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Present study aimed to establish the stimulatory effects of bee drone larvae (BDL) on the androgenic effects and growth performance of goat male kids (GMK). The effects of BDL on growth and testosterone hormone levels were investigated in Saanen male kids. A total of 26 Saanen male kids (13 heads control, 13 heads treatment groups) were used for determining the effects of BDL 60 days after the weaning period. BDL was obtained from good beekeeping practices hives. Hormone levels, growth trials, testes characteristics, and body measurements were determined every 14 days on the days 75, 90, 105, 120, and 135 of the trial. The increasing level of testosterone hormone in the treatment group on 135 days strengthened the hypothesis that the BDL could have greater effects in the case of more application that is expensive and considering the time of maturity of Saanen GMK. The lipid composition of BDL was identified by GC/MS. Oleic acid (64.75 %) and palmitic acid (26.08 %) were the dominant lipid compounds of BDL. Additionally, the phenolic/organic acid profile investigated by HPLC-DAD revealed that trans-aconitic acid (11.20 +/- 0.32 mu g/g) and fumaric acid (5.03 +/- 0.41 mu g/g) were found as major compounds in BDL., Ege University Scientific Research Projects Directorate [2017 ZRF 036], This study was supported by Ege University Scientific Research Projects Directorate under Grant 2017 ZRF 036: Effects of bee drone larvae (apilarnil) on development, sexual maturity and testis characteristics in pure Saanen goat male kids, 2017-2019.

Metastasis or the progression of malignancy poses a major challenge in cancer therapy and is the principal reason for increased mortality. The epithelial-mesenchymal transition (EMT) of the basement membrane (BM) allows cells of epithelial phenotype to transform into a mesenchymal-like (quasi-mesenchymal) phenotype and metastasize via the lymphovascular system through a metastatic cascade by intravasation and extravasation. This helps in the progression of carcinoma from the primary site to distant organs. Collagen, laminin, and integrin are the prime components of BM and help in tumor cell metastasis, which makes them ideal cancer drug targets. Further, recent studies have shown that collagen, laminin, and integrin can be used as a biomarker for metastatic cells. In this review, we have summarized the current knowledge of such therapeutics, which are either currently in preclinical or clinical stages and could be promising cancer therapeutics.Data availability: Not applicable Scientific Research at Majmaah University [R-2022-117] Dr. Niraj Kumar Jha is thankful to Sharda University for the infra-structure and facility. The author would like to thank Deanship of Sci-entific Research at Majmaah University for supporting this work under project number No. R-2022-117. The authors would like to acknowledge the support from their respective institutes throughout the review writing process.

The control of ovulation helps guarantee the success of reproduction and as such, contributes to the fitness of a species. In mammals, two types of ovulation are observed: induced and spontaneous ovulation. Recent work on camelids, that are induced ovulators, highlighted the role of a factor present in seminal plasma, beta Nerve Growth Factor (β-NGF), as the factor that triggers ovulation in a GnRH dependent manner. In the present work, we characterized alpaca β-NGF (aβ-NGF) and its 3D structure and compared it with human recombinant β-NGF (hβ-NGF). We showed that the β-NGF enriched fraction of alpaca semen and the human recombinant protein, both stimulated spontaneous electrical activity of primary GnRH neurons derived from mouse embryonic olfactory placodes. This effect was dose-dependent and mediated by p75 receptor signaling. P75 receptors were found expressed in vitro by olfactory ensheathing cells (OEC) in close association with GnRH neurons and in vivo by tanycytes in close vicinity to GnRH fibers in adult mouse. Altogether, these results suggested that β-NGF induced ovulation through an increase in GnRH secretion provoked by a glial dependent P75 mediated mechanism.

The implications of lysine-specific demethylase-1 (LSD1) in tumorigenesis have urged scientists to develop diagnostic tools in order to explore the function of this enzyme. In this work, we present our efforts on the development of tranylcypromine (TCP)-based functionalized probes for activity-based protein profiling (ABPP) of LSD1 activity. Biotinylated forms of selected compounds enabled dose-dependent enzyme labeling of recombinant LSD1. However, treatment with LSD1 inhibitors did not clearly reduce the LSD1 labeling efficiency thus indicating that labeling using these probes is not activity dependent. This calls for alternative strategies to develop probes for ABPP of the enzyme LSD1.

