Hydrazone Activation in the Aminocatalytic Cascade Reaction for the Synthesis of Tetrahydroindolizines.

In this Letter, we demonstrate the usefulness of hydrazone activation for the synthesis of biologically relevant tetrahydroindolizines. A pyrrol-derived hydrazone bearing a Michael acceptor moiety in the N-alkyl side chain has been designed with the aim of participating in the aminocatalytic cascade reaction leading to the annulation of the new six-membered heterocyclic scaffold. The application of (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the aminocatalyst allows for the iminium ion-enamine-mediated cascade to proceed in a fully stereoselective manner.

Asymmetric Organocatalysis in the Remote (3 + 2)-Cycloaddition to 4-(Alk-1-en-1-yl)-3-cyanocoumarins.

The application of organocatalytic bifunctional activation in the remote (3 + 2)-cycloaddition between 4-(alk-1-en-1-yl)-3-cyanocoumarins and imines derived from salicylaldehyde is demonstrated. Products, bearing two biologically relevant units, have been obtained with good chemical and stereochemical efficiency. The stereochemical outcome of the process results from the application of a quinine-derived catalyst. Selected transformations of the cycloadducts leading to further chemical diversity have been demonstrated.

Vinylogous hydrazone strategy for the organocatalytic alkylation of heteroaromatic derivatives.

A new umpolung approach for the asymmetric Friedel-Crafts-type alkylation of electron-poor heteroaromatic systems has been developed. It is based on the vinylogous reactivity of hydrazones derived from heteroaromatic aldehydes. The donating effect of the hydrazone moiety can be efficiently transferred over the heteroaromatic system activating it towards an asymmetric Friedel-Crafts reaction with α,ß-unsaturated aldehydes realized under aminocatalytic conditions. Excellent enantioselectivities have been obtained owing to the application of a MacMillan imidazolidinone catalyst. Unmasking of the hydrazone moiety has also been realized resulting in the development of a unique strategy for the asymmetric functionalization of electron-poor heteroaromatic systems.

Highly Fluorescent Distyrylnaphthalene Derivatives as a Tool for Visualization of Cellular Membranes.

Fluorescent imaging, which is an important interdisciplinary field bridging research from organic chemistry, biochemistry and cell biology has been applied for multi-dimensional detection, visualization and characterization of biological structures and processes. Especially valuable is the possibility to monitor cellular processes in real time using fluorescent probes. In this work, conjugated oligoelectrolytes and neutral derivatives with the distyrylnaphthalene core (SN-COEs) were designed, synthetized and tested for biological properties as membrane-specific fluorescent dyes for the visualization of membrane-dependent cellular processes. The group of tested compounds includes newly synthesized distyrylnaphthalene derivatives (DSNNs): a trimethylammonium derivative (DSNN-NMe3+), a phosphonate derivative (DSNN-P), a morpholine derivative (DSNN-Mor), a dihydroxyethylamine derivative (DSNN-DEA), a phosphonate potassium salt (DSNN-POK), an amino derivative (DSNN-NH2) and pyridinium derivative (DSNN-Py+). All compounds were tested for their biological properties, including cytotoxicity and staining efficiency towards mammalian cells. The fluorescence intensity of SN-COEs incorporated into cellular structures was analyzed by fluorescence activated cell sorting (FACS) and photoluminescence spectroscopy. The cytotoxicity results have shown that all tested SN-COEs can be safely used in the human and animal cell studies. Fluorescence and confocal microscopy observations confirm that tested COEs can be applied as fluorescent probes for the visualization of intracellular membrane components in a wide range of different cell types, including adherent and suspension cells. The staining procedure may be performed under both serum free and complete medium conditions. The presented studies have revealed the interesting biological properties of SN-COEs and confirmed their applicability as dyes for staining the membranous structures of eukaryotic cells, which may be useful for visualization of wide range of biological processes dependent of the extra-/intracellular communications and/or based on the remodeling of cellular membranes.

A novel route to a chiral building block for the preparation of cyclopentenyl carbocyclic nucleosides. Synthesis and anticancer activity of enantiomeric neplanocins A.

