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Autoimmune uveitis is a blinding disease presenting with autoantibodies against eye-specific proteins as well as autoagressive T cells invading and attacking the immune-privileged target tissue retina. The molecular events enabling T cells to invade and attack the tissue have remained elusive. Changes in membrane protein expression patterns between diseased and healthy stages are especially interesting because initiating events of disease will most likely occur at membranes. Since disease progression is accompanied with a break-down of the blood-retinal barrier, serum-derived proteins mask the potential target tissue-related changes. To overcome this limitation, we used membrane-enriched fractions derived from retinas of the only available spontaneous animal model for the disease equine recurrent uveitis, and compared expression levels by a label-free LC-MSMS-based strategy to healthy control samples. We could readily identify a total of 893 equine proteins with 57% attributed to the Gene Ontology project term "membrane." Of these, 179 proteins were found differentially expressed in equine recurrent uveitis tissue. Pathway enrichment analyses indicated an increase in proteins related to antigen processing and presentation, TNF receptor signaling, integrin cell surface interactions and focal adhesions. Additionally, loss of retina-specific proteins reflecting decrease of vision was observed as well as an increase in Müller glial cell-specific proteins indicating glial reactivity. Selected protein candidates (caveolin 1, integrin alpha 1 and focal adhesion kinase) were validated by immunohistochemistry and tissue staining pattern pointed to a significant increase of these proteins at the level of the outer limiting membrane which is part of the outer blood-retinal barrier. Taken together, the membrane enrichment in combination with LC-MSMS-based label-free quantification greatly increased the sensitivity of the comparative tissue profiling and resulted in detection of novel molecular pathways related to equine recurrent uveitis.

Background Yeast expression systems with altered N-glycosylation are now available to produce glycoproteins with homogenous, defined N-glycans. However, data on the behaviour of these strains in high cell density cultivation are scarce. Results Here, we report on cultivations under controlled specific growth rate of a GlycoSwitch-Man5 Pichia pastoris strain producing Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) at high levels (hundreds of milligrams per liter). We demonstrate that homogenous Man5GlcNAc2 N-glycosylation of the secreted proteins is achieved at all specific growth rates tested. Conclusions Together, these data illustrate that the GlycoSwitch-Man5 P. pastoris is a robust production strain for homogenously N-glycosylated proteins.

8 páginas, 6 figuras, 2 tablas -- PAGS nros. 9139-9146, A novel trans-platinum(II) complex bearing one dimethylamine (dma) and one methylamine (ma) ligand, namely trans-[PtCl(2)(dma)(ma)], recently synthesised and characterised in our laboratory, displayed relevant antiproliferative properties in vitro, being more active than the parent complex, trans-[PtCl(2)(dma)(ipa)], which has isopropylamine (ipa) in place of methylamine. We have analysed comparatively the solution behaviour of these two complexes under various experimental conditions, and investigated their reactivity with horse heart cytochrome c by mass spectrometry, inductively coupled plasma-optical emission spectroscopy (ICP-OES), 2D [(1)H,(15)N],[(1)H,(13)C] HSQC and [(1)H,(1)H] NOESY NMR. Some important changes that occurred in the [(1)H,(13)C] HSQC NMR spectrum of cytochrome c treated with trans-[PtCl(2)(dma)(ma)] in water, after two days' incubation, most probably arose from direct platinum coordination to the protein side chain; this was proved conclusively by [(1)H,(1)H] NOESY NMR and [(1)H,(15)N] HSQC NMR measurements. Met65 was identified as the primary Pt binding site on cytochrome c. Electrospray mass spectrometry (ESIMS) results provided evidence for extensive platinum-protein adduct formation. A fragment of the [Pt(amine)(amine')] type was established to be primarily responsible for protein metalation. ICP-OES analysis revealed that these trans-platinum(II) complexes bind preferentially to the serum proteins albumin and transferrin rather than to calf thymus DNA. Pt binding to DNA was found to be far lower than in the case of cisplatin. The implications of the results for the mechanism of action of novel cytotoxic trans-platinum complexes are discussed, We would like to thank the International cooperation program: HI2007-0153 and the COST D39 Action for financial support, in particular WG6. C.N.R., A.G.Q. and L.C. thank the Spanish Comisión Interministerial de Ciencia y Tecnología (CICYT-SAF-2006-03296) for funding. A.C. thanks the Swiss National Science Foundation for financial support (Ambizione project no. PZ00P2_121933)