Hydrogels are three-dimensional polymeric networks capable of absorbing large amounts of water or biological fluids with the properties resembling natural living tissues. Herein, polyvinyl alcohol (PVA)/N-succinyl chitosan (NSCS)/lincomycin hydrogels for wound dressing were prepared by the freezing/thawing method, then characterized by FTIR, SEM, and TGA. The compression strength, swelling behavior, water retention capacity, antibacterial activity, drug release and cytotoxicity were systematically investigated. The results showed that the introduction of NSCS remarkably enhanced the swelling capacity, leading to the maximum swelling ratio of 19.68 g/g in deionized water. The optimal compression strength of 0.75 MPa was achieved with 30 % NSCS content.Additionally, the incorporation of lincomycin brought a remarkable antibacterial activity against both Escherichia coli and Staphylococcus aureus. Specifically, 77.71 % of Staphylococcus aureus was inhibited with 75 μg/mL lincomycin, while the MTT assay demonstrated the nontoxic nature of the composite hydrogels. In summary, this PVA/NSCS/lincomycin hydrogel showed promising potential for wound dressing. ispartof: CARBOHYDRATE POLYMERS vol:261 ispartof: location:England status: published

The field of photopharmacology uses molecular photoswitches to establish control over the action of bioactive molecules. It aims to reduce systemic drug toxicity and the emergence of resistance, while achieving unprecedented precision in treatment. By using small molecules, photopharmacology provides a viable alternative to optogenetics. We present here a critical overview of the different pharmacological targets in various organs and a survey of organ systems in the human body that can be addressed in a non-invasive manner. We discuss the prospects for the selective delivery of light to these organs and the specific requirements for light-activatable drugs. We also aim to illustrate the druggability of medicinal targets with recent findings and emphasize where conceptually new approaches have to be explored to provide photopharmacology with future opportunities to bring smart molecular design ultimately to the realm of clinical use.

Benzothiadiazine type compounds (BTDs) have gained great attention for their potential therapeutic activity as nootropic and neuroprotective agents. BTDs, acting as AMPA positive allosteric modulators, potentiate the glutamatergic neurotransmission without the side effects typically associated with direct agonists. Studies regarding the binding mode of racemic BTDs into the receptor binding pocket demonstrated that one enantiomer establishes a more favourable interaction and possesses a higher biological activity with respect to the other one. The S enantiomer was proved to be the eutomer for both IDRA21 and S18986, two of the most studied BTD AMPA positive allosteric modulators. However, recent data highlighted an opposite stereoselectivity for some substituted BTDs (7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide and 7-chloro-2,3,4-trimethyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) showing unexpected structure–activity relationships. In this work, the synthesis and configuration assignment of the stereoisomers of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, one of the most active BTDs, are reported. Electrophysiological tests demonstrated that the R form is the eutomer. Docking and molecular dynamics simulations on the AMPA GluA2 binding site revealed new insights into the stereodiscrimination process. Lastly, metabolic studies disclosed a stereoselective hepatic metabolization of this chiral BTD.

Five copper(II) complexes 1-5 with aromatic nitrogen-containing heterocycles, pyrimidine (pm, 1), pyrazine (pz, 2), quinazoline (qz, 3 and 4) and phthalazine (phtz, 5) have been synthesized and structurally characterized by spectroscopic and single-crystal X-ray diffraction techniques. The crystallographic results show that, dependent on the ligand structure, complexes 1-5 are of different nuclearity. The antimicrobial efficiency of complexes 1-5 has been evaluated against three clinically relevant microorganisms and none of the complexes showed significant growth inhibiting activity, with values of minimum inhibitory concentrations (MIC) in the mM range. Since in many bacteria, pathogenicity and virulence are regulated by intercellular communication processes, quorum sensing (QS), the effect of the copper(II) complexes on bacterial QS has also been examined. The results indicate that the investigated complexes inhibit violacein production in Chromobacterium violaceum CV026, suggesting an anti-QS activity. In order to differentiate, which of the QS pathways was affected by the copper(II) complexes, three biosensor strains were used: the PAO1 Delta rhlIpKD-rhlA and the PA14-R3 Delta lasIPrsaI lux strain to directly measure the levels of C4-HSL (N-butanoyl-homoserine lactone) and 3OC12-HSL (N-3-oxo-dodecanoyl- homoserine lactone), respectively, and PAO1 Delta pqsA mini-CTX luxPpqsA for the detection of AHQs (2-alkyl-4-quinolones). Complexes 1-5 were shown to be efficient inhibitors of biofilm formation of the human opportunistic pathogen Pseudomonas aeruginosa PAO1, with the qz-containing complex 3 being the most active. Finally, the most anti-QS-active complexes 1 and 3 showed synergistic activity against a multi-drug resistant clinical isolate of P. aeruginosa, when supplied in combination with the known antibiotics piperacillin and ceftazidime.

