Stereoselective synthesis of some 17beta-dihydrooxazinyl steroids, as novel presumed inhibitors of 17alpha-hydroxylase-C17,20-lyase

17beta-Dihydrooxazinyl steroids 5a-l and 6a-l were synthetized. The acid-catalyzed reactions of 21-azidomethyl-20-hydroxy- and 21-hydroxymethyl-20-azidosteroids with substituted aromatic aldehydes led to the formation of androst-5-en-3beta-ols substituted in position 17beta with dihydrooxazine residues. The inhibitory effects of these compounds on rat testicular C(17,20)-lyase were investigated with an in vitro radioincubation technique.     

The effects of corticotropin-releasing factor and the urocortins on hypothalamic gamma-amino butyric acid release--the impacts on the hypothalamic-pituitary-adrenal axis

Corticotropin-releasing factor (CRF) and the urocortins (UCNs) are structurally and pharmacologically related neuropeptides which regulate the endocrine, autonomic, emotional and behavioral responses to stress. CRF and UCN1 activate both CRF receptors (CRFR1 and CRFR2) with CRF binding preferentially to CRFR1 and UCN1 binding equipotently to both receptors. UCN2 and UCN3 activate selectively CRFR2. Previously an in vitro study demonstrated that superfusion of both CRF and UCN1 elevated the GABA release elicited by electrical stimulation from rat amygdala, through activation of CRF1 receptors. In the present experiments, the same in vitro settings were used to study the actions of CRF and the urocortins on hypothalamic GABA release. CRF and UCN1 administered in equimolar doses increased significantly the GABA release induced by electrical stimulation from rat hypothalamus. The increasing effects of CRF and UCN1 were inhibited considerably by the selective CRFR1 antagonist antalarmin, but were not influenced by the selective CRFR2 antagonist astressin 2B. UCN2 and UCN3 were ineffective. We conclude that CRF1 receptor agonists induce the release of GABA in the hypothalamus as well as previously the amygdala. We speculate that CRF-induced GABA release may act as a double-edged sword: amygdalar GABA may disinhibit the hypothalamic CRF release, leading to activation of the hypothalamic-pituitary-adrenal axis, whereas hypothalamic GABA may inhibit the hypothalamic CRF release, terminating this activation.     

Quinolinyl- and phenantridinyl-acetamides as bradykinin B1 receptor antagonists

A new series of quinolinyl- and phenantridinyl-acetamides were synthesizer and evaluated against bradykinin B1 receptor. In vitro metabolic stability data were reported for the key compounds.The analgesic effect of compound 20 from the phenantridine series was proved in-vivo.     

Synthesis, characterization and biological evaluation of some novel 17-isoxazoles in the estrone series

Regioselective 1,3-dipolar cycloadditions of different aryl nitrile oxides to mestranol were carried out to furnish novel steroidal 17α-isoxazoles in good to excellent yields. Copper(I) was found to be an efficient catalyst, accelerating the intermolecular ring-closures and leading exclusively to 3,5-disubstituted isoxazoles. The yields of the cycloadducts, however, were influenced by the substituents on the aromatic moiety of the 1,3-dipoles. Moreover, dehydration of the primary products resulted in the corresponding Δ(16,17)exo-heterocyclic derivatives. All the synthesized compounds were subjected to in vitro pharmacological studies of their antiproliferative effects relative to three human malignant cell lines (HeLa, MCF7 and A2780).     

Synthesis of D-ring-substituted (5'R)- and (5'S)-17β-pyrazolinylandrostene epimers and comparison of their potential anticancer activities

Various steroidal benzylidenes were synthetized from pregnenolone with benzaldehyde and p-substituted benzaldehydes. The resulting 17β-chalconyl derivatives of pregnenolone were reacted with hydrazine hydrate in acetic acid solution. Regardless of the starting material, the ring-closure reaction afforded (in contrast with the literature data) a mixture of two steroidal pyrazoline epimers. The epimers were critical isomer pairs, which could be separated only in their acetylated form; their structures were investigated by NMR techniques. The in vitro inhibition of rat testicular C(17,20)-lyase activity and the antiproliferative effects on four human cancer cell lines were measured, and the results obtained from the two epimer series were compared.     

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.     

A facile 'click' approach to novel 15β-triazolyl-5α-androstane derivatives, and an evaluation of their antiproliferative activities in vitro

Intermolecular Cu(I)-catalyzed azide-alkyne cycloadditions of 15β-azido-17β-hydroxy-5α-androstan-3β-yl acetate with different terminal alkynes under optimized reaction conditions were carried out to furnish 15β-triazolyl derivatives in good yields. Subsequent oxidation of the 'click' products with the Jones reagent afforded the corresponding 17-ketones. All the synthetized compounds were tested on three malignant human cell lines (HeLa, MCF7 and A431) in order to investigate their antiproliferative activities in vitro. Evidence of cell cycle blockade and apoptosis induction was obtained for the most effective five selected compounds by means of flow cytometry and microscopic techniques. The 15β-triazolyl-5α-androstane framework may be considered an appropriate base for the design of steroidal antiproliferative agents.     

Long persistence of importin-beta explains extended survival of cells and zygotes that lack the encoding gene

Importin-beta is an essential component of nuclear protein import, spindle formation and nuclear envelope assembly. Formerly, the function of the Drosophila Ketel gene, which encodes importin-beta and is essential for the survival to adulthood, seemed to be required only in the mitotically active cells. We report here that importin-beta function is required in every cell and that this protein possesses an exceptionally long life span. Mosaic analysis, using gynanders, indicated that zygotic function of the Ketel gene is essential in a large group of cells in the embryos. Expression of a UAS-Ketel transgene by different tissue specific Gal4 drivers on ketel(null)/- hemizygous background revealed the requirement of Ketel gene function in the ectoderm. Elimination of the Ketel gene function using a UAS-Ketel-RNAi transgene driven by different Gal4 drivers confirmed the indispensability of the Ketel gene in the ectoderm. Using GFP-tagged importin-beta (encoded by a ketel(GFP) allele) we revealed that the maternally provided GFP-importin-beta molecules persist up to larval life. The zygotic Ketel gene is expressed in every cell during early gastrulation. Although the gene is then turned off in the non-dividing cells, the produced importin-beta molecules persist long and carry out nuclear protein import throughout the subsequent stages of development. In the continuously dividing diploid cells, the Ketel gene is constitutively expressed to fulfill all three functions of importin-beta.     

Littoral macrophyte–periphyton complexes in two Hungarian shallow waters

Periphyton developing on the surfaces of emergent and submerged aquatic plants has a significant influence on water quality. The periphyton types that form on various plant species can be characterized by their mass values, the proportion of the present organic and inorganic fractions, as well as their chlorophyll-a contents. Studies on periphyton complexes constituting integrated biomonitoring systems are useful to gain essential long-term information about the performance of shallow water bodies. The filtering and settling effect of Phragmites and other aquatic plants, as well as their periphyton was examined and clearly observable in the water areas and non-flooded aquatic habitats belonging to the second phase of Kis-Balaton Protection System, as it was indicated by the mass values and ash contents. The periphyton forming on the aquatic vegetation that annually develops in Kisköre Reservoir and yields a considerable biomass has a critical part in influencing water quality. The only difference (p<0.05) was found in the ash content of the periphyton, being lower in Kis-Balaton (48.64 ± 2.29 S.E., %) and higher in Kisköre Reservoir (57.42 ± 2.54 S.E., %). This paper presents the dry mass of the periphyton, as well as its ash and chlorophyll-a content, and the results obtained on the composition of the alga species of the periphyton.