Analysis of gadobenate dimeglumine by capillary zone electrophoresis coupled with electrospray-mass spectrometry

Highly reliable and accurate analytical methods are needed for the determination of magnetic resonance imaging (MRI) contrast agents in complex matrices of clinical interest. We demonstrate the reliability of capillary zone electrophoresis (CZE) coupled with electrospray ionization-mass spectrometry (ESI-MS) for the analysis of MultiHance (gadobenate dimeglumine), a gadolinium-based MRI agent. A sheath liquid interface connected the CE system with an electrospray mass spectrometer equipped with an ion-trap analyzer. CZE with ultraviolet (CZE-UV) and with mass detection (CZE-MS) were compared by analyzing gadobenate dimeglumine and the free ligand diluted in water and in biological fluids (i.e., human serum and urine). The optimization of some relevant CZE-MS parameters was accomplished, like CE buffer composition, sheath liquid composition and flow, and type and length of the separation capillary. CZE-UV was highly influenced by the biological sample components, which hindered a reliable quantification of both gadobenate and free ligand in serum and urine. In CZE-MS, on the other hand, the electrophoretic runs turned out to be independent of the clinical matrices, due to the informative potential and to the selectivity of MS detection.     

[2+2] Carbonylative cycloaddition catalyzed by palladium: stereoselective synthesis of β-lactams

[2+2] Carbonylative cycloaddition of chiral imines to various allyl halides, under CO pressure, in the presence of Et₃N, a catalytic amount of Pd(OAc)₂ and PPh₃ as ligand, are carried out. Separable diastereomeric mixtures of chiral alkenyl-β-lactams are isolated with good yields and high trans diastereoselections. Absolute configurations are assigned by X-ray measurements and ¹H NMR spectroscopy.     

Application of high-resolution magic-angle spinning NMR spectroscopy to define the cell uptake of MRI contrast agents

A new method, based on proton high-resolution magic-angle spinning ((1)H HR-MAS) NMR spectroscopy, has been employed to study the cell uptake of magnetic resonance imaging contrast agents (MRI-CAs). The method was tested on human red blood cells (HRBC) and white blood cells (HWBC) by using three gadolinium complexes, widely used in diagnostics, Gd-BOPTA, Gd-DTPA, and Gd-DOTA, and the analogous complexes obtained by replacing Gd(III) with Dy(III), Nd(III), and Tb(III) (i.e., complexes isostructural to the ones of gadolinium but acting as shift agents). The method is based on the evaluation of the magnetic effects, line broadening, or induced lanthanide shift (LIS) caused by these complexes on NMR signals of intra- and extracellular water. Since magnetic effects are directly linked to permeability, this method is direct. In all the tests, these magnetic effects were detected for the extracellular water signal only, providing a direct proof that these complexes are not able to cross the cell membrane. Line broadening effects (i.e., the use of gadolinium complexes) only allow qualitative evaluations. On the contrary, LIS effects can be measured with high precision and they can be related to the concentration of the paramagnetic species in the cellular compartments. This is possible because the HR-MAS technique provides the complete elimination of bulk magnetic susceptibility (BMS) shift and the differentiation of extra- and intracellular water signals. Thus with this method, the rapid quantification of the MRI-CA amount inside and outside the cells is actually feasible.     

Gd-AAZTA]-: a new structural entry for an improved generation of MRI contrast agents

An innovative MRI contrast agent based on the unprecedented and easily obtained ligand AAZTA is described. The simple and straightforward synthesis of the ligand, together with the potentiometric and relaxometric behavior of the corresponding Gd(III) chelate, is reported. The complex [Gd(AAZTA)]- shows outstanding magnetic properties connected with high thermodynamic stability in aqueous solution and a nearly complete inertness toward the influence of bidentate endogenous anions, placing this compound as one of the most promising candidates for the development of high performance MRI contrast agents.     

On the α-ketols obtained from α,β-unsaturated aromatic aldehydes and bakers'yeast

From α-methylcinnamaldehyde (1b), acetaldehyde and fermenting bakers'yeast, at pH 5, the $\text{R}$ α-ketol (6) is obtained in $\text{ca}$. 15% yield, togheter with unreacted (1b); from cinnamaldehyde (1a), under identical conditions, optically inactive (5) has been isolated as the only transformation product.     