The structure-activity relationship was investigated in a series of synthetic TLR4 antagonists formed by a glucosamine core linked to two phosphate esters and two linear carbon chains. Molecular modeling showed that the compounds with 10, 12, and 14 carbons chains are associated with higher stabilization of the MD-2/TLR4 antagonist conformation than in the case of the C16 variant. Binding experiments with human MD-2 showed that the C12 and C14 variants have higher affinity than C10, while the C16 variant did not interact with the protein. The molecules, with the exception of the C16 variant, inhibited the LPS-stimulated TLR4 signal in human and murine cells, and the antagonist potency mirrored the MD-2 affinity calculated from in vitro binding experiments. Fourier-transform infrared, nuclear magnetic resonance, and small angle X-ray scattering measurements suggested that the aggregation state in aqueous solution depends on fatty acid chain lengths and that this property can influence TLR4 activity in this series of compounds.

A methodology for the lithiation of pyrimidine (1a) was developed and used for the synthesis of pyrimidylselenium compounds. The procedure involved prior complexation of 1a with 2.2 equiv. of BF3 center dot Et2O followed by a reaction with LDA or LTMP. The pyrazinylselenium derivatives were synthesized from the direct lithiation of pyrazine (1b) as the BF3-directed lithiation failed to give the desired products. All the synthesized compounds were characterized by elemental analysis, NMR (H-1 and C-13) and Mass spectroscopy. In addition, 2,5-bis(methylselenenyl)pyrazine (9b) was characterized by single crystal X-ray crystallography. (C) 2014 Elsevier B.V. All rights reserved.

In this article, we present OntoDM-core, an ontology of core data mining entities. OntoDM-core defines the most essential data mining entities in a three-layered ontological structure comprising of a specification, an implementation and an application layer. It provides a representational framework for the description of mining structured data, and in addition provides taxonomies of datasets, data mining tasks, generalizations, data mining algorithms and constraints, based on the type of data. OntoDM-core is designed to support a wide range of applications/use cases, such as semantic annotation of data mining algorithms, datasets and results; annotation of QSAR studies in the context of drug discovery investigations; and disambiguation of terms in text mining. The ontology has been thoroughly assessed following the practices in ontology engineering, is fully interoperable with many domain resources and is easy to extend. OntoDM-core is available at http://www.ontodm.com .

Photochemical reactions of ferrocenylacetylene with dialkyldithiophosphoric acid in hexane at low temperature led to the formation of (E)-[FcC(PS2(OR)(2))-CH(PS2(OR)(2))] (R = Me, Et, Pr-i). Formation of these compounds have been studied experimentally and computationally in different solvents. (C) 2013 Elsevier B.V. All rights reserved.

The ability of peforelin (l-GnRH-III) to stimulate follicular growth, FSH release, and estrus in gilts after altrenogest treatment and in sows after weaning was investigated. In three farrow-to-wean herds, with at least 600 sows and average production performance, 216 gilts, 335 primiparous, and 1299 pluriparous sows were randomly allocated to three treatments: peforelin (M group: Maprelin), eCG (F group: Folligon), and physiological saline solution (C group). Animals were treated 48 hours after their last altrenogest treatment (gilts) or 24 hours after weaning (sows). The weaning-to-estrus interval, estrus duration, estrus rate (ER), pregnancy rate, and total born (TB), live born, and stillborn (SB) numbers were recorded and compared between treatments for the different parity groups (gilts and primiparous and pluriparous sows). Follicle sizes were measured in representative animals from each group on the occasion of their last altrenogest treatment or at weaning, and also on the occasions of their first (FS1) and second (FS2) attempted inseminations. Blood samples were taken to determine FSH concentrations at weaning and 2 hours after injection, and progesterone concentrations 10 days after the first insemination attempt. The relative change in FSH concentrations was calculated. Significant differences were found for ER within 7 days of weaning in pluriparous sows (95%, 91%, and 90% for the M, F, and C groups, respectively, P = 0.005). Gilts in the F-group had high TB numbers, and pluriparous sows in the M group had high SB numbers (TB gilts = 13.6, 15.4, and 14.9 [P = 0.02] and SB pluriparous sows = 1.8, 1.4, and 1.7 [P = 0.05] for the M, F, and C groups, respectively). The M group had the highest FS1 (for gilts) and FS2 (for pluriparous sows) values: FS1 = 5.4, 4.9, and 4.9 mm [P = 0.02] and FS2 = 6.8, 5.3, and 6.3 mm [P = 0.03] for the M, F, and C groups, respectively. There were no significant differences between the different treatments within each parity group with respect to any of the other variables. Overall, peforelin treatment had small but positive effects on the ER and follicle growth in certain parity groups but did not seem to affect litter sizes or FSH and progesterone levels in sows on the occasions of the corresponding examinations.