Three analogues of 1α,25-dihydroxyvitamin D 3 (calcitriol), featuring a trans- fused decalin C,D-core with local S 2 -symmetry, and possessing identical side-chain and seco-B,A-ring structures, have been synthesized starting from readily available (4a R ,8a S )-octahydronaphthalene-1,5-dione ( 7 ). The very short sequences involve the simultaneous introduction of the side-chain and seco-B,A-ring fragments via Suzuki and Sonogashira coupling reactions. The analogues are devoid of relevant biological activity. Keywords: Suzuki coupling; Sonogashira reaction; Calcitriol analogues. Introduction Since the discovery that the biological action of vitamin D 3 originates from the dihydroxylated metabolite 1α,25-dihydroxyvitamin D 3 ( 1 , calcitriol) and that, next to its classical role in the regulation of calcium homeostasis, these actions also involve immunomodulation, cell differentiation and antiproliferation, there has been an intense search for structural analogues of calcitriol that might show a separation in calcemic and antiproliferative-prodifferentiating activities (Scheme 1) [1]. In this context various successful structural modifications have been introduced in each one of the three parts that one may distinguish in its structure: the rigid central C,D-ring system and the flexible parts of the molecule, comprising the side chain and the seco-B,A-ring [2].

Tin compounds and their therapeutic potentials are under consideration from many research groups, while a number of early reviews recording advances in the screening for anti proliferative potential of organotins are also available. This review focuses upon results obtained on the antiproliferative activity of tin compounds in the past 5 years. (C) 2008 Elsevier B.V. All rights reserved. Coordination Chemistry Reviews

Reactions of thiosemicarbazones of 2-formyl and 2-acetyl pyridine and containing an azepane ring (hexamethyleneiminyl ring) incorporated at N(4)-position, HL(1) (1) and HL(2) (2) with platinum(II) afforded the complexes, [Pt(L(1))Cl] (3) and [Pt(L(2))Cl] (4). Characterization of the compounds was accomplished by means of elemental analysis and spectroscopic techniques NMR, UV-vis and IR spectroscopy. The single-crystal X-ray structure of complex [Pt(L(2))Cl] (4) shows that the ligand monoanion coordinates in a planar conformation to the metal via the pyridyl N atom, the imine-N atom, and thiolato S-atom. Compounds 1-4 have been evaluated for antiproliferative activity in vitro against three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse L-929 (a fibroblast-like cell line cloned from strain L). Ligand 2 exhibited high activity as anticancer agent against all four cancer cell lines, while ligand 1 exhibited selectivity against MCF-7, L-929 cell lines and complex 4 against A-549, T-24 cancer cell lines. Also, the acute toxicity and antitumor activity were evaluated on leukemia P388-bearing mice. Complex 3 afforded five to six cures against leukemia P388. The in vivo results of the antitumor activity show the two platinum complexes as very effective chemotherapeutic antileukemic agents. (C) 2008 Elsevier Masson SAS. All rights reserved. Eur J Med Chem

Essential oils obtained from Gomortega keule, Laurelia sempervirens, Origanum vulgare, Eucalyptus globulus, and Thymus vulgaris were analyzed by gas chromatography and gas chromatography-mass spectrometry and evaluated for their toxicity against adults of Sitophilus zeamais (Motschulky) and Acanthoscelides obtectus (Say) (Coleóptera). Contact toxicity was assayed by impregnating filter paper discs with the oils. The amount of essential oils applied in each desiccator (4 1 capacity) was 4, 8, 16, or 32 ul, corresponding to 1, 2, 4, or 8 fj.1/1 air. The results showed significant differences between the tested dosages and exposure periods of the essential oils. Although desirable insecticidal activities against A obtectus were achieved with the essential oils of all five plants, the oils from G. keule and L. sempervirens were the most effective at 96 h. On the other hand, the essential oils of E. globulus and T. vulgaris were most effective against S. zeamais. In all plant species, higher doses or longer exposure periods were more effective against both insects. No mortality was observed in the control group (acetone only) of each species. Therefore, these results suggest that essential oils from the studied plants may be used against insect pests in grain storage

