Attila Kiss-Szikszai

Efficient Synthesis of Chromones with Alkenyl Functionalities by the Heck Reaction

The usefulness of the Heck reaction in the field of chromones has been demonstrated. Bromochromones with the halogen atom in their rings A and B were reacted with various terminal alkenes to give hitherto unknown alkenyl‐substituted chromones. Reactivity of the substrates was found to markedly depend on the position of the bromine atom. Under phosphine‐free conditions using a phase‐transfer catalyst additive (tetrabutylammonium bromide), shorter reaction periods and usually higher yields were obtained.

Synthesis of isoindole and benzoisoindole derivatives of teicoplanin pseudoaglycon with remarkable antibacterial and antiviral activities

The primary amino function of teicoplanin pseudoaglycon has been transformed into arylthioisoindole or benzoisoindole and glycosylthioisoindole derivatives, in a reaction with o-phthalaldehyde or naphtalene-2,3-dicarbaldehyde and various thiols. All of the obtained semisynthetic antibiotics exhibited potent antibacterial activities against Gram-positive bacteria in the ng per ml concentration range. A few of them showed antiviral activity, in particular against influenza virus.

Synthesis of 5-aryl-3-C-glycosyl- and unsymmetrical 3,5-diaryl-1,2,4-triazoles from alkylidene-amidrazones

Among 1,2,4-triazole derivatives with versatile biological activities 3-C-glucopyranosyl-5-substituted-1,2,4-triazoles belong to the most efficient inhibitors of glycogen phosphorylase, and are thus potential antidiabetic agents. In seeking new synthetic methods for this class of compounds oxidative ring closures of N1-alkylidene carboxamidrazones were studied. O-Peracylated N1-(β-D-glycopyranosylmethylidene)-arenecarboxamidrazones were prepared from the corresponding glycosyl cyanides and amidrazones by Raney-Ni® reduction in the presence of NaH2PO2. Bromination of the so obtained compounds by NBS gave hydrazonoyl bromide type derivatives which were ring closed to 3-C-glycosyl-5-substituted-1,2,4-triazoles in pyridine or by NH4OAc in AcOH. Under the same conditions O-perbenzoylated N1-arylidene-C-(β-D-glucopyranosyl)-formamidrazones gave the expected 1,2,4-triazoles as minor products only. N1-Arylidene-arenecarboxamidrazones were also transformed into 3,5-diaryl-1,2,4-triazoles with NBS/NH4OAc in AcOH indicating high functional group tolerance and general applicability of the method.

Effects of N source concentration and NH 4 + /NO 3 − ratio on phenylethanoid glycoside pattern in tissue cultures of Plantago lanceolata L.: A metabolomics driven full-factorial experiment with LC–ESI–MS 3

Tissue cultures of a medicinal plant, Plantago lanceolata L. were screened for phenylethanoid glycosides (PGs) and other natural products (NPs) with LC-ESI-MS(3). The effects of N source concentration and NH4(+)/NO3(-) ratio were evaluated in a full-factorial (FF) experiment. N concentrations of 10, 20, 40 and 60mM, and NH4(+)/NO3(-) ratios of 0, 0.11, 0.20 and 0.33 (ratio of NH4(+) in total N source) were tested. Several peaks could be identified as PGs, of which, 16 could be putatively identified from the MS/MS/MS spectra. N source concentration and NH4(+)/NO3(-) ratio had significant effects on the metabolome, their effects on individual PGs were different despite these metabolites were of the same biosynthethic class. Chief PGs were plantamajoside and acteoside (verbascoside), their highest concentrations were 3.54±0.83% and 1.30±0.40% of dry weight, on media 10(0.33) and 40(0.33), respectively. NH4(+)/NO3(-) ratio and N source concentration effects were examined on a set of 89 NPs. For most NPs, high increases in abundance were observed compared to Murashige-Skoog medium. Abundances of 42 and 10 NPs were significantly influenced by the N source concentration and the NH4(+)/NO3(-) ratio, respectively. Optimal media for production of different NP clusters were 10(0), 10(0.11) and 40(0.33). Interaction was observed between NH4(+)/NO3(-) ratio and N source concentration for many NPs. It was shown in simulated experiments, that one-factor at a time (OFAT) experimental designs lead to sub-optimal media compositions for production of many NPs, and alternative experimental designs (e.g. FF) should be preferred when optimizing medium N source for optimal yield of NPs. If using OFAT, the N source concentration is to be optimized first, followed by NH4(+)/NO3(-) ratio, as this reduces the likeliness of suboptimal yield results.