A concise and highly diastereoselective synthesis of (+)-astropaquinone B and (+)-astropaquinone C is reported. The synthetic strategy is based on an efficient combination of Dotz benzannulation using a chiral alkyne to construct the naphthalene unit and a highly diastereoselective oxa-Pictet-Spengler reaction to install the trans-configured pyran ring as the key steps. (C) 2013 Elsevier Ltd. All rights reserved.

A novel synthesis of natural drimanic compounds, (-)-albrassitriol (2) and (-)-6-epi-albrassitriol (3), has been carried out starting from an easily available labdane diterpenoid, (+)-larixol (1). In a two-step procedure, (+)-larixol (1) was converted into 14,15-bisnorlab-7-ene-6,13-dione (9), which was then submitted to a Norrish type II photochemical degradation yielding drim-7,9(11)-diene-6-one (10), whose treatment with OsO4 led selectively to the formation of drim-7-ene-9α,11-diol-6-one (12). The same compound was obtained by selective epoxidation of the C(9)-C(11) double bond in drim-7,9(11)-diene-6-one (10) with monoperphtalic acid. Treatment of the resulting mixture of α- and β-epoxides (13 and 14) with HClO4 yielded drim-7-ene-9α,11-diol-6-one (12). Reduction of the C6-carbonyl group in drim-7-ene-9α,11-diol-6-one (12) with LiAlH4 afforded (-)-albrassitriol (2) and (-)-6-epi-albrassitriol (3), 12.4% and 13.6% overall yields, respectively.

A one-pot, two-step, three-component method for the conversion of commercially available aldehydes to phosphonylpyrazoles has been developed, demonstrating, for the first time, the dual reactivity of the Bestmann-Ohira reagent (BOR) in a single-pot transformation. This method, extended to the synthesis of sulfonylpyrazoles by employing BOR in the first step and a diazomethyl sulfone in the second step, is complementary, with regard to regioselectivity, to the previous methods for the synthesis of such functionalized pyrazoles.

An efficient one-step synthesis of piperidin-2-yl and pyrrolidin-2-yl flavonoid alkaloids was achieved in good to excellent yields by a highly regioselective phenolic Mannich reaction of chrysin with cyclic imines or iminium salts. Performing the reaction in a mixture of H2O/THF in the absence of an external reagent afforded the C-6 alkylated product exclusively. The same reaction in water in the presence of NaOH provided the C-8 alkylated flavonoid as a major product. The reaction has been successfully extended to simple phenols.

Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. Utilizing the crystal structure of the PKC delta C1B domain, we have developed hydrophobic isophthalic acid derivatives that modify PKC functions by binding to the C1 domain of the enzyme. In the present study, we aimed to improve the drug-like properties of the isophthalic acid derivatives by increasing their solubility and enhancing the binding affinity. Here we describe the design and synthesis of a series of multisubstituted pyrimidines as analogs of C1 domain - targeted isophthalates and characterize their binding affinities to the PKC alpha isoform. In contrast to our computational predictions, the scaffold hopping from phenyl to pyrimidine core diminished the binding affinity. Although the novel pyrimidines did not establish improved binding affinity for PKC alpha compared to our previous isophthalic acid derivatives, the present results provide useful structure-activity relationship data for further development of ligands targeted to the C1 domain of PKC.

