In Silico Identification of Tripeptides as Lead Compounds for the Design of KOR Ligands

The kappa opioid receptor (KOR) represents an attractive target for the development of drugs as potential antidepressants, anxiolytics and analgesics. A robust computational approach may guarantee a reduction in costs in the initial stages of drug discovery, novelty and accurate results. In this work, a virtual screening workflow of a library consisting of ~6 million molecules was set up, with the aim to find potential lead compounds that could manifest activity on the KOR. This in silico study provides a significant contribution in the identification of compounds capable of interacting with a specific molecular target. The main computational techniques adopted in this experimental work include: (i) virtual screening; (ii) drug design and leads optimization; (iii) molecular dynamics. The best hits are tripeptides prepared via solution phase peptide synthesis. These were tested in vivo, revealing a good antinociceptive effect after subcutaneous administration. However, further work is due to delineate their full pharmacological profile, in order to verify the features predicted by the in silico outcomes.     

Ytterbium triflate catalysed Meerwein-Ponndorf-Verley (MPV) reduction

Ytterbium triflate was shown to be effective in promoting the reduction of substituted aromatic and aliphatic aldehydes and ketones using isopropanol as the solvent and the reducing agent. The whole process furnished the desired adducts in 22-98% yield.     

Rheoreversible polymeric organogels: the art of science for art conservation

A new category of gels where gelification and breaking of the gels are chemically induced is presented. In particular, the latent gellant polyallylamine produced stable gels with some organic solvents after reaction with CO2 at room temperature, giving the gellant polyallylammonium carbamate. The rheological behavior switches from solution-type to gel-type. After weak acid-catalyzed displacement of CO2, the gel character disappears in a few seconds, making these polymeric organogels rheoreversible by a simple chemical action. This "intelligent" chemical switch between solution-type and gel-type rheological behavior has been exploited to clean pictorial surfaces in art conservation. In fact, during the cleaning procedure, there is a need for the gel supporting the cleaning solvent to have a very high viscosity. After cleaning has been successful, there is a strong necessity to reduce the viscosity, to better eliminate traces of the gellant that must be completely removed from the work of art. In the present study, we show that the art of science, in the sense of designing new physicochemical systems exploiting the "science palette", can lead to an improvement in the techniques used to protect and conserve the results of the "artists' palette".     

Decoding two-dimensional polyacrylamide gel electrophoresis complex maps by autocovariance function: a simplified approach useful for proteomics

This paper describes a mathematical approach applied for decoding the complex signal of two-dimensional polyacrylamide gel electrophoresis maps of protein mixtures. The method is helpful in extracting analytical information since separation of all the proteins present in the sample is still far from being achieved and co-migrating proteins are generally present in the same spot. The simplified method described is based on the study of the 2-D autocovariance function (2D-ACVF) computed on an experimental digitized map. The first part of the 2D-ACVF allows for the estimation of the number of proteins present in the sample (2D-ACVF computed at the origin) and of the separation performance (mean spot size). Moreover, the 2D-ACVF plot is a powerful tool in identifying order in the spot position, and singling it out from the complex separation pattern. This method was validated on synthetic maps obtained by computer simulation to describe 2-D PAGE real maps and reference maps retrieved from the SWISS-2DPAGE database. The results obtained are discussed by focusing on specific information relevant in proteomics: sample complexity, separation performance, and identification of spot trains related to post-translational modifications.     

Preparation of Constrained Unnatural Aromatic Amino Acids via Unsaturated Diketopiperazine Intermediate

Unnatural aromatic amino acids are useful tools in drug discovery, since their insertion in bioactive peptide sequences can change the side chains spatial orientation, the backbone conformation and above all, their bioactivity. In this communication, we propose a straightforward method to synthesize 2′,6′‐dimethyl‐tyrosine and 2′,6′‐dimehylphenyl‐alanine derivatives as handling building blocks for peptide synthesis via unsaturated diketopiperazine (DKP) intermediate.     

Self‐assembling amphiphilic block copolymer from renewable δ‐decalactone and δ‐dodecalactone

Aliphatic polyesters have many applications in the biomedical field due to their properties and facile degradation. They are commonly synthesized via ring opening polymerization (ROP) with metal‐based catalysts, but as high temperatures are needed and the products contain metal, organocatalysts are now widely adopted to polymerize them at room temperature while also ensuring short reaction times. Here, 1,7,7‐triazabicyclo[4.4.0]‐dec‐5‐ene is used to polymerize less reactive but renewably‐derived lactones, namely δ‐decalactone and δ‐dodecalactone. These monomers were chosen in the attempt of creating renewable and highly lipophilic materials for drug delivery applications as alternatives to the more traditional, but non‐renewable δ‐valerolactone and ?‐caprolactone. A combination of ROP and living radical polymerization Reversible Addition‐Fragmentation Chain Transfer is proposed here to synthesize grafted block copolymers. They are able to self‐assemble in water, forming micelles where the lipophilic polyester core is able to entrap a lipophilic drug, thus making the system a good candidate for drug delivery. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55 , 3788–3797     

A Theoretical and Experimental Investigation of the Spectroscopic Properties of a DNA‐Intercalator Salphen‐Type ZnII Complex