Carbon-carbon bond formation in neutral aqueous medium by modification of the Nozaki-Hiyama reaction

Abstract A carbon carbon bond forming reaction has been developed by modifying the Nozaki–Hiyama reaction using a chromium(II)-aminopolycarboxylate complexes in a neutral aqueous medium at room temperature. Aldehydes and ketones can be coupled with aralkyl and aryl halides in good yields.

Antioxidant Properties and Oxidative Transformation of Different Chromone Derivatives

Nowadays, there is an increase in the application of natural products for the prevention of different disorders or adjuvant substances next to pharmacological treatment. Phytochemicals include different chromone derivatives, which possess a wide spectrum of biological activity. The aim of the present study was the investigation of the antioxidant activity, cytotoxicity and oxidative transformation of nine chromone derivatives. First, we investigated the radical scavenging activity (ABTS), the oxygen radical absorption capacity (ORAC) and the ferric reducing antioxidant power (FRAP) of the investigated molecules. The cytotoxic effects of the compounds were tested on H9c2 cell cultures by the MTT assay. Each compound showed a significant ORAC value compared to the reference. However, the compound 865 possess significantly higher FRAP and ABTS activity in comparison with the reference and other tested molecules, respectively. Based on these assays, the compound 865 was selected for further analysis. In these experiments, we investigated the oxidative metabolism of the compound in vitro. The molecule was oxidized by the Fenton reaction, artificial porphyrin and electrochemistry; then, the formed products were identified by mass spectrometry. Four possible metabolites were detected. The results revealed the compound 865 to possess good antioxidant properties and to be stable metabolically; hence, it is worth investigating its effects in vivo.

The ratio of 2-AG to its isomer 1-AG as an intrinsic fine tuning mechanism of CB1 receptor activation

Endocannabinoids are pleiotropic lipid messengers that play pro-homeostatic role in cellular physiology by strongly influencing intracellular Ca2+ concentration through the activation of cannabinoid receptors. One of the best-known endocannabinoid ‘2-AG’ is chemically unstable in aqueous solutions, thus its molecular rearrangement, resulting in the formation of 1-AG, may influence 2-AG-mediated signaling depending on the relative concentration and potency of the two isomers. To predict whether this molecular rearrangement may be relevant in physiological processes and in experiments with 2-AG, here we studied if isomerization of 2-AG has an impact on 2-AG-induced, CB1-mediated Ca2+ signaling in vitro. We found that the isomerization-dependent drop in effective 2-AG concentration caused only a weak diminution of Ca2+ signaling in CB1 transfected COS7 cells. We also found that 1-AG induces Ca2+ transients through the activation of CB1, but its working concentration is threefold higher than that of 2-AG. Decreasing the concentration of 2-AG in parallel to the prevention of 1-AG formation by rapid preparation of 2-AG solutions, caused a significant diminution of Ca2+ signals. However, various mixtures of the two isomers in a fix total concentration – mimicking the process of isomerization over time – attenuated the drop in 2-AG potency, resulting in a minor decrease in CB1 mediated Ca2+ transients. Our results indicate that release of 2-AG into aqueous medium is accompanied by its isomerization, resulting in a drop of 2-AG concentration and simultaneous formation of the similarly bioactive isomer 1-AG. Thus, the relative concentration of the two isomers with different potency and efficacy may influence CB1 activation and the consequent biological responses. In addition, our results suggest that 1-AG may play role in stabilizing the strength of cannabinoid signal in case of prolonged 2-AG dependent cannabinoid mechanisms.