The synthesis of both enantiomers of 3-[(tert-butyldimethylsilyl)oxy]methyl-4,5-O-isopropylidenecyclopent-2-en-1-ol was accomplished in six steps based on optically inactive dimethyl meso-tartrate. This key intermediate in the synthesis of cyclopentenyl carbocyclic nucleosides was subsequently applied in the preparation of enantiomeric neplanocins A. The toxic effect of these compounds was investigated for a series of suspension and adherent cancer cell lines and normal human fibroblasts. (-)-Neplanocin A ((-)-NPA) was more toxic against all tested cancer cell lines than its dextrorotary counterpart. The highest toxicity with IC50 values of 7 and 10 µM was observed for the MOLT-4 and A431 cells, respectively. Moreover, (-)-NPA also induced apoptosis in A431 cell while this effect was not observed for (+)-NPA.

Ventricular bigeminy and trigeminy caused by hypophosphataemia during diabetic ketoacidosis treatment: a case report.

BACKGROUND: Hypophosphatemia has many causes, and is often encountered during DKA (Diabetic Ketoacidosis) treatment. However, it rarely requires clinical intervention. CASE PRESENTATION: Ventricular arrhythmia was observed in a 10-year-old girl with newly diagnosed type 1 diabetes mellitus and hypophosphatemia while undergoing treatment for ketoacidosis. Oral phosphate supplementation ceased ventricular arrhythmia almost completely. CONCLUSIONS: The clinical signs of hypophosphatemia are potentially life-threatening. Therefore, physicians should be vigilant when treating patients who are at risk of hypophosphatemia. Severe hypophosphatemia accompanied by clinical symptoms requires oral or intravenous supplementation of phosphate.

Theoretical and experimental study on the effects of pH and surfactant on the internal charge transfer process in distyrylnaphthalene-based conjugated oligoelectrolytes.

In this study we have investigated the effects of pH and surfactant on the internal charge transfer (ICT) process in the DSNN derivative, DSNN-NMe+3 (4,4'-bis(4'-(N,N-bis(6″-(N,N,N-trimethylammonium)hexyl)amino)-styryl) naphthalene tetraiodide) with the aim to show that environmentally-induced changes in the degree of ICT process determine the spectral response of the DSNN chromophore. Obtained results showed that DSNN chromophore exhibits evident changes in linear optical properties (absorption/emission wavelengths, quantum yield) upon protonation. These changes are a manifestation of the attenuation of the internal charge transfer processes, which accompanies binding of proton to the nitrogen atoms of the dialkylamino groups at the termini of DSNN chromophore. The results obtained in this study clearly demonstrated the sensitivity of the ICT process in DSNN upon protonation, which, together with the affinity of DSNN towards biological and artificial membranes, may open new perspectives for its utility in fluorescence-based sensing. Moreover, the studied compound showed substantial surfactochromic effects in the ionic and non-ionic surfactant solutions, which indicate the formation of various self-organized DSNN-surfactant aggregates. The structure of these aggregates is determined by the type of specific intermolecular interactions between the chromophore and surfactant molecules. The knowledge of the nature of these interactions may be substantial in the future development of DSNN-based sensing platforms with suitable optical properties.

Fluorescence and confocal imaging of mammalian cells using conjugated oligoelectrolytes with phenylenevinylene core.

Over the last few years, considerable efforts are taken, in order to find a molecular fluorescent probe fulfilling their applicability requirements. Due to a good optical properties and affinity to biological structures conjugated oligoelectrolytes (COEs) can be considered as a promising dyes for application in fluorescence-based bioimaging. In this work, we synthetized COEs with phenylenevinylene core (PV-COEs) and applied as fluorescent membranous-specific probes. Cytotoxicity effects of each COE were probed on cancerous and non-cancerous cell types and little to no toxicity effects were observed at the high range of concentrations. The intensity of cell fluorescence following the COE staining was determined by the photoluminescence analysis and fluorescence activated cell sorting method (FACS). Intercalation of tested COEs into mammalian cell membranes was revealed by fluorescent and confocal microscopy colocalization with commercial dyes specific for cellular structures including mitochondria, Golgi apparatus and endoplasmic reticulum. The phenylenevinylene conjugated oligoelectrolytes have been found to be suitable for fluorescent bioimaging of mammalian cells and membrane-rich organelles. Due to their water solubility coupled with spontaneous intercalation into cells, favorable photophysical features, ease of cell staining, low cytotoxicity and selectivity for membranous structures, PV-COEs can be applied as markers for fluorescence imaging of a variety of cell types.

