Combined Experimental and Multivariate Model Approaches for Glycoalkaloid Quantification in Tomatoes

The intake of tomato glycoalkaloids can exert beneficial effects on human health. For this reason, methods for a rapid quantification of these compounds are required. Most of the methods for α-tomatine and dehydrotomatine quantification are based on chromatographic techniques. However, these techniques require complex and time-consuming sample pre-treatments. In this work, HPLC-ESI-QqQ-MS/MS was used as reference method. Subsequently, multiple linear regression (MLR) and partial least squares regression (PLSR) were employed to create two calibration models for the prediction of the tomatine content from thermogravimetric (TGA) and attenuated total reflectance (ATR) infrared spectroscopy (IR) analyses. These two fast techniques were proven to be suitable and effective in alkaloid quantification (R² = 0.998 and 0.840, respectively), achieving low errors (0.11 and 0.27%, respectively) with the reference technique.     

Quality-by-Design-Based Development of n-Propyl-Gallate-Loaded Hyaluronic-Acid-Coated Liposomes for Intranasal Administration

The present study aimed to develop n-propyl gallate (PG)-encapsulated liposomes through a novel direct pouring method using the quality-by-design (QbD) approach. A further aim was to coat liposomes with hyaluronic acid (HA) to improve the stability of the formulation in nasal mucosa. The QbD method was used for the determination of critical quality attributes in the formulation of PG-loaded liposomes coated with HA. The optimized formulation was determined by applying the Box–Behnken design to investigate the effect of composition and process variables on particle size, polydispersity index (PDI), and zeta potential. Physiochemical characterization, in vitro release, and permeability tests, as well as accelerated stability studies, were performed with the optimized liposomal formulation. The optimized formulation resulted in 90 ± 3.6% encapsulation efficiency, 167.9 ± 3.5 nm average hydrodynamic diameter, 0.129 ± 0.002 PDI, and −33.9 ± 4.5 zeta potential. Coated liposomes showed significantly improved properties in 24 h in an in vitro release test (>60%), in vitro permeability measurement (420 μg/cm²) within 60 min, and also in accelerated stability studies compared to uncoated liposomes. A hydrogen-peroxide-scavenging assay showed improved stability of PG-containing liposomes. It can be concluded that the optimization of PG-encapsulated liposomes coated with HA has great potential for targeting several brain diseases.     

Synthesis and Biological Studies of O3-Aryl Galactosides as Galectin Inhibitors

β-Galactose derivatives have recently been reported to selectively inhibit galectin-3, and a library of O3-arylated galactosides with varying substitution patterns was designed to study such inhibitions further. The O3-arylated galactosides were synthesized using diaryliodonium salts under mild and transition metal free conditions, providing the target products in moderate to good yields. An O3-trifluoroethylated galactoside was also synthesized using iodonium salt chemistry. Azido-substituted products were subsequently transformed into the corresponding triazoles. After deprotection, a selection of galactoside derivatives were evaluated for inhibitory potencies against galectins-1, 3, 4 N (N-terminal domain), 4 C (C-terminal domain), 7, 8 N, 8 C, 9 N, and 9 C and one compound with promising affinity and selectivity for both the N- and C-terminal domain of galectin-9 was discovered.     

HPLC‐MS/MS method for quantitative determination of the novel dual inhibitor of FGF and VEGF receptors E‐3810 in tumor tissues from xenograft mice and human biopsies

We developed and validated a high‐performance liquid chromatography–tandem mass spectrometry analytical method to measure E‐3810, a novel dual inhibitor of fibroblast growth factor receptor 1 and vascular endothelial growth factor receptor 1–3 in tissues and determined the drug concentration in a biopsy of human breast cancer for the first time. The method is a modification of our previous one in plasma to study the clinical pharmacokinetics of the drug during the phase I/II trial. In view of the changes in matrix, we applied a partial validation protocol to determine recovery, sensitivity, range of linearity, precision, accuracy and stability of the method over three runs in a mouse tumor tissue and liver. The recovery of E‐3810 from liver or tumor homogenate was >69%, and the lower limit of quantification was 5 ng/ml. The method was linear in the concentration range 5.0–500.0 ng/ml, as demonstrated by a determination coefficient R² ≥ 0.9955. The range of the calibration curve was appropriate for the analysis, as demonstrated by the accuracy, which was between 91.4% and 106.7%. Interday precision and accuracy on quality control samples at 9, 30 and 300 ng/ml were 3.1‐11.2% and 98.3–111.4%, respectively. The assay was applied successfully to determine the intratumor concentration of E‐3810 in different mouse xenograft tumor models and in a biopsy of a patient with breast cancer included in the phase I/II trial of the drug. In mouse tumors, the concentrations of E‐3810 were higher than necessary to exert antitumor activity in vitro (1 µM). Even more of interest was the result obtained in a human biopsy of few milligrams, where E‐3810 reached 4.9 µg/g (11 µM). Copyright © 2014 John Wiley & Sons, Ltd.     