New platinum complexes have been synthesized by the reaction of Na2PtCl4 with 2-acetylpyridine-4-cyclohexyl-thiosemicarbazone, HAc4CyclHexyl (1). The new complexes [Pt(Ac4Cyc1Hexyl)Cl] (2) and [Pt(Ac4CyclHexyl)(2)] (3) have been characterized by elemental analyses and spectroscopic studies. The crystal structure of the complex [Pt(Ac4CyclHexy1)Cl] - DMF has been solved by single-crystal X-ray diffraction. The anion of Ac4CyclHexyl coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine N and thiolato S atoms. The crystal packing is determined by double intermolecular hydrogen interactions, pi-pi, Pt-C and Pt-pi contacts. The cytotoxic activities of 1-3 have been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse L-929 (a fibroblast-like cell line cloned from strain L). The compounds 1-3 display IC50 values in a mu M range better than that of the antitumor drug cisplatin and are considered as agents with potential antitumor activity candidates for further stages of screening in vitro and/or in vivo. (C) 2007 Elsevier Ltd. All rights reserved. Polyhedron

Paclitaxel (Pac) is the most important anticancer drug used mainly in treatment of breast, lung, and ovarian cancer and is being investigated for use as a single agent for treatment of lung cancer, advanced head and neck cancers, and adenocarcinomas of the upper gastrointestinal tract. In this work, we present the synthesis of five 2'-paclitaxel-substituted analogs in which paclitaxel was covalently bound to peptides or as multiple copies to synthetic carriers. Ac-Cys(CH2CO-2'Pac)-Arg-Gly-Asp-Arg-NH2, Folyl-Cys(CH2CO-2'-Pac)-Arg-Gly-Asp-Ser-NH2, Ac-[Lys-Aib-Cys(CH2CO-2'-Pac))(2)-NH2, Ac-[Lys-Aib-Cys(CH2CO-2'-Pac)](3)-NH2 and Ac-[Lys-Aib-Cys(CH2CO-2'-Pac))(4)-NH2 were synthesized using 2'-halogeno-acetylated paclitaxel derivatives. Paclitaxel conjugates showed greater solubility in water than paclitaxel and inhibited the proliferation of human breast, prostate, and cervical cancer cell lines. Although all synthesized compounds had an antiproliferative activity, the Ac[Lys-Aib-Cys(CH2CO-2'-Pac)](4)-NH2 derivative showed improved biological activity in comparison with paclitaxel in cervical and prostate human cancer cells. Copyright (C) 2007 European Peptide Society and John Wiley & Sons, Ltd. Journal of Peptide Science

Single layers Of C-60 mono- and bis-adducts have been obtained by functionalizing an acid-terminated self-assembled monolayer (SAM) of thiols on gold. X-ray photoelectron spectroscopy demonstrated the grafting onto the SAM by covalent bonding, via the formation of an amide bond, while cyclic voltammetry and electrochemical impedance spectroscopy provided information on the redox properties of the C-60-films, as well as on structural characteristics. (c) 2006 Elsevier Ltd. All rights reserved.

''Click chemistry" was explored to synthesize two series of 2-(1,2,3-triazolyl) adenosine derivatives (1-14). Binding affinity at the human A(1), A(2A), and A(3)ARs (adenosine receptors) and relative efficacy at the A(3)AR were determined. Some triazol-1-yl analogues showed A(3)AR affinity in the low nanomolar range, a high ratio of A(3)/A(2A) selectivity, and a moderate-to-high A(3)/A(1) ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A(3)AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A(3)AR efficacy. Thus, several 5'-OH derivatives appeared to be selective A(3)AR antagonists, i.e., 10, with 260-fold binding selectivity in comparison to the A(1)AR and displaying a characteristic docking mode in an A(3)AR model. The corresponding 5'-ethyluronamide analogues generally showed increased A(3)AR affinity and behaved as full antagonists, i.e., 17, with 910-fold A(3)/A(1) selectivity. Thus, N-6-substituted 2-( 1,2,3-triazolyl)-adenosine analogues constitute a novel class of highly potent and selective nucleoside-based A(3)AR antagonists, partial agonists, and agonists.

