Italian Children Exposure to Bisphenol A: Biomonitoring Data from the LIFE PERSUADED Project

A human biomonitoring (HBM) study on bisphenol A (BPA) in Italian children and adolescents was performed within the LIFE PERSUADED project, considering the residing areas, sex and age. The median urinary BPA level was 7.02 mu g/L, with children living in the South of Italy or in urban areas having higher levels than those residing in the North or in rural areas. Children aged 4-6 years had higher BPA levels than those aged 7-10 and 11-14 years, but no differences were detected between sexes. The exposure in Italian children was higher compared to children from other countries, but lower than the HBM guidance value (135 mu g/L). The estimated daily intake was 0.17 mu g/kg body weight (bw) per day, about 24-fold below the temporary Tolerable Daily Intake of 4 mu g/kg bw per day established by the European Food Safety Authority. However, this threshold was exceeded in 1.44% of the enrolled children, raising concern about the overall exposure of Italian young population

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs

Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 \u3bcM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 \u3bcM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability

Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors

Medicinal Chemistry in Parasitology: New Avenues in Drug Discovery

Conference report on the Medicinal Chemistry in Parasitology meeting held in Modena, Italy under the COST action B22, which is focused on target identification and drug development for parasitic diseases

Synthesis and free radical scavenging activity of 4-(2H-1,2,4-benzothiadiazine-1,1-dioxide-3-yl)-2,6-bis(1,1-dimethylethyl)phenols

4-(2H-1,2,4-benzothiadiazine-1,1-dioxide-3-yl)-2,6-bis(1,1-dimethylethyl)phenols (1-11) were prepared by cyclization of the corresponding 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-2-(sulphamoylphenyl)benzamides (12-22). Compounds 1-22 were tested as free radical scavengers by reaction with DPPH using UV and ESR spectrometry and the formation of stable phenoxy radicals by their oxidation with lead tetraacetate was also studied. Copyrigh

Pyrrolidine Derivatives as New Ligands for 5-HT1A Receptors

Our research group has long been involved in the development of new 5-HT1A selective ligands and 1,3-dioxolane derivatives bearing a phenoxyethylamine basic portion in position 4 were reported1. They were shown to have interesting 5-HT1A agonist activity accompanied by a good affinity, even if a certain alpha1 affinity was still present. 5-HT1A agonists and partial agonists have proved useful in the treatment of neuropsychiatric disorders such as anxiety and depression, to prevent neurodegeneration and for their antinociceptive activity2,3. On this basis and with the aim to improve 5-HT1A affinity and selectivity, compound A derivatives have been synthesized. A frozen structure of the ethylamine portion characterizes the new ligand and this variation4 with respect to the lead A has been designed in order to decrease the flexibility of this part of the molecule (figure 1). Stereospecific synthesis has been planned to give the desired four enantiomers (figure 1) so that it has been evaluated: 1. the effect on 5-HT1A affinity of the molecular rigidity provided by pyrrolidine core in comparison to that of the lead compound A; 2. stereoisomeric preferences for the receptor interaction. Several reactions and different synthetic schemes have been followed to obtained these four stereoisomers with good yield and a process optimization has been pursued. Structural characterization by NMR and mass (Q-TOF) analysis have been performed on the final compounds together with their optical purity determination

Synthesis and antiviral activity of new benzothiadiazine dioxide derivates

In continuing our search in the benzothiadiazine field, we have synthesized new alkylated 2,1,3-BTD and 1,2,4-BTD derivatives. The procedure of alkylation is led via Mitsunobu reaction with good yields. The compounds were tested for their antiviral activity versus some viral strain (ADV, HHV-6, Cox-B5 and H-CMV) and most of them are resulted active at micromolar level. Except compound 1a that presents a high cytotoxicity (maximum non toxic concentration was 3\u3bcM), all the other molecules prepared are poorly cytotoxic (maximum non toxic concentrations were >25\u3bcM)

2,1,3-Benzothiadiazine derivatives: synthesis and screening versus PDE4 enzyme

A series of N-1,3 disubstituted 2,1,3-benzothiadiazine derivatives (BTDs) were synthesized and evaluated for their inhibitory activity versus enzymatic isoform PDE4 extracted from U937 cell line. Some of the tested compounds showed a high PDE4 inhibitory activity at 100 μM and the IC50 value of the most interesting terms were evaluated. The structure–activity relationships of these compounds showed that the 3,5-di-tert-butyl-4-hydroxybenzyl moiety at N-1 position is important to obtain activity at micromolar level as previously reported. For the same compounds the antioxidant activity were evaluated highlighting 14 as the most significative one. The introduction of other bulky substituents in N-1 position is detrimenta

Synthesis of 5-Methyl-1,3-oxathiolane-based Nucleoside Analogues as Potential Antiviral Agents

A series of 1,3-oxathiolane-based nucleoside analogues 5-methyl substituted was synthesized and tested as potential antiviral agents. Structural characterization and C2-C4 / C2-C5 relative stereochemistry assignments were performed by NMR experiments. All tested isomers were found to be inactive and cytotoxic