A potent integrin antagonist from a small library of cyclic RGD pentapeptide mimics including benzyl-substituted azabicycloalkane amino acids

A small library of cyclic RGD pentapeptide mimics, including benzyl-substituted azabicycloalkane amino acids, was synthesized with the aim of developing active and selective integrin antagonists. In vitro binding assays established one particular compound with affinity for both the alpha(v)beta(3) and the alpha(v)beta(5) integrins. The synthesis in solution and the in vitro screening of these RGD derivatives, as well as the determination of the conformational properties of the integrin ligands by spectroscopic and computational methods are described.     

High‐density polyethylene reinforced with submicron titania particles

Submicron titania particles were prepared by means of two different synthetic procedures in order to obtain different particle size (diameter ranging from 20 to 350 nm), shapes, and morphologies (amorphous or crystalline). Titania particles were surface modified with octadecylsilane in order to improve their compatibility with respect to polymeric matrices. High‐density polyethylene (HDPE)–titania composites were prepared by melt blending by using an internal mixer. The obtained composites were mechanically characterized in quasi static and creep tensile conditions. The presence of submicron titania particles (1 %vol) led to a significant increase of elastic modulus (20–25%) with respect to the unreinforced HDPE together with a slight increase of yield stress and a decrease of ultimate elongation. An interesting reduction for both elastic and viscoelastic creep compliance components was also evidenced. POLYM. ENG. SCI., 2008. © 2008 Society of Plastics Engineers     

The identification and characterization of fusogenic domains in herpes virus glycoprotein B molecules

The molecular mechanism of entry of herpes viruses requires a multicomponent fusion system. Virus entry and cell-cell fusion of Herpes simplex virus (HSV) requires four glycoproteins: gD, gB and gH/gL. The role of gB remained elusive until recently, when the crystal structure of HSV-1 gB became available. Glycoprotein B homologues represent the most highly conserved group of herpes virus glycoproteins; however, despite the high degree of sequence and structural conservation, differences in post-translational processing are observed for different members of this virus family. Whereas gB of HSV is not proteolytically processed after oligomerization, most other gB homologues are cleaved by a cellular protease into subunits that remain linked through disulfide bonds. Proteolytic cleavage is common for activation of many other viral fusion proteins, so it remains difficult to envisage a common role for different herpes virus gB structures in the fusion mechanism. We selected bovine herpes virus type 1 (BoHV-1) and herpes simplex virus type 1 (HSV-1) as representative viruses expressing cleaved and uncleaved gBs, and have screened their amino acid sequences for regions of highly interfacial hydrophobicity. Synthetic peptides corresponding to such regions were tested for their ability to induce the fusion of large unilamellar vesicles and to inhibit herpes virus infection. These results underline that several regions of the gB protein are involved in the mechanism of membrane interaction.     

Peptide-containing aggregates as selective nanocarriers for therapeutics

New nanocarriers are obtained by assembling two amphiphilic monomers: one containing the bioactive peptide CCK8 spaced, by a polydisperse poly(ethylene glycol), from two hydrophobic tails ((C18)2PEG2000CCK8), and the other containing a chelating agent able to give stable radiolabeled indium-111 complexes linked to the same hydrophobic moiety ((C18)2DTPAGlu). The size and shape of the supramolecular aggregates were structurally characterized by dynamic light scattering, small-angle neutron scattering, and cryogenic transmission electronic microscopy. Under the experimental conditions we investigated (pH 7.4 and molar ratio between monomers 30:70), there is the presence of high polydisperse aggregates: rod-like micelles with a radius of approximately 40 A and length >700 A, open bilayer fragments with thickness approximately 65 A, and probably vesicles. The presence of the bioactive peptide well exposed on the external surface of the aggregate allows selective targeting of nanocarriers towards the cholecystokinin receptors overexpressed by the cancerous cells. In vitro binding assays and in vivo biodistribution studies by nuclear medicine experiments using indium-111 are reported. Moreover, preliminary data concerning the drug loading capability of the aggregates and their drug efficiency on the target cells is reported by using the cytotoxic drug doxorubicin. Incubation of receptor-positive and control cells with peptide-containing aggregates filled with doxorubicin shows significantly lower cell survival in receptor-expressing cells relative to the control, for samples incubated in the presence of doxorubicin.     

Anodic,cathodic and combined treatments for the electrochemical oxidation of an effluent from the flame retardant industry

The electrochemical oxidation of an effluent from the manufacture of phosphorus based flame retardants was studied. To reach a residual concentration of reduced phosphorus lower than 10 mg L⁻¹, in compliance with Italian law for industrial wastewater disposal, anodic oxidation using a boron-doped diamond (BDD) anode and electro-Fenton (EF) treatment were tested. The effects of some factors are optimised and a comparison of the reaction pathways is also presented. A combined treatment using EF with BDD conducted in an undivided cell is shown not to enhance the data obtained with BDD while a novel combined treatment using EF and BDD in a divided cell shows promising results when an anionic membrane is used as separation. In this last case the cell operates as two different batch reactors working with the same current. The anodic compartment, fed with raw effluent, provides partial oxidation, while the cathodic compartment, fed with the partially anodically oxidised solution, completes the treatment. When the effluent is transferred in the cathodic compartment, the anodic one is fed with fresh untreated solution. The advantage of this kind of coupling consists in the simultaneity of the two treatments which allows total oxidation with notable saving of charge and time.     