Interleukin-1beta (Il-1beta) is a central component in innate immunity and the inflammatory response of mammals. Only recently, the first non-mammalian IL-1beta sequences were published. In this study, we describe a second IL-1beta sequence (IL-1beta2) in carp with 74% amino acid identity to the carp IL-1beta1 sequence. The existence of two IL-1beta copies in the carp genome probably originates from the tetraploid nature of the species. In contrast to the first carp Il-1beta sequence, IL-1beta2 is represented by multiple genes with 95-99% identity. Detection of several IL-1beta2 sequences within individual homozygous fish suggests the presence of multiple copies of the Il-1beta2 gene in the carp genome, possibly as a result of subsequent gene duplication of IL-1beta2. In vivo, constitutive mRNA expression of both IL-1beta genes was found in healthy carp. IL-1beta2 mRNA expression could be up-regulated in head kidney cells similar to carp IL-1beta1, in vivo by infection with Trypanoplasma borreli and in vitro by stimulation with lipopolysaccharide (LPS). Cortisol, the major glucocorticoid in fish, is an endocrine-derived factor mediating Il-1beta expression. Although constitutive IL-1beta expression was inhibited by a physiological dose of cortisol, cortisol synergistically enhanced LPS-induced IL-1beta expression in carp. Involvement of the transcription factor nuclear factor (NF)-kappaB in expression of IL-1beta1 and IL-1beta2 was demonstrated. Ratio of IL-1beta expression was determined and this showed IL-1beta1 mRNA expression to be at least tenfold higher compared with IL-1beta2. The possibilities of IL-1beta2 being a functional gene or approaching pseudogene status are discussed. (C) 2002 Elsevier Science Ltd. All rights reserved.

Various vinyl sulfide and ketene dithioacetal derivatives of truncated 2,3-oxidosqualene were developed. These compounds, having the reactive functions at positions C-2, C-15 and C-19 of the squalene skeleton, were studied as inhibitors of pig liver and Saccharomyces cerevisiae oxidosqualene cyclases (OSC) (EC 5.4.99.7) and of Alicyclobacillus acidocaldarius squalene hopene cyclase (SHC) (EC 5.4.99.-). They contain one or two sulfur atoms in alpha-skeletal position to carbons considered to be cationic during enzymatic cyclization of the substrate and should strongly interact with enzyme nucleophiles of the active site. Most of the new compounds are inhibitors of the OSC and of SHC, with various degrees of selectivity. The methylthiovinyl derivative, having the reactive group at position 19, was the most potent and selective inhibitor of the series toward S. cerevisiae OSC, with a concentration inhibiting 500% of the activity of 50 nM, while toward the animal enzyme it was 20 times less potent. These results could offer new insight for the design of antifungal drugs.

A heterocyclic compound, pyridine-2-carbaldehyde thiosemicarbazone (HFoTsc), and its six metal coordinated bound complexes, three with platinum (II) and three with palladium (II), were studied for their activity against herpes simplex virus 1 (HSV-1) infection in cultured cells. According to their cytotoxicity the compounds were divided into two groups. Group 1 (cytotoxic compounds) included all three palladium complexes and [Pt(HFoTsc)(2)] Cl-2, with maximum non-toxic concentration (MNC) of 1-10 mu mol/l and a 50% cytotoxic concentration (CC50) of 20-100 mu mol/l. Group 2 (low cytotoxic compounds) with MNC of 100 mu moL/l and CC50 of 548-5820 mu mol/l included compounds in the following order: [Pt(HFoTsc)(2)] Cl-2

