Tacrines as Therapeutic Agents for Alzheimer's Disease. V. Recent Developments

Herein we have reviewed our recent developments for the identification of new tacrine analogues for Alzheimer's disease (AD) therapy. Tacrine, the first cholinesterase inhibitor approved for AD treatment, did not stop the progression of AD, producing only some cognitive improvements, but exhibited secondary effects mainly due to its hepatotoxicity. Thus, the drug was withdrawn from the clinics administration. Since then, many publications have described non‐hepatotoxic tacrines, and in addition, important efforts have been made to design multitarget tacrines by combining their cholinesterase inhibition profile with the modulation of other biological targets involved in AD.     

Two Ecdysteroids Isolated from Micropropagated Lychnis flos-cuculi and the Biological Activity of Plant Material

Genetically uniform plant material, derived from Lychnis flos-cuculi propagated in vitro, was used for the isolation of 20-hydroxyecdysone and polypodine B and subjected to an evaluation of the antifungal and antiamoebic activity. The activity of 80% aqueous methanolic extracts, their fractions, and isolated ecdysteroids were studied against pathogenic Acanthamoeba castellani. Additionally, a Microtox^® acute toxicity assay was performed. It was found that an 80% methanolic fraction of root extract exerts the most potent amoebicidal activity at IC₅₀ of 0.06 mg/mL at the 3rd day of treatment. Both ecdysteroids show comparable activity at IC₅₀ of 0.07 mg/mL. The acute toxicity of 80% fractions at similar concentrations is significantly higher than that of 40% fractions. Crude extracts exhibited moderate antifungal activity, with a minimum inhibitory concentration (MIC) within the range of 1.25–2.5 mg/mL. To the best of our knowledge, the present report is the first to show the biological activity of L. flos-cuculi in terms of the antifungal and antiamoebic activities and acute toxicity. It is also the first isolation of the main ecdysteroids from L. flos-cuculi micropropagated, ecdysteroid-rich plant material.     

Diagnosis of suspicious breast lesions using an empirical mathematical model for dynamic contrast-enhanced MRI

The purpose of this study was to test whether an empirical mathematical model (EMM) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can distinguish between benign and malignant breast lesions. A modified clinical protocol was used to improve the sampling of contrast medium uptake and washout. T(1)-weighted DCE magnetic resonance images were acquired at 1.5 T for 22 patients before and after injection of Gd-DTPA. Contrast medium concentration as a function of time was calculated over a small region of interest containing the most rapidly enhancing pixels. Then the curves were fitted with the EMM, which accurately described contrast agent uptake and washout. Results demonstrate that benign lesions had uptake (P<2.0 x 10(-5)) and washout (P<.01) rates of contrast agent significantly slower than those of malignant lesions. In addition, secondary diagnostic parameters, such as time to peak of enhancement, enhancement slope at the peak and curvature at the peak of enhancement, were derived mathematically from the EMM and expressed in terms of primary parameters. These diagnostic parameters also effectively differentiated benign from malignant lesions (P<.03). Conventional analysis of contrast medium dynamics, using a subjective classification of contrast medium kinetics in lesions as "washout," "plateau" or "persistent" (sensitivity=83%, specificity=50% and diagnostic accuracy=72%), was less effective than the EMM (sensitivity=100%, specificity=83% and diagnostic accuracy=94%) for the separation of benign and malignant lesions. In summary, the present research suggests that the EMM is a promising alternative method for evaluating DCE-MRI data with improved diagnostic accuracy.     

Correction to: Aziridine-2-Carboxylic Acid Derivatives and Its Open-Ring Isomers as a Novel PDIA1 Inhibitors

Chemistry of Heterocyclic Compounds -     

2- and 2,7-Substituted para-N-Methylpyridinium Pyrenes: Syntheses,Molecular and Electronic Structures,Photophysical, Electrochemical,and Spectroelectrochemical Properties and Binding to Double-Stranded (ds) DNA

Two N-methylpyridinium compounds and analogous N-protonated salts of 2- and 2,7-substituted 4-pyridyl-pyrene compounds were synthesised and their crystal structures, photophysical properties both in solution and in the solid state, electrochemical and spectroelectrochemical properties were studied. Upon methylation or protonation, the emission maxima are significantly bathochromically shifted compared to the neutral compounds, although the absorption maxima remain almost unchanged. As a result, the cationic compounds show very large apparent Stokes shifts of up to 7200 cm⁻¹. The N-methylpyridinium compounds have a single reduction at ca. −1.5 V vs. Fc/Fc⁺ in MeCN. While the reduction process was reversible for the 2,7-disubstituted compound, it was irreversible for the mono-substituted one. Experimental findings are complemented by DFT and TD-DFT calculations. Furthermore, the N-methylpyridinium compounds show strong interactions with calf thymus (ct)-DNA, presumably by intercalation, which paves the way for further applications of these multi-functional compounds as potential DNA-bioactive agents.     