Fast-acting recombinant baculoviruses have potential for improved insect pest suppression. However, the ecological impact of using such viruses must be given careful consideration. One strategy for mitigating risks might be simultaneous release of a wild-type baculovirus, so as to facilitate rapid displacement of the recombinant baculovirus by a wild-type. However, at what ratio must the two baculoviruses be released? An optimum release ratio must ensure both fast action, and the eventual competitive displacement of the recombinant virus and fixation of the wild-type baculovirus in the insect population. Here we challenged Trichoplusia ni larvae with different ratios of wild-type Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) and a derived recombinant, vEGTDEL, which has the endogenous egt gene (coding for ecdysteroid UDP-glucosyltransferase) deleted. Time to death increased with the proportion wild-type virus in the inoculum mixture, although a 1:10 ratio (wild-type: recombinant) resulted in equally rapid insecticidal action as vEGTDEL alone. Five serial passages of three different occlusion body (OB) mixtures of the two viruses were also performed. OBs from 10 larval cadavers were pooled and used to initiate the following passage. Although the wild-type baculovirus was maintained over five passages, it did not go to fixation in most replicates of the serial passage experiment (SPE), and there was no good evidence for selection against the recombinant. Long-term maintenance of a recombinant in serial passage suggests an ecosystem safety risk. We conclude that for assessing ecological impact of recombinant viruses, SPEs in single and multiple larvae are relevant because of potential modulating effects at the between-host level.

The Vav family of proteins are guanine nucleotide exchange factors (GEFs) for the Rho family of GTPases, which regulate various cellular functions, including T‐cell activation. They contain a catalytic Dbl homology (DH) domain that is invariably followed by a pleckstrin homology (PH) domain, which is often required for catalytic activity. Vav proteins are the first GEFs for which an additional C1 domain is required for full biological activity. Here, we present the structure of a Vav1 fragment comprising the DH–PH–C1 domains bound to Rac1. This structure shows that the PH and C1 domains form a single structural unit that packs against the carboxy‐terminal helix of the DH domain to stabilize its conformation and to promote nucleotide exchange. In contrast to previous reports, this structure shows that there are no direct contacts between the GTPase and C1 domain but instead suggests new mechanisms for the regulation of Vav1 activity.

The crystal structure and magnetic properties of a penta-coordinate iron(III) complex of pyridoxal-4-methylthiosemicarbazone, [Fe(H(2)mthpy)Cl-2](CH3C6H4SO3), are reported. The synthesised ligand and the metal complex were characterised by spectroscopic methods (H-1 NMR, IR, and mass spectroscopy), elemental analysis, and single crystal X-ray diffraction. The complex crystallises as dark brown microcrystals. The crystal data determined at 100(l) K revealed a triclinic system, space group P (1) over bar (Z = 2). The ONSCl2, geometry around the iron(III) atom is intermediate between trigonal bipyramidal and square pyramidal (tau = 0.40). The temperature dependence of the magnetic susceptibility (5-300 K) is consistent with a high spin Fe(III) ion (S = 5/2) exhibiting zero-field splitting. Interpretation of these data yielded: D = 0.34(1) cm(-1) and g = 2.078(3). (c) 2007 Elsevier B.V. All rights reserved.

4(5)-aryl-1H-imidazoles can be efficiently and selectively prepared by PdCl2(dppf)-catalyzed Suzuki-Miyaura reaction of commercially available 4(5)-bromo-1H-imidazole with arylboronic acids under phase-transfer conditions. On the other hand, N-unprotected 4(5)-aryl-1H-imidazoles can undergo highly selective Pd(OAc)2-catalyzed and CuI-mediated direct C-2-arylation with a variety of aryl bromides and iodides under base-free and ligandless conditions to produce 2,4(5)-diaryl-1H-imidazoles in modest to good yields. No N-arylation byproducts are observed under the experimental conditions used to prepare 2,4(5)-diaryl-1H-imidazoles.