Myrosinase Compatible Simultaneous Determination of Glucosinolates and Allyl Isothiocyanate by Capillary Electrophoresis Micellar Electrokinetic Chromatography (CE-MEKC)

INTRODUCTION The functional food Cruciferous vegetables contain glucosinolates which are decomposed by the myrosinase enzyme upon tissue damage. The isothiocyanates are the most frequent decomposition products. Because of their various bioactivities, these compounds and the myrosinase is of high interest to many scientific fields. OBJECTIVE Development of a capillary electrophoresis method capable of myrosinase-compatible, simultaneous quantification of glucosinolates and isothiocyanates. METHODS Capillary electrochromatography parameters were optimised, followed by optimisation of a myrosinase-compatible derivatisation procedure for isothiocyanates. Vegetable extracts (Brussels sprouts, horseradish, radish and watercress) were tested for myrosinase activity, glucosinolate content and isothiocyanate conversion rate. Allyl isothiocyanate was quantified in some food products. RESULTS The method allows quantification of sinigrin, gluonasturtiin and allyl isothiocyanate after myrosinase compatible derivatisation in-vial by mercaptoacetic acid. The chromatograhpic separation takes 2.5 min (short-end injection) or 15 min (long-end injection). For the tested vegetables, measured myrosinase activity was between 0.960-27.694 and 0.461-26.322 µmol/min/mg protein, glucosinolate content was between 0-2291.8 and 0-248.5 µg/g fresh weight for sinigrin and gluconastrutiin, respectively. The possible specificity of plants to different glucosinolates was also shown. Allyl isothiocyanate release rate was different in different vegetables (73.13 - 102.13%). The method could also be used for quantification of allyl isothiocyanate from food products. CONCLUSIONS The presented capillary electrophoresis method requires a minimal amount of sample and contains only a few sample preparation steps, and can be used in several applications (glucosinolate determination, myrosinase activity measurement, isothiocyanate release estimation). Copyright

Cytoprotective dibenzoylmethane derivatives protect cells from oxidative stress-induced necrotic cell death☆

Screening of a small in-house library of 1863 compounds identified 29 compounds that protected Jurkat cells from hydrogen peroxide-induced cytotoxicity. From the cytoprotective compounds eleven proved to possess antioxidant activity (ABTS radical scavenger effect) and two were found to inhibit poly(ADP-ribosyl)ation (PARylation), a cytotoxic pathway operating in severely injured cells. Four cytoprotective dibenzoylmethane (DBM) derivatives were investigated in more detail as they did not scavenge hydrogen peroxide nor did they inhibit PARylation. These compounds protected cells from necrotic cell death while caspase activation, a parameter of apoptotic cell death was not affected. Hydrogen peroxide activated extracellular signal regulated kinase (ERK1/2) and p38 MAP kinases but not c-Jun N-terminal kinase (JNK). The cytoprotective DBMs suppressed the activation of Erk1/2 but not that of p38. Cytoprotection was confirmed in another cell type (A549 lung epithelial cells), indicating that the cytoprotective effect is not cell type specific. In conclusion we identified DBM analogs as a novel class of cytoprotective compounds inhibiting ERK1/2 kinase and protecting from necrotic cell death by a mechanism independent of poly(ADP-ribose) polymerase inhibition.

Optimization of the Synthesis of Flavone-Amino Acid and Flavone-Dipeptide Hybrids via Buchwald-Hartwig Reaction

The article describes the development of Buchwald-Hartwig amination of different bromoflavones with amino acid and peptide derivatives as nitrogen source giving unique structures. The previously observed racemization, which occurred during the synthesis of flavone-amino acid hybrids, was successfully prevented in most cases. The biological assays of these novel structures showed cytotoxic effects on different cancer cell lines.