The first kinetic evidence for acid catalysis in a monocyclic rearrangement of heterocycles: conversion of the Z-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole into N,5-diphenyl-2H-1,2,3-triazol-4-ylurea

The title reaction has been studied in dioxane/water in a large (0.1-14.9) pS+ range, evidencing, together with an uncatalyzed process at intermediate (3.5-8.0) pS+ values, the occurrence of a catalyzed pathway both in the acidic (pS+ 0.1-3.5) and in the basic region (pS+ 8.0-14.9): specific-acid catalysis and general-base catalysis, respectively, have been found to take place by means of kinetic investigations at different buffer concentrations. Mechanisms for the three pathways have been advanced on the grounds of structural features. In a comparison with previous data particular attention has been paid to the acid-catalyzed pathway, herein observed for the first time in an azole-to-azole interconversion. The mechanistic hypotheses seem well supported by ab initio calculations.     

Highly emissive,nine-coordinate enantiopure lanthanide complexes incorporating tetraazatriphenylenes as probes for DNA

The interaction of q = 0 delta- and lambda-Tb and Eu complexes with poly(dAdT), poly(dGdC) and calf-thymus DNA has been examined by absorption, emission and chiroptical spectroscopy and is sensitive to complex helicity, base-pair type and the nature of the lanthanide excited state.     

Nonlinear perturbations and abstract evolution equations in general banach spaces

Summary Part I deals with the problem of determining sufficient conditions under which the sum of two m-accretive operators on a closed convex set Q₁ is m-accretive on Q₁. Part II is concerned with the initial value problem: u′+Au+g(u)=v, u(0)=u₀. Applications are given to the Boltzmann equation. Entrata in Redazione il 2 luglio 1975.     

Substrate binding to vanadate-dependent bromoperoxidase from Ascophyllum nodosum: a vanadium K-edge XAS approach

The EXAFS region of vanadium K-edge XAS spectra of native vanadate-dependent bromoperoxidase (isoenzyme I) from Ascophyllum nodosum in the presence of the substrate bromide can be fitted to three shells (at 1.62, 1.73-1.78 and 1.99-2.07 A) in the first coordination sphere of vanadium plus two more distant shells at 4.1A, possibly corresponding to bromide, and 4.7 A due to light scatterers stemming from the protein pocket. Bromide does not directly bind to the vanadium centre. The XANES and the EXAFS features for the enzyme are essentially reproduced by model complexes of the general composition [VO(H(2)O)(n)(ONO)] (n= 1 or 2) where ONO is the dianion of a Schiff base from bromosalicylaldehydes (Brsal; with the Br substituent in the position 3, 4, 5 or 6) and amino acids. The 3-Brsal derivatives exhibit an outer sphere shell at 3.8 A, which is traced back to intermolecular contacts. The data obtained from EXAFS are compared to those obtained from single crystal X-ray diffraction of [VO(H(2)O)(2)(4-Brsal-gly)] and [VO(H(2)O)(2)(6-Brsal-gly)] (gly = glycinate). In the complex [VOBr(2)(ONO)']] ((ONO)' is the Schiff base from o-anisole and o-hydroxyaniline), the V-Br distance is 2.44 A.     

Synthesis of alpha-hydrazino ketones via regio- and stereoselective electrophilic amination of manganese enolates and enamines

A straightforward procedure for the regio- and stereoselective synthesis of alpha-hydrazino ketones is described. Manganese enolates and manganese enamines derived from ketones and from the corresponding N-sulfinylimines react with azodicarboxylate esters (DTBAD and DEAD) in a regioselective fashion to afford in good to excellent yields the kinetic alpha-hydrazino ketones as sole or highly prevalent products. When enantiopure N-sulfinyl manganese enamines were used the stereoselectivity of these reactions ranged from 40% to 68% ee.