Synthesis of new azulene derivatives and study of their effect on lipid peroxidation and lipoxygenase activity

The relationship between free radicals and acute or chronic inflammation has been well established. We have previously reported the significant antioxidant activity of the natural azulene derivatives chamazulene and guaiazulene. Furthermore, some synthetic azulene analogues have been found to possess anti-inflammatory activity. In this investigation we report the synthesis of five 3-alkyl or 3-(hydroxy)alkylazulene-1-carboxylic acids and esters, from tropolone, via the corresponding furanone. The synthesised compounds were tested for their effect on the peroxidation of rat hepatic microsomal membrane lipids, applying the 2-thiobarbituric acid test. Their anti-inflammatory activity was evaluated in vitro by the offered inhibition of soybean lipoxygenase. All the tested molecules were found to inhibit lipid peroxidation by 100% at 1 mM. They were also found to considerably inhibit lipoxygenase activity. The above results are discussed in relation to the structure and physicochemical properties of the examined azulene derivatives.     

Antioxidant activity of novel indole derivatives and protection of the myocardial damage in rabbits

Novel indole derivatives containing a triazole moiety (1a-d, 2a-c) were synthesized as lead compounds with interesting pharmacological profiles. Their antioxidant activity was investigated on in vitro non-enzymatic rat hepatic microsomal lipid peroxidation. All compounds showed significant effect in the above assay. The effect depended mainly on the attachment position of the triazole moiety on the indole nucleus. The most potent antioxidant derivatives la, 1c and 1d were tested for their protective ability against the oxidative damage of the myocardium after ischemia-reperfusion, in male rabbits which were subjected to 30 min regional ischemia followed by reperfusion. The tested antioxidant compounds 1a, 1c and 1d were continuously infused for 30 min starting at 10th min of ischemia and lasted at 10th min of reperfusion. The concentration of malondialdehyde (MDA, a marker of lipid peroxidation) and hemodynamic parameters (blood pressure and heart rate) were measured in the baseline, at 20th min of the sustained ischemia, 1st and 20th min of reperfusion. It was found that the examined compounds la, 1c and 1d reduced significantly the level of MDA in rabbits under ischemia-reperfusion and proved to be promising substances for further evaluation of anti-ischemic properties.     

13C-nmr of carbonyl compounds 1. Stereodynamic behaviour of acyclic and cyclic dienones

The conformational mobility of a series of conjugated dienones is investigated by low-temperature NMR- and IR-spectroscopy and interpreted in terms of substituent effects.     

Switchable photocatalysis for the chemodivergent benzylation of 4-cyanopyridines

We report a photocatalytic strategy for the chemodivergent radical benzylation of 4-cyanopyridines. The chemistry uses a single photoredox catalyst to generate benzyl radicals upon N–F bond activation of 2-alkyl N-fluorobenzamides. The judicious choice of different photocatalyst quenchers allowed us to select at will between mechanistically divergent processes. The two reaction manifolds, an ipso-substitution path proceeding via radical coupling and a Minisci-type addition, enabled selective access to regioisomeric C4 or C2 benzylated pyridines, respectively. Mechanistic investigations shed light on the origin of the chemoselectivity switch.

We report a photocatalytic strategy for the chemodivergent radical benzylation of 4-cyanopyridines. The chemistry uses a single photoredox catalyst to generate benzyl radicals upon N–F bond activation of 2-alkyl N-fluorobenzamides.     

Amphiphilic gradient copolymers of 2‐methyl‐ and 2‐phenyl‐2‐oxazoline: self‐organization in aqueous media and drug encapsulation

Gradient (or pseudo‐diblock) copolymers were synthesized from 2‐methyl‐2‐oxazoline and 2‐phenyl‐2‐oxazoline monomer mixtures via cationic polymerization. The self‐assembling properties of these biocompatible gradient copolymers in aqueous solutions were investigated, in an effort to use the produced nanostructures as nanocarriers for hydrophobic pharmaceutical molecules. Dynamic and static light scattering as well as AFM measurements showed that the copolymers assemble in different supramolecular nanostructures (spherical micelles, vesicles and aggregates) depending on copolymer composition. Fluorescence spectroscopy studies revealed a microenvironment of unusually high polarity inside the nanostructures. This observation is related partly to the gradient structure of the copolymers. The polymeric nanostructures were stable with time. Their structural properties in different aqueous media—PBS buffer, RPMI solution—simulating conditions used in pharmacological/medicinal studies, have been also investigated and a composition dependent behavior was observed. Finally, the hydrophobic drug indomethacin was successfully encapsulated within the gradient copolymer nanostructures and the properties of the mixed aggregates were studied in respect to the initial copolymer assemblies. The produced aggregates encapsulating indomethacin showed a significant increase of their mass and size compared to original purely polymeric ones. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Artificial Neural Networks in water analysis: Theory and applications

