Entry to nitrogen-containing heterocycles by based-promoted heterocyclization on allenylamides of l-α-aminoacids

Allenylamides of Boc-protected α-aminoacids easily gave in basic medium heterocyclic products arising from attack of the NH group on the inside C-C double bond of the 1,2-diene moiety, namely imidazolidinones, pyrazinones, and a pyrrole compound. The microwave-assisted heterocyclization occurred cleanly at C-β of the allenyl group with formation of pyrazin-2-ones having an endo- or exocyclic double bond.     

Human serum albumin unfolding pathway upon drug binding: A thermodynamic and spectroscopic description

The interest on phenothiazine drugs has been increased during last years due to their proved utility in the treatment of several diseases and biomolecular processes. In the present work, the binding of the amphiphilic phenothiazines promazine and thioridazine hydrochlorides to the carrier protein human serum albumin (HSA) has been examined by ζ-potential, isothermal titration calorimetry (ITC), fluorescence and circular dichorism (CD) spectroscopies, and dynamic light scattering (DLS) at physiological pH with the aim of analyzing the role of the different interactions in the drug complexation process with this protein. The ζ-potential results were used to check the existence of complexation. This is confirmed by a progressive screening of the protein charge up to a reversal point as a consequence of drug binding. On the other hand, binding causes alterations on the tertiary and secondary structures of the protein, which were observed by fluorescence and CD spectroscopies, involving a two-step, three-state transition. The thermodynamics of the binding process was derived from ITC results. The binding enthalpies were negative, which reveal the existence of electrostatic interactions between protein and drug molecules. In addition, increases in entropy are consistent with the predominance of hydrophobic interactions. Two different classes of binding sites were detected, viz. Binding to the first class of binding sites is dominated by an enthalpic contribution due to electrostatic interactions whereas binding to a second class of binding sites is dominated by hydrophobic bonding. In the light of these results, protein conformational change resembles the acid-induced denaturation of HSA with accumulation of an intermediate state. Binding isotherms were derived from microcalorimetric results by using a theoretical model based on the Langmuir isotherm. On the other hand, the population distribution of the different species in solution and their sizes were determined through dynamic light scattering (DLS). Aggregation of drug/protein complexes was found as a result of a possible expansion of protein structure induced at high drug concentrations. In addition, the presence of free drug aggregates at concentrations below the drug critical micelle concentration was also detected.     

Development of a Stability-Indicating LC Assay Method for Determination of Chloroquine

A simple and rapid development of a stability-indicating LC method for determination of chloroquine diphosphate in the presence of its hydrolysis, oxidative and photolysis degradation products is described. Stress testing showed that chloroquine diphosphate was degraded under basic conditions and by photolytic treatment but was stable under the other stress conditions investigated. Separation of the drug from its degradation products was achieved with a Nova Pack C18 column, 0.01 M PIC B7 and acetonitrile (40:60 v/v) pH 3.6, as mobile phase. Response was linear over the range 0.08–5.70 μg mL⁻¹ (r = 0.996), with limits of detection and quantification (LOD and LOQ) of 0.17 and 0.35 μg mL⁻¹, respectively.

     

The structured distance to normality of banded Toeplitz matrices

Spectral properties of normal (2k+1)-banded Toeplitz matrices of order n, with k≤⌊ n/2⌋, are described. Formulas for the distance of (2k+1)-banded Toeplitz matrices to the algebraic variety of similarly structured normal matrices are presented.     

Ultrasound energy focused in a glass probe: An approach to the simultaneous and fast extraction of trace elements from sediments

The 3051 USEPA method (or alternatively, the 3051A) can be considered nowadays as a reference method to extract metals from sediments. However, after microwave heating, the sample must be allowed to cool down, which results in a considerable lengthening of the whole analytical process. Microwave ovens and their maintenance are, in addition, expensive, and its use is relatively dangerous. The use of ultrasound focused energy to assist the extraction of chemicals from solid samples is a safe and relatively cheap technique. In this work we propose a new method to extract simultaneously several elements from sediments using ultrasound energy focused in a glass probe to accelerate the process, and check its possibilities to become an alternative to the EPA3051(A) approach. The optimised procedure allows extracting 13 elements in only 6 min, with similar recoveries and, in general, better repetitivities than the EPA3051. In addition, the suspension is only slightly heated during the leaching process.     