The mass spectrometric study on aminohydroxamic acids‐based metallacrowns

Electrospray ionization mass spectrometry (MS) has been widely used to detect noncovalent interactions in supramolecular compounds, especially in biological systems. In our work, we present the application of the electrospray ionization MS technique to characterize the metallamacrocycles, known as metallacrowns. This project involves investigations of the aminohydroxamic acids structure and chirality influence on formation of ternary 12‐metallacrown‐4 complexes. For our experiments, we used a series of β‐aminohydroxamic acids and derivatives of histidinehydroxamic acid. A high stability of the studied supramolecular systems in the gas phase was confirmed by MS/MS experiments. We also proposed the fragmentation pathways for the studied compounds. Obtained results reveal that the ternary 12‐metallacrown‐4 formation process is not selective, and ligands of various structures and chiralities can be incorporated into these systems. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis,characterization, and thermal properties of new flavor compounds

Synthesis, characterization, and thermal properties of new, flavor, long chain esters were presented. The new compounds were obtained in the catalytic esterification process of a stoichiometric ratio of trans-3,7-dimethyl-2,6-octadien-1-ol, succinic anhydride, and aliphatic chain diol. As diols ethylene glycol, 1,4-buthylene glycol, 1,5-pentylene glycol, and 1,6-hexylene glycol were applied. The spectroscopic analyses completely confirmed that the applied synthesis conditions allowed obtaining the new compounds with high yield and purity. Their thermal properties were studied in inert and oxidative atmospheres. The esters were less thermally stable in inert (IDT 186–195 °C) than in oxidative (IDT 210–228 °C) atmosphere. Two, non-completely divided decomposition steps were visible during their pyrolysis. In contrast, the new, long chain compounds decompose in three major steps in air. The analyses of the volatile products emitted during their pyrolysis indicated on the asymmetrical disrupt of their bonds. The formation of acyclic and alicyclic monoterpene hydrocarbons, succinic anhydride, diols, alcohols, alkenes, and water was observed. It indicated mainly on the β-elimination reactions during their pyrolysis. Also, β-elimination reactions of esters are mainly expected in air. Initially, it resulted in the formation of acyclic and alicyclic monoterpene hydrocarbons, hydroxyl compounds (diols, alcohols), and its β-elimination products: aldehydes, alkenes, and water. However, the presence of oxygen in the medium causes the partial decarboxylation and oxygenation of aldehydes and thus the formation of alkenes and carbon dioxide. In addition, the beginning of evaporation of succinic anhydride was detected at T _max1. At T _max2 the evaporation of succinic anhydride, their partial decarboxylation to CO₂, the small amounts of diols, alcohols, and aldehyde fragments were indicated. Finally, succinic anhydride, water, and carbon dioxide were only observed during decomposition of studied esters in air.     

Mono‐ and Bis(pyrrolo)tetrathiafulvalene Derivatives Tethered to C60: Synthesis,Photophysical Studies,and Self‐Assembled Monolayers

A series of mono‐ (MPTTF) and bis(pyrrolo)tetrathiafulvalene (BPTTF) derivatives tethered to one or two C₆₀ moieties was synthesized and characterized. The synthetic strategy for these dumbbell‐shaped compounds was based on a 1,3‐dipolar cycloaddition reaction between aldehyde‐functionalized MPTTF/BPTTF derivatives, two different tailor‐made amino acids, and C₆₀. Electronic communication between the MPTTF/BPTTF units and the C₆₀ moieties was studied by a variety of techniques including cyclic voltammetry and absorption spectroscopy. These solution‐based studies indicated no observable electronic communication between the MPTTF/BPTTF units and the C₆₀ moieties. In addition, femtosecond and nanosecond transient absorption spectroscopy revealed, rather surprisingly, that no charge transfer from the MPTTF/BPTTF units to the C₆₀ moieties takes place on excitation of the fullerene moiety. Finally, it was shown that the MPTTF–C₆₀ and C₆₀–BPTTF‐C₆₀ dyad and triad molecules formed self‐assembled monolayers on a Au(111) surface by anchoring to C₆₀.     

HOMO Stabilisation in π‐Extended Dibenzotetrathiafulvalene Derivatives for Their Application in Organic Field‐Effect Transistors

Three new organic semiconductors, in which either two methoxy units are directly linked to a dibenzotetrathiafulvalene (DB‐TTF) central core and a 2,1,3‐chalcogendiazole is fused on the one side, or four methoxy groups are linked to the DB‐TTF, have been synthesised as active materials for organic field‐effect transistors (OFETs). Their electrochemical behaviour, electronic absorption and fluorescence emission as well as photoinduced intramolecular charge transfer were studied. The electron‐withdrawing 2,1,3‐chalcogendiazole unit significantly affects the electronic properties of these semiconductors, lowering both the HOMO and LUMO energy levels and hence increasing the stability of the semiconducting material. The solution‐processed single‐crystal transistors exhibit high performance with a hole mobility up to 0.04 cm² V^?1 s^?1 as well as good ambient stability.     

Tailoring the Structure of Two‐Dimensional Self‐Assembled Nanoarchitectures Based on NiII–Salen Building Blocks

The synthesis of a series of Ni^II–salen‐based complexes with the general formula of [Ni(H₂L)] (H₄L=R²‐N,N′‐bis[R¹‐5‐(4′‐benzoic acid)salicylidene]; H₄L1: R²=2,3‐diamino‐2,3‐dimethylbutane and R¹=H; H₄L2: R²=1,2‐diaminoethane and R¹=tert‐butyl and H₄L3: R²=1,2‐diaminobenzene and R¹=tert‐butyl) is presented. Their electronic structure and self‐assembly was studied. The organic ligands of the salen complexes are functionalized with peripheral carboxylic groups for driving molecular self‐assembly through hydrogen bonding. In addition, other substituents, that is, tert‐butyl and diamine bridges (2,3‐diamino‐2,3‐dimethylbutane, 1,2‐diaminobenzene or 1,2‐diaminoethane), were used to tune the two‐dimensional (2D) packing of these building blocks. Density functional theory (DFT) calculations reveal that the spatial distribution of the LUMOs is affected by these substituents, in contrast with the HOMOs, which remain unchanged. Scanning tunneling microscopy (STM) shows that the three complexes self‐assemble into three different 2D nanoarchitectures at the solid–liquid interface on graphite. Two structures are porous and one is close‐packed. These structures are stabilized by hydrogen bonds in one dimension, while the 2D interaction is governed by van der Waals forces and is tuned by the nature of the substituents, as confirmed by theoretical calculations. As expected, the total dipolar moment is minimized