BACKGROUND: The plant microbiome represents an enormous untapped resource for discovering novel genes and bioactive compounds. Previously, we isolated Pseudomonas sp. SH-C52 from the rhizosphere of sugar beet plants grown in a soil suppressive to the fungal pathogen Rhizoctonia solani and showed that its antifungal activity is, in part, attributed to the production of the chlorinated 9-amino-acid lipopeptide thanamycin (Mendes et al. 2011. Science). To get more insight into its biosynthetic repertoire, the genome of Pseudomonas sp. SH-C52 was sequenced and subjected to in silico, mutational and functional analyses. The sequencing revealed a genome size of 6.3 Mb and 5,579 predicted ORFs. Phylogenetic analysis placed strain SH-C52 within the Pseudomonas corrugata clade. In silico analysis for secondary metabolites revealed a total of six nonribosomal peptide synthetase (NRPS) gene clusters, including the two previously described NRPS clusters for thanamycin and the 2-amino acid antibacterial lipopeptide brabantamide. Here we show that thanamycin also has activity against an array of other fungi and that brabantamide A exhibits anti-oomycete activity and affects phospholipases of the late blight pathogen Phytophthora infestans. Most notably, mass spectrometry led to the discovery of a third LP, designated thanapeptin, with a 22-amino-acid peptide moiety. Seven structural variants of thanapeptin were found with varying degrees of activity against P. infestans. Of the remaining four NRPS clusters, one was predicted to encode for yet another and unknown lipopeptide with a predicted peptide moiety of 8-amino acids. Collectively, these results show an enormous metabolic potential for Pseudomonas sp. SH-C52, with at least three structurally diverse lipopeptides, each with a different antimicrobial activity spectrum.

Valuable chiral drimanic dienic synthons have been prepared by a photolytic Norrish type II degradation of the corresponding 14,15-bisnorlabdene-13-ones. Minor by-products with unexpected bi- and tricyclic structures were formed and some of them were isolated and identified.

Peroxynitrite mediates the oxidation of the sulphinic group of both HTAU (hypotaurine) and CSA (cysteine sulphinic acid), producing the respective sulphonates, TAU (taurine) and CA (cysteic acid). The reaction is associated with extensive oxygen uptake, suggesting that HTAU and CSA are oxidized by the one-electron transfer mechanism to sulphonyl radicals, which may initiate an oxygen-dependent radical chain reaction with the sulphonates as final products. Besides the one-electron mechanism, HTAU and CSA can be oxidized by the two-electron pathway, leading directly to sulphonate formation without oxygen consumption. The apparent second-order rate constants for the direct reaction of peroxynitrite with HTAU and CSA at pH 7.4 and 25 degrees C are 77.4 +/- 5 and 76.4 +/- 9 M-1.s(-1) respectively. For both sulphinates, the apparent second-order rate constants increase sharply with decrease in pH, and the sigmoidal curves obtained are consistent with peroxynitrous acid as the species responsible for sulphinate oxidation. The kinetic data, together with changes in oxygen uptake, sulphinate depletion, sulphonate production, and product distribution of nitrite and nitrate, suggest that oxidation of sulphinates by peroxynitrite may take place by the two reaction pathways whose relative importance depends on reagent concentrations and pH value. In the presence of bicarbonate, the direct reaction of sulphinates with peroxynitrite is inhibited and the oxidative reaction probably involves only the radicals (NO2)-N-center dot and CO3center dot-, generated by decomposition of the peroxynitrite-CO2 adduct.

Two cyclic peptides with a thioether bond have been synthesised corresponding to the 9-22 ((9)LKMADPNRFRGKDL(22)) sequence of glycoprotein D (gD-1) of Herpes simplex virus. The role of the secondary structure in protein-specific monoclonal antibody recognition was investigated. The sequence selected for this study comprises a strongly antigenic site adopting a beta-turn at residues (14)Pro-(15)Asn. Thioether bond was formed between the free thiol group of cysteine or homocysteine inserted in position 11 and the chloroacetylated side chain of lysine in position 18. We report here the preparation of cyclic peptides containing Cys or Hcy in position 11, differing only in one methylene group. The linear precursor peptides were synthesised by Boc/Bzl strategy on MBHA resin, and the cyclisation was carried out in alkaline solution. The secondary structure of the peptides was studied by CD, FT-IR and NMR spectroscopy. The CD and FT-IR data have revealed fundamental changes in the solution conformation of the two compounds. The CH, group difference significantly resulted in the altered turn structure at the 12 Ala and (13)Asp as identified by NMR spectroscopy. The antibody binding properties of the cyclopeptides studied by gD-specific monoclonal antibody (A16) in direct and competition enzyme-linked immunosorbent assay (ELISA) were also not the same. We found that peptide LK[HcyADPNRFK]GKDL exhibited higher affinity to Mab A16 than peptide LK[CADPNRFK]GKDL, however, their reactivity was significantly lower compared to the linear ones. Our results clearly show the importance of secondary structure in an antibody binding and demonstrate that even a slight modification of the primary structure dramatically could influence the immune recognition of the synthetic antigens. (C) 2003 Elsevier B.V. All rights reserved.