Development and NMR validation of minimal pharmacophore hypotheses for the generation of fragment libraries enriched in heparanase inhibitors

A combined strategy based on the development of pharmacophore hypotheses and NMR approaches is reported for the identification of novel inhibitors of heparanase, a key enzyme involved in tumor metastasis through the remodeling of the subepithelial and subendothelial basement membranes, resulting in the dissemination of metastatic cancer cells. Several pharmacophore hypotheses were initially developed from the most active heparanase inhibitors known to date and, after their application to a pool of 27 known heparanase inhibitors and a database of 1,120 compounds approved by the FDA, a four-point pharmacophore model was selected as the most predictive. This model was subsequently applied to a database of 686 chemical fragments, and a subset of 100 fragments accomplishing completely or partially the four-point model was selected to perform nuclear magnetic resonance experiments to validate the hypothesis. The experimental studies confirmed the reliability of our pharmacophore model, its applicability to in silico databases in order to reduce the number of compounds to be experimentally screened, and the possibility of generating fragment libraries enriched in heparanase inhibitors. Rafael Gozalbes and Silvia Mosulén contributed equally to this work.     

IR and NMR time-resolved studies on the hydrolysis and condensation of methacryloxyalkylsilanes

The sol–gel reactions of the two methacrylate-modified silanes methacryloxymethyltriethoxysilane (MAMTES) and methacryloxypropyltrimethoxysilane (MAPTMS) were followed by using two independent time-resolved spectroscopic methods, viz., IR ATR and NMR with the aim to optimise their pre-hydrolysis times and consequently their use as precursors for hybrid materials. Time resolved measurements were carried out on the two systems under sol–gel conditions. Whereas the hydrolysis of both siloxanes is very fast, condensation proceeds gradually and is not completely finished within 5 h.     

Enhanced Aryltetralin Lignans Production in Linum Adventi-Tious Root Cultures

Lignans are the main secondary metabolites synthetized by Linum species as plant defense molecules. They are also valuable for human health, in particular, for their potent antiviral and antineoplastic properties. In this study, the adventitious root cultures of three Linum species (L. flavum, L. mucronatum and L. dolomiticum) were developed to produce aryltetralin lignans. The effect of two elicitors, methyl jasmonate and coronatine, on aryltetralin lignans production was also evaluated. The adventitious root cultures from L. dolomiticum were obtained and analyzed for the first time and resulted as the best producer for all the aryltetralins highlighted in this system: Podophyllotoxin, 6-methoxypodophyllotoxin and 6-methoxypodophyllotoxin-7-O-β-glucoside, the last showing a productivity of 92.6 mg/g DW. The two elicitors differently affected the production of the 6-methoxypodophyllotoxin and 6-methoxypodophyllotoxin-7-O-β-glucoside.     

Multimodal investigations of trans-endothelial cell trafficking under condition of disrupted blood-brain barrier integrity

Background  

Stem cells or immune cells targeting the central nervous system (CNS) bear significant promises for patients affected by CNS disorders. Brain or spinal cord delivery of therapeutic cells is limited by the blood-brain barrier (BBB) which remains one of the recognized rate-limiting steps. Osmotic BBB disruption (BBBD) has been shown to improve small molecule chemotherapy for brain tumors, but successful delivery of cells in conjunction with BBBD has never been reported.     

Is the placental proteome impaired in well‐controlled gestational diabetes?

In pregnancy complicated by gestational diabetes mellitus (GDM), the human placenta shows several pathological functional and structural changes, but the extent to which maternal glycemic control contributes to placental abnormalities remains unclear. The aim of this study was to profile and compare the proteome of placentas from healthy pregnant women and those with GDM, to investigate the placenta‐specific protein composition and possible changes of its function in presence of GDM. Quantitative proteomic analysis, based on LC‐MS^E approach, revealed that higher (approximately 15% increase) levels of galectin 1 and collagen alpha‐1 XIV chain (although the difference regarding the latter was at the limit of significance) were present in GDM samples, while heat shock 70 kDa protein 1A/1B was less abundant in GDM placental tissue. These data seem to indicate that GDM, when well controlled, did not markedly affect the placental proteome.