The photophysical and DNA‐binding properties of the cationic zinc(II) complex of 5‐triethylammonium methyl salicylidene ortho‐phenylenediiminato (ZnL²⁺) were investigated by a combination of experimental and theoretical methods. DFT calculations were performed on both the ground and the first excited states of ZnL²⁺ and on its possible mono‐ and dioxidation products, both in vacuo and in selected solvents mimicked by the polarizable continuum model. Comparison of the calculated absorption and fluorescence transitions with the corresponding experimental data led to the conclusion that visible light induces a two‐electron photooxidation process located on the phenylenediiminato ligand. Kinetic measurements, performed by monitoring absorbance changes over time in several solvents, are in agreement with a slow unimolecular photooxidation process, which is faster in water and slower in less polar solvents. Moreover, structural details of ZnL–DNA binding were obtained by DFT calculations on the intercalation complexes between ZnL and the d(ApT)₂ and d(GpC)₂ dinucleoside monophosphate duplexes. Two main complementary binding interactions are proposed: 1) intercalation of the central phenyl ring of the ligand between the stacked DNA base pairs; 2) external electrostatic attraction between the negatively charged phosphate groups and the two cationic triethylammonium groups of the Schiff‐base ligand. Such suggestions are supported by fluorescence titrations performed on the ZnL/DNA system at different ionic strengths and temperatures. In particular, the values of the DNA‐binding constants obtained at different temperatures provided the enthalpic and entropic contributions to the binding and confirmed that two competitive mechanisms, namely, intercalation and external interaction, are involved. The two mechanisms are coexistent at room temperature under physiological conditions.     

Immobilization of Laccase from Trametes versicolor on Chitosan Macrobeads for Anthracene Degradation

Anthracene bioconversion was achieved by immobilized enzyme technology. An oxidation yield of 0.7?mg/L of polycyclic aromatic hydrocarbons reached 60% following 24?h of incubation with laccase from Trametes versicolor covalently immobilized on glutaraldehyde-activated chitosan at the optimal pH of 5 in the presence of diammonium 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) as the radical mediator. High-performance liquid chromatography indicated that the main product of anthracene oxidation was 9,10-anthraquinone which is less toxic than its precursor. Highly porous 3?mm diameter chitosan macrobeads were synthesized by precipitation in alkaline solution. Support activation with glutaraldehyde was confirmed by elemental analysis, thermogravimetry, and infrared spectroscopy. The bioreactor system was characterized for kinetic parameters obtaining a Michaelis–Menten constant of 0.13?mM and a maximum rate of 0.0011?µmol/min/mg, thermal stability, and reuse. The protein and glutaraldehyde concentrations were optimized to enhance the efficiency of the bioreactor.     

Synthesis and bioactivity of secondary metabolites from marine sponges containing dibrominated indolic systems

Marine sponges. (e.g., Hyrtios sp., Dragmacidin sp., Aglophenia pleuma, Aplidium cyaneum, Aplidium meridianum.) produce bioactive secondary metabolites involved in their defence mechanisms. Recently it was demonstrated that several of those compounds show a large variety of biological activities against different human diseases with possible applications in medicinal chemistry and in pharmaceutical fields, especially related to the new drug development process. Researchers have focused their attention principally on secondary metabolites with anti-cancer and cytotoxic activities. A common target for these molecules is the cytoskeleton, which has a central role in cellular proliferation, motility, and profusion involved in the metastatic process associate with tumors. In particular, many substances containing brominated indolic rings such as 5,6-dibromotryptamine, 5,6-dibromo-N-methyltryptamine, 5,6-dibromo-N-methyltryptophan (dibromoabrine), 5,6-dibromo-N,N-dimethyltryptamine and 5,6-dibromo-L-hypaphorine isolated from different marine sources, have shown anti-cancer activity, as well as antibiotic and anti-inflammatory properties. Considering the structural correlation between endogenous monoamine serotonin with marine indolic alkaloids 5,6-dibromoabrine and 5,6-dibromotryptamine, a potential use of some dibrominated indolic metabolites in the treatment of depression-related pathologies has also been hypothesized. Due to the potential applications in the treatment of various diseases and the increasing demand of these compounds for biological assays and the difficult of their isolation from marine sources, we report in this review a series of recent syntheses of marine dibrominated indole-containing products.     

Comparison of different technologies for alginate beads production

This paper describes the results of the round robin experiment “Bead production technologies” carried out during the COST 840 action “Bioencapsulation Innovation and Technologies” within the 5th Framework Program of the European Community. In this round robin experiment, calcium alginate hydrogel beads with the diameter of (800 ± 100) μm were produced by the most common bead production technologies using 0.5–4 mass % sodium alginate solutions as starting material. Dynamic viscosity of the alginate solutions ranged from less than 50 mPa s up to more than 10000 mPa s. With the coaxial air-flow and electrostatic enhanced dropping technologies as well as with the JetCutter technology in the soft-landing mode, beads were produced from all alginate solutions, whereas the vibration technology was not capable to process the high-viscosity 3 % and 4 % alginate solutions. Spherical beads were generated by the electrostatic and the JetCutter technologies. Slightly deformed beads were obtained from high-viscosity alginate solutions using the coaxial airflow and from the 0.5 % and 2 % alginate solutions using the vibration technology. The rate of bead production using the JetCutter was about 10 times higher than with the vibration technology and more than 10000 times higher than with the coaxial air-flow and electrostatic technology. In memory of our colleague Stefan Rosinski