Artificial Neural Networks (ANNs) have seen an explosion of interest over the last two decades and have been successfully applied in all fields of chemistry and particularly in analytical chemistry. Inspired from biological systems and originated from the perceptron, i.e. a program unit that learns concepts, ANNs are capable of gradual learning over time and modelling extremely complex functions. In addition to the traditional multivariate chemometric techniques, ANNs are often applied for prediction, clustering, classification, modelling of a property, process control, procedural optimisation and/or regression of the obtained data. This paper aims at presenting the most common network architectures such as Multi-layer Perceptrons (MLPs), Radial Basis Function (RBF) and Kohonen's self-organisations maps (SOM). Moreover, back-propagation (BP), the most widespread algorithm used today and its modifications, such as quick-propagation (QP) and Delta-bar-Delta, are also discussed. All architectures correlate input variables to output variables through non-linear, weighted, parameterised functions, called neurons. In addition, various training algorithms have been developed in order to minimise the prediction error made by the network. The applications of ANNs in water analysis and water quality assessment are also reviewed. Most of the ANNs works are focused on modelling and parameters prediction. In the case of water quality assessment, extended predictive models are constructed and optimised, while variables correlation and significance is usually estimated in the framework of the predictive or classifier models. On the contrary, ANNs models are not frequently used for clustering/classification purposes, although they seem to be an effective tool. ANNs proved to be a powerful, yet often complementary, tool for water quality assessment, prediction and classification.     

On the Rational Drug Design for Hypertension through NMR Spectroscopy

Antagonists of the AT1receptor (AT1R) are beneficial molecules that can prevent the peptide hormone angiotensin II from binding and activating the specific receptor causing hypertension in pathological states. This review article summarizes the multifaced applications of solid and liquid state high resolution nuclear magnetic resonance (NMR) spectroscopy in antihypertensive commercial drugs that act as AT1R antagonists. The 3D architecture of these compounds is explored through 2D NOESY spectroscopy and their interactions with micelles and lipid bilayers are described using solid state ¹³CP/MAS, ³¹P and ²H static solid state NMR spectroscopy. Due to their hydrophobic character, AT1R antagonists do not exert their optimum profile on the AT1R. Therefore, various vehicles are explored so as to effectively deliver these molecules to the site of action and to enhance their pharmaceutical efficacy. Cyclodextrins and polymers comprise successful examples of effective drug delivery vehicles, widely used for the delivery of hydrophobic drugs to the active site of the receptor. High resolution NMR spectroscopy provides valuable information on the physical-chemical forces that govern these drug:vehicle interactions, knowledge required to get a deeper understanding on the stability of the formed complexes and therefore the appropriateness and usefulness of the drug delivery system. In addition, it provides valuable information on the rational design towards the synthesis of more stable and efficient drug formulations.     

Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol

The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified with 3,4,5 trimethoxybenzyl alcohol. The activity of the novel derivatives was examined in vivo on carrageenan-induced inflammation, and in vitro, as cyclooxygenase and lipoxygenase inhibitors. It was found that the new compounds were more potent anti-inflammatory agents than the parent drugs. Thus, the ibuprofen (21) and ketoprofen (16) derivatives reduced rat paw edema by 67 and 91% (the reduction by the relevant NSAIDs was 36 and 47%, respectively). They inhibited COX-2 more than the starting drugs (21 by 67%, ibuprofen 46%, 19 by 94%, ketoprofen 49%). Docking of compounds on the active sites of COX-1 and COX-2 reflects their in vitro activity. Thus, 19 adopts an unfavorable orientation for COX-1 inhibition, but it binds effectively in the binding pocket of COX-2, in agreement with the absence of activity for COX-1 and the high inhibition of COX-2. In conclusion, the performed structural modifications result in the enhancement of the anti-inflammatory activity, compared with the parent NSAIDs.     

Shellability and higher Cohen-Macaulay connectivity of generalized cluster complexes

Let Φ be a finite root system of rank n and let m be a nonnegative integer. The generalized cluster complex Δ^m(Φ) was introduced by S. Fomin and N. Reading. It was conjectured by these authors that Δ^m(Φ) is shellable and by V. Reiner that it is (m + 1)-Cohen-Macaulay, in the sense of Baclawski. These statements are proved in this paper. Analogous statements are shown to hold for the positive part Δ₊^m(Φ) of Δ^m(Φ). An explicit homotopy equivalence is given between Δ₊^m(Φ) and the poset of generalized noncrossing partitions, associated to the pair (Φ, m) by D. Armstrong.     

Stereoselectivity in rhodium antibiotics

The biological activities of the enantiomeric rhodium(III)-nicotine complexes trans-[Rh(S-(–)-nicH⁺)₄Cl₂](PF₆)₅, trans-[Rh(R-(+)-nicH⁺)₄Cl₂](PF₆)₅ (97% enantiomerically pure) and trans-[Rh(RS-(±)-nicH⁺)₄Cl₂](PF₆)₅ were examined in detail on the Gram positive bacteria B. subtilis. Minimal inhibitory concentrations and exponential phases for each complex were calculated: the complexes were bactericidal at certain concentrations. Novel stereoselective phenomena are reported.