Synthesis of Enantiomerically Pure Stereomers of Rosaprostol.

Enantiopure stereomers of rosaprostol 1, an antiulcer drug, were synthesized from diastereomeric building blocks (-)-5a and (+)-5b. Conversion of (-)-5a into rosaprostol stereomer (-)-(1S,2R,5R)-1a was accomplished in nine steps in 18% overall yield. In this sequence, fully diastereoselective hydrogeneration of the endocyclic carbon double bond in the cyclopentenone ring was key, generating a new stereogenic center (C-2 in 1a). C-5 epimeric rosaprostol (-)-(1S,2R,5S)-1b was obtained from (-)-1a in 72% yield by a two-reaction sequence involving methylation and one-pot Mitsunobu esterification-hydrolysis.

Synthesis and the absolute configuration of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide as a new chiral building block for prostanoid synthesis.

The synthesis of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide (5) was accomplished in five steps starting from meso-tartaric acid (6). The key steps involved are preparation of the isopropylidene protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enone (9), resolution of the diastereoisomeric products 10 of the Horner reaction of racemic 9 with (R)-glyceraldehyde acetonide and the final regioselective ozonolysis of the exocyclic carbon­carbon double bond of the separated dienones 10 leading to both enantiomeric title compounds 5. The absolute configuration of both enantiomers was initially assigned based on the comparison of the chiroptical properties obtained from the DFT calculations with the experimental data and finally confirmed by X-ray analysis.

Type III Polyglandular Autoimmune Syndromes in children with type 1 diabetes mellitus.

INTRODUCTION: Type III Polyglandular Autoimmune Syndrome (PAS III) is composed of autoimmune thyroid diseases associated with endocrinopathy other than adrenal insufficiency. This syndrome is associated with organ-specific and organ-nonspecific or systemic autoimmune diseases. The frequency of PAS syndromes in diabetic children is unknown. OBJECTIVES: The aim of the study was to evaluate the incidence of PAS III in children with diabetes mellitus type 1. PATIENTS AND METHODS: The study consisted of 461 patients with diabetes mellitus type 1(T1DM), who were 1-19 years of age. TSH, free thyroxin, TPO autoantibodies, and thyroglobulin autoantibodies were determined annually. Autoimmune Hashimoto's thyroiditis was diagnosed in children with positive tests for TPO Ab and Tg Ab and thyroid parenchymal hypogenicity in the ultrasound investigation. Elevated TSI antibodies were used to diagnose Graves' disease. Additionally, Anti-Endomysial Antibodies IgA class were determined every year as screening for celiac disease. During clinical control, other autoimmune diseases were diagnosed. Adrenal function was examined by the diurnal rhythm of cortisol. RESULTS: PAS III was diagnosed in 14.5% children: PAS IIIA (T1DM and autoimmune thyroiditis) was recognized in 11.1 % and PAS III C (T1DM and other autoimmune disorders: celiac disease, and JIA, psoriasis and vitiligo) in 3.5% children. PAS IIIA was more prevalent in girls than in boys - 78.4% versus 21.6% (p<0.05). PAS III was observed between 1-5 years of life in 66.6% children; the frequency decreased in consecutive years and successively increased in the adolescence period to 22.7%. CONCLUSIONS: PAS III occurs in 14.5% of children with DM type1 and the incidence is positively correlated with patients' age and female gender. Children with PAS III should be carefully monitored as a group at risk for the development of other autoimmune diseases.