensitivity level.Comment: 12 pages, 4 figure

The read-across hypothesis and environmental risk assessment of pharmaceuticals

This article is made available through the Brunel Open Access Publishing Fund. Copyright © 2013 American Chemical Society.Pharmaceuticals in the environment have received increased attention over the past decade, as they are ubiquitous in rivers and waterways. Concentrations are in sub-ng to low μg/L, well below acute toxic levels, but there are uncertainties regarding the effects of chronic exposures and there is a need to prioritise which pharmaceuticals may be of concern. The read-across hypothesis stipulates that a drug will have an effect in non-target organisms only if the molecular targets such as receptors and enzymes have been conserved, resulting in a (specific) pharmacological effect only if plasma concentrations are similar to human therapeutic concentrations. If this holds true for different classes of pharmaceuticals, it should be possible to predict the potential environmental impact from information obtained during the drug development process. This paper critically reviews the evidence for read-across, and finds that few studies include plasma concentrations and mode of action based effects. Thus, despite a large number of apparently relevant papers and a general acceptance of the hypothesis, there is an absence of documented evidence. There is a need for large-scale studies to generate robust data for testing the read-across hypothesis and developing predictive models, the only feasible approach to protecting the environment.BBSRC Industrial Partnership Award BB/ I00646X/1 and BBSRC Industrial CASE Partnership Studentship BB/I53257X/1 with AstraZeneca Safety Health and Environment Research Programme

Mutant p53 prevents GAPDH nuclear translocation in pancreatic cancer cells favoring glycolysis and 2-deoxyglucose sensitivity

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating human malignancies. In about 70% of PDACs the tumor suppressor gene TP53 is mutated generally resulting in conformational changes of mutant p53 (mutp53) proteins, which acquire oncogenic functions triggering aggressiveness of cancers and alteration of energetic metabolism. Here, we demonstrate that mutant p53 prevents the nuclear translocation of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) stabilizing its cytoplasmic localization, thus supporting glycolysis of cancer cells and inhibiting cell death mechanisms mediated by nuclear GAPDH. We further show that the prevention of nuclear localization of GAPDH is mediated by both stimulation of AKT and repression of AMPK signaling, and is associated with the formation of the SIRT1:GAPDH complex. By using siRNA-GAPDH or an inhibitor of the enzyme, we functionally demonstrate that the maintenance of GAPDH in the cytosol has a critical impact on the anti-apoptotic and anti-autophagic effects driven by mutp53. Furthermore, the blockage of its mutp53-dependent cytoplasmic stabilization is able to restore the sensitivity of PDAC cells to the treatment with gemcitabine. Finally, our data suggest that mutp53-dependent enhanced glycolysis permits cancer cells to acquire sensitivity to anti-glycolytic drugs, such as 2-deoxyglucose, suggesting a potential personalized therapeutic approach in human cancers carrying mutant TP53 gene

Prospects for the measurement of muon-neutrino disappearance at the FNAL-Booster

Neutrino physics is nowadays receiving more and more attention as a possible source of information for the long-standing problem of new physics beyond the Standard Model. The recent measurement of the mixing angle $\theta_{13}$ in the standard mixing oscillation scenario encourages us to pursue the still missing results on leptonic CP violation and absolute neutrino masses. However, puzzling measurements exist that deserve an exhaustive evaluation. The NESSiE Collaboration has been setup to undertake conclusive experiments to clarify the muon-neutrino disappearance measurements at small $L/E$, which will be able to put severe constraints to models with more than the three-standard neutrinos, or even to robustly measure the presence of a new kind of neutrino oscillation for the first time. To this aim the use of the current FNAL-Booster neutrino beam for a Short-Baseline experiment has been carefully evaluated. This proposal refers to the use of magnetic spectrometers at two different sites, Near and Far. Their positions have been extensively studied, together with the possible performances of two OPERA-like spectrometers. The proposal is constrained by availability of existing hardware and a time-schedule compatible with the CERN project for a new more performant neutrino beam, which will nicely extend the physics results achievable at the Booster. The possible FNAL experiment will allow to clarify the current $\nu_{\mu}$ disappearance tension with $\nu_e$ appearance and disappearance at the eV mass scale. Instead, a new CERN neutrino beam would allow a further span in the parameter space together with a refined control of systematics and, more relevant, the measurement of the antineutrino sector, by upgrading the spectrometer with detectors currently under R&D study.Comment: 76 pages, 52 figure

Measurement of the atmospheric muon depth intensity relation with the NEMO Phase-2 tower

The results of the analysis of the data collected with the NEMO Phase-2 tower, deployed at 3500 m depth about 80 km off-shore Capo Passero (Italy), are presented. Cherenkov photons detected with the photomultipliers tubes were used to reconstruct the tracks of atmospheric muons. Their zenith-angle distribution was measured and the results compared with Monte Carlo simulations. An evaluation of the systematic effects due to uncertainties on environmental and detector parameters is also included. The associated depth intensity relation was evaluated and compared with previous measurements and theoretical predictions. With the present analysis, the muon depth intensity relation has been measured up to 13 km of water equivalent.Comment: submitted to Astroparticle Physic