Total Syntheses and In Vivo Quantitation of Novel Neurofuran and Dihomo‐isofuran Derived from Docosahexaenoic Acid and Adrenic Acid

Neurofurans (NeuroFs) and dihomo‐isofurans (dihomo‐IsoFs) are produced in vivo by non‐enzymatic free‐radical pathways from docosahexaenoic and adrenic acids, respectively. As these metabolites are produced in minute amounts, their analyses in biological samples remain challenging. Syntheses of neurofuran and dihomo‐isofurans described are based on a pivotal strategy, thanks to an enantiomerically enriched intermediate, which allowed, for the first time, access to both families: the alkenyl and enediol. Owing to this formation, quantitation of specific NeuroF and dihomo‐IsoFs in biological samples was attainable.     

New examples of template catalysis based processes: glycerol-like units as efficient promoters for dehydrative nucleophilic substitutions of ferrocenylmethanol

The direct high-yield synthesis without solvent and catalyst, under mild conditions, of eleven novel mono substituted ferrocenylmethyl ethers and amine derivatives from ferrocenemethanol and vicinal oxygenated alcohols and amines is here reported. The peculiar ability of these classes of non acidic compounds to favor the dehydrative nucleophilic substitution is attributed to the presence of vicinal oxygen atoms to the reactive group able to build a hydrogen bonding network with the reactant. The role of carbon dioxide and hexafluoroisopropanol was investigated to support the hypothesis that a template catalysis effect is occurring. The in vitro anti-fungal activity of some of these derivatives was tested on two plant fungi, Botrytis cinerea and Penicillium species, with moderate activity.     

Weak -property in Σ-products

It is shown that each Σ-product of paracompact p-spaces has the weak -property.     

Random field singularities in renormalization group transformations on Van der Waals-Ising models

Griffiths-Pearce “peculiarities” of renormalization transformations acting on nonrandom mean field Ising models are studied exactly and shown to occur in connection with critical singularities in the quenched free energies of systems with random magnetic fields. The result applies to the transformations of the full hamiltonian, considered as a function of spin configurations, and not only to the recurrence relations for its interaction constants.     

Discovery of a new series of jatrophane and lathyrane diterpenes as potent and specific P-glycoprotein modulators

A new series of diterpenes, the jatrophanes euphoscopin M (1), euphoscopin N (2) and euphornin L (3), and the lathyrane euphohelioscopin C (7) were isolated from plants of Euphorbia helioscopia L., together with four other known analogues, euphoscopin C (4), euphornin (5), epieuphoscopin B (6) and euphohelioscopin A (8). The new compound stereostructures were elucidated by NMR analysis and computational data. The resulting isolated diterpenes were found to be potent inhibitors of P-glycoprotein (ABCB1), while showing an absence of significant activity against BCRP (ABCG2), despite the high substrate overlapping of these transporters, thus including them in the third-generation class of specific multidrug transporter modulators.     

Carrier ampholytes for IEF, on their fortieth anniversary (1967-2007), brought to trial in court: the verdict

The present review summarizes the data accumulated in 1-year work, by exploring, via a 3-D methodology (Rotofor fractionation followed by CE-MS), all the narrow (2 pH unit wide) carrier ampholyte (CA) compounds for IEF, produced by three companies (Pharmacia with Pharmalyte and Ampholine, BioRad with Bio-Lyte and Serva with Servalyt). All species have been assessed by measuring the types of pH gradient produced, the total number of individual chemicals (with M(r) values) and isoforms and their focusing behavior ('good' or 'poor' ampholytes). Servalyt contains a grand total of 686 chemical entities and no less than 3899 isoforms; Pharmalyte 643 and 2211; Bio-Lyte 255 and 1192; Ampholine 294 and 1182, respectively. In terms of M(r) distribution, although all 2-pH-unit ranges start with the same low M(r) values (ca. 200) their upper limits are quite different. Thus, Pharmalyte reaches an upper M(r) value of 1179 (in the pH 4-6 range), versus 907 for Servalyt, 835 for Bio-Lyte and 893 for Ampholine. In general, in going towards the more alkaline pH intervals (e.g. pH 8-10) the molecular mass of carrier ampholytes (CAs) is reduced to as low as 491 (Bio-Lyte), indicating that the alkaline species are probably made with shorter oligoamines and are, in general, less substituted. All acidic pH intervals (up to pH 6-8) appear to be constituted by a very large proportion of well focusing species, indicating small values of DeltapK across their pI. Above pH 8, all brands of CAs worsen, the vast majority being unable to focus properly and sustain adequately the pH gradient. General guidelines are given for the synthesis of new alkaline species for improving the basic pH ranges.     

Sarcosine as a marker in prostate cancer progression: a rapid and simple method for its quantification in human urine by solid-phase microextraction–gas chromatography–triple quadrupole mass spectrometry

Sarcosine is an amino acid derivative of N-methylglycine and is involved in the amino acid metabolism and methylation processes that are enriched during prostate cancer progression. It could also serve as a new target to be measured during therapeutic interventions and help in the identification of aggressive tumors for radical treatment. In this study, we present a new urine test that can help early diagnosis of prostate cancer. The method for the quantification of sarcosine in urine consists of a solid-phase microextraction (SPME) step followed by gas chromatography–triple quadrupole mass spectrometry analysis. We used a preliminary derivatization step with ethyl chloroformate/ethanol and the corresponding ester was then extracted by SPME in immersion mode. Several fibers were evaluated and the optimization of the parameters affecting the SPME process was carried out using an experimental design. The optimal values were 20 min extraction time, 10% NaCl, and 270°C using a divinylbenzene/Carboxen/polydimethylsiloxane fiber. The triple quadrupole analyzer acquired data in selected reaction monitoring mode, allowing us to obtain reconstructed chromatograms with well-defined chromatographic peaks. The accuracy and precision of this method were evaluated at concentrations of 70, 250, and 800 ng/ml and were found to be acceptable. Very satisfactory values (0.10 and 0.16 ng/ml, respectively) were also achieved for the limit of detection and the limit of quantification. The proposed protocol represents a rapid, simple, selective, and sensitive tool to quantify sarcosine in urine samples for prostate cancer diagnosis and for a screening test.     

Molecular motions in drug design: the coming age of the metadynamics method

Metadynamics is emerging as a useful free energy method in physics, chemistry and biology. Recently, it has been applied also to investigate ligand binding to biomolecules of pharmacological interest. Here, after introducing the basic idea of the method, we review applications to challenging targets for pharmaceutical intervention. We show that this methodology, especially when combined with a variety of other computational approaches such as molecular docking and/or molecular dynamics simulation, may be useful to predict structure and energetics of ligand/target complexes even when the targets lack a deep binding cavity, such as DNA and proteins undergoing fibrillation in neurodegenerative diseases. Furthermore, the method allows investigating the routes of molecular recognition and the associated binding energy profiles, providing a molecular interpretation to experimental data.