The actin-ADP-ribosylating binary Clostridium botulinum C2 toxin consists of two individual proteins, the binding/translocation component C2II and the enzyme component C2I. To elicit its cytotoxic action, C2II binds to a receptor on the cell surface and mediates cell entry of C2I via receptor-mediated endocytosis. Here we report that binding of C2II to the surface of target cells requires cleavage of C2II by trypsin, Trypsin cleavage causes oligomerization of the activated C2II (C2IIa) to give SDS-stable heptameric structures, which exhibit a characteristic annular or horseshoe shape and form channels in lipid bilayer membranes. Cytosolic delivery of the enzyme component C2I is blocked by bafilomycin bat Plot by brefeldin A or nocodazole, indicating uptake from an endosomal compartment and requirement of endosomal acidification for cell entry. In the presence of C2IIa and C2I, short term acidification of the extracellular medium (pH 5.4) allows C2I to enter the cytosol directly. Our data indicate that entry of C2 toxin into cells involves (i) activation of C2II by trypsin-cleavage, (ii) oligomerization of cleaved C2IIa to heptamers, (iii) binding of the C2IIa oligomers to the carbohydrate receptor on the cell surface and assembly with C2I, (iv) receptor-mediated endocytosis of both C2 components into endosomes, and finally (v) translocation and release of C2I into the cytosol after acidification of the endosomal compartment.

The reactions of Na2PtCl4 with pyridine-2-carbaldehyde and 2-acetyl pyridine N(4)-ethyl-thiosemicarbazones, HFo4Et and HAc4Et respectively, afforded the complexes [Pt(Fo4Et)Cl], [Pt(HFo4Et)(2)]Cl-2, [Pt(Fo4Et)(2)] and [Pt(Ac4Et)Cl], [Pt(HAc4Et)(2)]Cl-2. 2H(2)O, [Pt(Ac4Et)(2)]. The new complexes have been characterized by elemental analyses and spectroscopic studies. The crystal structure of the complex [Pt(Ac4Et)Cl] has been solved. The anion of Ac4E coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine Nand thiolato S atoms. Intermolecular hydrogen, non-hydrogen bonds, pi-pi and weak Pt-pi contacts lead to aggregation and a supramolecular assembly. The cytotoxic activity for the platinum( II) complexes in comparison to that of cisplatin and thiosemicarbazones was evaluated in a pair of cisplatin-sensitive and -resistant ovarian cancer cell lines A2780 and A2780/Cp8. The platinum(II) complexes showed a cytotoxic potency in a very low micromolar range and were found able to overcome the cisplatin resistance of A2780/Cp8 cells. (C) 2000 Elsevier Science Inc. All rights reserved. J Inorg Biochem

We determined the in vitro cytotoxic activity of the sesquiterpene lactone endoperoxide artemisinin (1) and some chemically prepared derivatives, which have been found to display cytotoxicity to cloned murine Ehrlich ascites tumour (EAT) cells and human HeLa cells and against murine bone marrow using a clonogenic assay for committed progenitor cells of the granulocyte-monocyte lineage (CFU-GM assay). Comparing artemisinin (1) to deoxyartemisinin (2), the endoperoxide group appeared to play a role in cytotoxicity to CFU-GM cells. Dimers of dihydroartemisinin and dihydrodeoxyartemisinin revealed that the stereochemistry of the ether linkage of the dimers was a more important determinant for this cytotoxic activity. The nonsymmetrical dimer of dihydroartemisinin (3) and the corresponding endoperoxide-lacking dimer of dihydrodeoxyartemisinin (5) were equally cytotoxic to CFU-GM cells. Despite the differences between both systems, it may be stated that most compounds displayed higher cytotoxicity to CFU-GM cells than to EAT cells. Dimers of dihydroartemisinin (3, 4) were selected as potential antitumour compounds and subjected to the National Cancer Institute drug-screening programme consisting of about sixty human cancer cell lines derived from nine different tissues. Both compounds displayed the same specific cytotoxicity pattern. Throughout the screen dimer 3 was more active than 4.