Hydrotreating data interpretation by chemometrics

Hydrotreating in the presence of dispersed catalysts has been considered a promising route to obtain valuable fuels from heavy hydrocarbon cuts. A laboratory-scale study on the effect of operating conditions on heavy feedstock hydrotreating performances is reported. In order to maximise the effectiveness of the research activity, chemometrics was exploited both for experimental design and data interpretation.     

Essential (Mg,Fe, Zn and Cu) and Non-Essential (Cd and Pb) Elements in Predatory Insects (Vespa crabro and Vespa velutina): A Molecular Perspective

The recent introduction of the Asian yellow-legged hornet, Vespa velutina, into Europe has raised concern regarding the threat to honeybees and the competition with the European hornet, Vespa crabro. The aim of this study was to investigated essential (Mg, Fe, Zn, Cu) and non-essential (Cd and Pb) elements in these two species. Element concentrations were determined in the whole body and separately in the head, thorax and abdomen using atomic absorption spectrometry (AAS). The changes in essential element concentration and speciation during metamorphosis were also studied using size exclusion chromatography followed by AAS and proteomic analysis. In both species, the essential elements were more concentrated in the abdomen due to the presence of fat bodies. Magnesium, Fe and Zn concentrations were significantly higher in V. crabro than in V. velutina and could have been related to the higher aerobic energy demand of the former species required to sustain foraging flight. Low concentrations of Cd and Pb were indicative of low environmental exposure. The concentration and speciation of essential elements, particularly Fe, varied among the developmental stages, indicating a modification of ligand preferences during metamorphosis. Overall, the results in the present study provide a better understanding of the hornet metal metabolism and a foundation for additional studies.     

Caffeic Acid Enhances the Anti-Leukemic Effect of Imatinib on Chronic Myeloid Leukemia Cells and Triggers Apoptosis in Cells Sensitive and Resistant to Imatinib

Among the phenolic acids tested on the K562 cell line, a model of chronic myeloid leukemia (CML), caffeic acid (CA) was biologically active on sensitive and imatinib (IM)-resistant cells at micro-molar concentration, either in terms of reduction of cell proliferation or triggering of apoptosis. The CA treatment provoked mitochondrial membrane depolarization, genomic DNA fragmentation and phosphatidylserine exposure, hallmarks of apoptosis. Cell cycle analysis following the treatment with comparable cytotoxic concentrations of IM or CA showed marked differences in the distribution profiles. The reduction of cell proliferation by CA administration was associated with increased expression of two cell cycle repressor genes, CDKN1A and CHES1, while IM at a cytotoxic concentration increased the CHES1 but not the CDKN1A expression. In addition, CA treatment affected the proliferation and triggered the apoptosis in IM-resistant cells. Taken together, these data suggested that CA induced the anti-proliferative effect and triggered apoptosis of CML cells by a different mechanism than IM. Finally, the combined administration of IM and CA at suboptimal concentrations evidenced a synergy of action in determining the anti-proliferative effect and triggering apoptosis. The ability of CA to potentiate the anti-leukemic effect of IM highlighted the nutraceutical potential of CA in CML.     

Coupling Interrupted Fischer and Multicomponent Joullié-Ugi to Chase Chemical Diversity: from Batch to Sustainable Flow Synthesis of Peptidomimetics

The generation of peptidomimetic substructures for medicinal chemistry purposes requires effective and divergent synthetic methods. We present in this work an efficient flow process that allows quick modulation of reagents for Joullié-Ugi multicomponent reaction, using spiroindolenines as core motifs. This sterically hindered imine equivalent could successfully be diversified using various isocyanides and amino acids in generally good space-time yields. A telescoped flow process combining interrupted Fischer reaction for spiroindolenine synthesis and subsequent Joullié-Ugi-type modification resulted in product formation in very good overall yield in less than 2 hours compared to 48 hours required in batch mode. The developed protocol can be seen as a general tool for rapid and facile generation of peptidomimetic compounds. We also showcase preliminary biological assessments for the prepared compounds.     

Synthesis and Evaluation of Voltage-Gated Sodium Channel Blocking Pyrroline Derivatives Endowed with Both Antiarrhythmic and Antioxidant Activities

Under the hypothesis that cardioprotective agents might benefit from synergism between antiarrhythmic activity and antioxidant properties, a small series of mexiletine analogues were coupled with the 2,2,5,5-tetramethylpyrroline moiety, known for its antioxidant effect, in order to obtain dual-acting drugs potentially useful in the protection of the heart against post-ischemic reperfusion injury. The pyrroline derivatives reported herein were found to be more potent as antiarrhythmic agents than mexiletine and displayed antioxidant activity. The most interesting tetramethylpyrroline congener, a tert-butyl-substituted analogue, was at least 100 times more active as an antiarrhythmic than mexiletine.