Stereoselective synthesis and functionalization of 4-heterosubstituted β-lactams

Polyfunctionalized β-lactams were prepared with high stereoselectivity in an efficient manner. A palladium-catalyzed [2+2] carbonylative cycloaddition of allyl bromide with heteroaryliden-anilines afforded 2-azetidinones N-phenyl substituted, with an heteroaryl moiety linked at the C-4 carbon, and an alkenyl group at the C-3 carbon. The C-3 and the C-4 positions could be further functionalized inserting alkyl and hydroxyl groups in the azetidinone ring, through the generation of a stable azetidinyl anion then captured by various electrophiles.     

Pectin-Based Formulations for Controlled Release of an Ellagic Acid Salt with High Solubility Profile in Physiological Media

Among bioactive phytochemicals, ellagic acid (EA) is one of the most controversial because its high antioxidant and cancer-preventing effects are strongly inhibited by low gastrointestinal absorption and rapid excretion. Strategies toward an increase of solubility in water and bioavailability, while preserving its structural integrity and warranting its controlled release at the physiological targets, are therefore largely pursued. In this work, EA lysine salt at 1:4 molar ratio (EALYS), exhibiting a more than 400 times increase of water solubility with respect to literature reports, was incorporated at 10% in low methoxylated (LM) and high methoxylated (HM) pectin films. The release of EA in PBS at pH 7.4 from both film preparations was comparable and reached 15% of the loaded compound over 2 h. Under simulated gastric conditions, release of EA from HM and LM pectin films was minimal at gastric pH, whereas higher concentrations—up to 300 μM, corresponding to ca. 50% of the overall content—were obtained in the case of the HM pectin film after 2 h incubation at the slightly alkaline pH of small intestine environment, with the enzyme and bile salt components enhancing the release. EALYS pectin films showed a good prebiotic activity as evaluated by determination of short chain fatty acids (SCFAs) levels following microbial fermentation, with a low but significant increase of the effects produced by the pectins themselves. Overall, these results highlight pectin films loaded with EALYS salt as a promising formulation to improve administration and controlled release of the compound.     

Stereoselective synthesis of heterosubstituted aziridines and their functionalization

Lithiated (α-chloroalkyl)heterocycles, generated by deprotonation with LDA at −78 °C in THF, add to various enantiopure imines affording ‘one pot’ chiral heterosubstituted aziridines in a diastereoselective manner. Lithiated heterosubstituted aziridines, obtained by deprotonation of the corresponding aziridines with n-BuLi at −78 °C in THF, were trapped by electrophiles (D₂O or CH₃I) with high stereoselectivity.     

Identification of prion protein genotype in sheep: 11 years of proficiency tests in Italy

Accreditation and Quality Assurance - Scrapie of sheep belongs to a group of fatal neurodegenerative diseases known as prion diseases. Scrapie is a naturally transmissible disease and sheep...     

Nitration versus nitrosation chemistry of menthofuran: remarkable fragmentation and dimerization pathways and expeditious entry into dehydromenthofurolactone

The reaction chemistry of menthofuran (1), a toxic furan terpenoid from various mint oils, with nitric acid and nitrous acid has been investigated. Treatment of 1 with nitric acid afforded a 1:1 mixture of the bisfuran derivatives 5 and 6, resulting from the unexpected cleavage of the furan into two carbonyl fragments (3-methylcyclohexanone and hydroxyacetone) and their subsequent trapping by unreacted 1. Under conditions of high dilution, the nitrofuran derivative 7 was formed instead as the major reaction product. During investigation of this chemistry, it was found that oxidation of 1 with DDQ led to the important fragrant monoterpenoid 4 [dehydromenthofurolactone (anhydro Woodward-Eastman lactone)] in 44% yield. Exposure of 1 to nitrite ions at pH 3 afforded a completely different type of products, encompassing the known lactone 14, the lactam 15, and the remarkable dimer 16, bearing a N-hydroxy-2-pyrrolinone moiety linked to a nitrooximinofuran unit by an oxygen bridge. By using a combined spectroscopic and DFT approach, the constitution and configuration of 16 could be determined. These results fill a gap in the chemistry of furan compounds and describe routes to menthofuran-derived scaffolds of potential synthetic and biomedical relevance.