We present the first 3-D model of the melatonin receptor based on the recently published amino acid sequence of the cloned melatonin receptor. The seven trans membrane helices were positioned using the helices found in the structure of BacterioRhodopsine. From the results of an indirect modeling study with six melatonergic agents, an alignment of these compounds was found directing towards common interaction points. These points are suggested to be the two serines in helix three and the histidine in helix five, forming hydrogen bonds with the amide function and the methoxy-oxygen in melatonin, respectively. The ligands were docked into these binding sites and the receptor-ligand complexes were energy minimized. Considering the position of the active and inactive ligands in the receptor and their respective occupied volumes, the structure-activity relationships are rationalized by the suggested model. This model can be of use as a pharmacological test model in molecular biological studies and as a basis to develop compounds being active as synchronizing circadian agents. Copyright (C) 1996 Elsevier Science Ltd

Asymmetric organocatalysis is now an established methodology for the preparation of chiral compounds. However, these are not the only valuable molecules which can be conveniently obtained. Organocatalytic reactions affording achiral compounds are gaining momentum, opening unexplored pathways in the synthesis of densely functionalized aromatic moieties, olefins and useful molecules such as natural substances.

Background: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency .0.02). Principal Findings: we identified one promoter SNP (rs2530547 [2103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPSinduced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 nonsynonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different ciscombinations of these functional SNPs variably affect disease risk. Significance: these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance. Citation: Anedda F, Zucchelli M, Schepis D, Hellquist A, Corrado L, et al. (2011) Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S

The direct and enantioselective functionalization of inert bonds such as carbon–hydrogen and carbon–carbon is an emerging tool towards more sustainable and efficient synthetic methods. The individual activation pathways like concerted deprotonation metalations, directed activations, ?-carbon eliminations or retro-allylations proceed by completely different mechanisms and therefore have complementary requirements and different associated challenges. A careful fine-tuning of the transition-metal complex is critical for each mechanism, but a very broad structural space can be covered as well. These methods enhance the synthetic chemist's toolbox allowing more concise, efficient synthetic routes to be executed in target-oriented synthesis. This is illustrated by the examples of a synthesis of largazole and the core of stachyflin from our group.

Four new binuclear complexes of formula [M2(bipy)2(BAA)]Cl2 (where M is Pt(II) or Pd(II), bipy is 2,2'-bipyridine, and BAA is a dianion of meso-alpha-alpha'-diaminoadipic acid (DAA) or meso-alpha-alpha'-diaminosuberic acid (DSA)) have been synthesized. These complexes have been characterized by chemical analysis and ultraviolet-visible, infrared, and H-1 NMR spectroscopy. The mode of binding of ligands in these complexes has been ascertained by infrared and detailed H-1 NMR spectroscopy. These complexes are 1:2 electrolyte in conductivity water. They have also been tested against P388 lymphocytic leukemia cells and their target is DNA molecules. [Pt2(bipy)2(DSA)]Cl2, [Pd2(bipy)2(DSA)]Cl2, and [Pd2(bipy)2(DAA)]Cl2 show I.D.50 values comparable or lower than cis-diamminedichloroplatinum(II) and [Pt(bipy)(Ala)]Cl. In addition, binding studies of [Pt2(bipy)2(DSA)]Cl2 and [Pd2(bipy)2(DAA)]Cl2 to calf thymus DNA have been carried out and the mode of binding seems to be hydrogen bonding, as suggested earlier for analogous mononuclear amino acid-DNA complexes.

While human chorionic gonadotropin (hCG) appears to have an essential role in early pregnancy, it is controversial whether the hyperglycosylated form of hCG (hCG-h), which is the major hCG isoform during the first 4–5 weeks of pregnancy, is able to activate LH/hCG receptor (LHCGR). To address this, we utilized different extensively characterized hCG and hCGβ reference reagents, cell culture- and urine-derived hCG-h preparations, and an in vitro reporter system for LHCGR activation. The WHO hCG reference reagent (99/688) was found to activate LHCGR with an EC50-value of 3.3 ± 0.6 pmol/L (n = 9). All three studied hCG-h preparations were also able to activate LHCGR, but with a lower potency (EC50-values between 7.1 ± 0.5 and 14 ± 3 pmol/L, n = 5–11, for all P

Carrier ampholyte-based capillary electrophoresis (CABCE) has recently been introduced as an alternative to CE (CZE) in the classical buffers. In this study, isoelectric BGEs were obtained by fractionation of Servalyt pH 4-9 carrier ampholytes to cuts of typical width of 0.2 pH unit. CABCE feasibility was examined on a series of insect oostatic peptides, i.e. proline-rich di- to decapeptides, and phosphinic pseudopeptides - tetrapeptide mimetics synthesized as a mixture of four diastereomers having the -P(O)(OH)-CH2- moiety embedded into the peptide backbone. With identical selectivity, the separation efficiency of CABCE proved to be as good as classical CE for the insect oostatic peptides and better for diastereomers of the phosphinic pseudopeptides. In addition, despite the numerous species present in the narrow pH cuts of carrier ampholytes, CABCE seems to be free of system zones that could hamper the analysis. Peak symmetry was good for moderately to low mobile peptides, whereas some peak distortion due to electromigration dispersion, was observed for short peptides of rather high mobility.

In extension with growing concern to develop new antimicrobial organometallic drugs, an attempt has been made to synthesize five new antimicrobial organotin(IV) carbodithioates with general formula, Me2SnClL (1), Me2SnL2 (2), Et2SnClL (3), Et2SnL2 (4), Bu2SnClL (5), Bu2SnL2 (6), (where L = Sodium 3,4-dihydroisoquinoline-2-(1H)-carbodithioate). Compounds have been synthesized by refluxing organotin(IV) chlorides with ligand in dry toluene for 7-8 h. Compound 1, 3 and 5 exhibited Penta coordination, while 2, 4 and 6 showed hexacoordination in solid state, as evident from the difference obtained between symmetric and asymmetric CSS stretches in IR spectra. Solid-state structures of 1 was further attested by single crystal analysis as distorted trigonal bipyramidal geometry. H-1-, C-13- and Sn-119- NMR spectroscopy was used to assess the geometry of the compounds in solution state. It was observed that 1, 3, 4 and 5 completely dissociated in solution and showed tetrahedral geometry, whereas 2 and 6 exhibit pentacoordinate geometry after partial dissociation in solution. The pronounced activity was observed for all the compounds against five different strains of bacteria. (C) 2021 Elsevier B.V. All rights reserved.

The preparation of [(2S,3S,4R)-3,4-dihydroxypyrrolidin-2-yl]furan derivatives in a stereoselective route starting from D-glucose and ethyl acetoacetate is presented. Ethyl ester (6), N,N-diethylamide (7) and N-isopropylamide (8) have been tested towards 25 glycosidases. Ester (6) is a selective inhibitor of beta-galactosidases. The new compounds represent a new type of imino-C-nucleoside analogues. (C) 2002 Published by Elsevier Science Ltd.

Inspired by the preferential, allosteric binding of RAPTA-T and auranofin to the nucleosome core particle, we describe the design and synthesis of a series of heterobimetallic ruthenium(II)-gold(I) complexes with varying spacer lengths ranging from four to eight polyethylene glycol units. Evaluation of their cytotoxicity reveals IC50 values in the low micromolar range against cisplatin sensitive and resistant human ovarian carcinoma (A2780, A2780cisR) and nontumoral human embryonic kidney (HEK293) cell lines. Binding studies monitored via mass spectrometry revealed an affinity for histidine residues on a fragment of the amyloid beta-protein (residues 1-16, employed as a model system), which is in accordance with the binding sites of parent drugs, RAPTA-C and auranofin, to the nucleosome core particle.

Several members of a new family of seven-membered azasugars, which can be seen as 1-azasugar ring homologues, have been obtained by simple chemical transformations starting from a sugar-derived azidolactol. Unlike their piperidine counterparts, these molecules are chemically stable when they possess a hydroxy group at the pseudo-C-2 position. Biological assays with a range of carbohydrate-processing enzymes have revealed interesting potential for these compounds. A trihydroxymethyl-substituted azepane displayed strong competitive inhibition on almond beta-glucosidase (K(i)=2.5 microM) while a trihydroxylated carboxylic acid derivative proved to be a potent and selective L-fucosidase inhibitor (K(i)=41 nM). N-Butylation of these seven-membered 1-azasugars generated derivatives with some activity towards the Gaucher's disease-related glucosylceramide transferase (IC(50) 75 microM) that did not interact significantly with digestive glucosidases.