Disaccharide and oligosaccharide mimics are potentially more selective glycosidases inhibitors than simple monosaccharide mimics. They represent also more selective ligands for lectins and oligosaccharide receptors and can become immunostimulating agents. The biological properties of disaccharide and oligosaccharide analogs containing thiosugars (5-thiopyranoses, 4-thiofuranoses) are revised together with the methods for their obtention.

The dinuclear zinc complex [Zn-2{bcmp(-H)}(mu-Cl)](ClO4)(2)center dot H2O {bcmp = 2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)-4-methylphenol} has been synthesized and structurally characterized. The DNA binding affinity was assessed by ethidium bromide fluorescence quenching experiments. The complex relaxes supercoiled pUC19 DNA into the nicked form at low micromolar concentration. Mechanistic studies were carried out using the DNA and RNA models bis(2,4-dinitrophenyl) phosphate (BDNPP) and 2-hydroxypropyl p-nitrophenyl phosphate (HPNP). A detailed kinetic analysis suggested that the bridging OH group of the solution species [Zn-2{bcmp(-H)}(mu-OH)](2+) acts as the nucleophile in the hydrolysis of BDNPP, while in the case of HPNP, the bridging OH group acts as a general base and seems to shift to a terminal position upon substrate coordination. Finally, the cytotoxicity profile of the dinuclear zinc(II) complex was assessed. The complex showed promising in vitro antitumour activity against pancreatic and lung cancers cell lines. Financial support from the European Commission and Science Foundation Ireland (Marie Curie FP7-IEF, grant to D. M. and Stokes Lectureship to A. E., grant number 07/SK/B1225b) are gratefully acknowledged. peer-reviewed

The copper(I) complexes containing phosphorus donor ligands such as diazadiphosphetidine, cis-{(o-OCH2C5H4N)P(mu-(NBu)-Bu-t)}(2) (1) and aminobis(phosphonite), C6H5N{P(OC6H3(OMe-o)(C3H5-p))(2)}(2) (2, PNP), have been synthesized. Treatment of 1 with copper iodide afforded the 1D coordination polymer [{Cu(mu-I)}(2){(o-OCH2C5H4N)P(mu-(NBu)-Bu-t)}(2)](n) (3). Treatment of 3 with 2,2'-bipyridine (bpy) and 1,10-phen-anthroline (phen) produced mixed-ligand complexes [(L)(2)Cu-2{(o-OCH2C5H4N)P(mu-(NBu)-Bu-t)}(2)][I](2) (4 L = bpy; 5 L = phen) in good yields. The reaction of 2 with copper iodide yielded a rare tetranuclear copper complex [(CuI)(2)C6H5N(PR2)(2)](2) (6), which on subsequent treatment with various pyridyl ligands produced binuclear complexes [{Cu(mu-I)(py)}(2)(mu-PNP)] (7), [Cu-2(mu-I)(bpy)(2)(mu-PNP)]I (8), [Cu-2(mu-I)I(bpy)(mu-PNP)] (9), [Cu-2(phen)(bpy)(mu-PNP)](OTf)(2) (10), [Cu-2(mu-I)I(phen)(mu-PNP)] (11) and [Cu-2(mu-I(phen)(2)(mu-PNP)]I (12), in an almost quantitative yield. The new copper(I) complexes (4, 5 and 7-12) were tested for anti-cancer activity against three human tumor cell lines. Compounds 5, 10 and 12 showed in vitro antitumor activity 5-7 fold higher than cisplatin, the most used anticancer drug. These three most potent compounds (5, 10 and 12) were chosen for detailed study to understand their mechanism of action. The copper(I) compounds studied in the present investigation were found to inhibit tumor cell growth by arresting cells at the S-phase of the cell cycle. The characteristic nuclear morphology of treated cells showed signs of DNA damage. The experimental evidence clearly indicated that these compounds initiated apoptosis, which is mediated through the p53 pathway.

Recent studies, both based on remote sensed data and coupled models, showed a reduction of biological productivity due to vigorous horizontal stirring in upwelling areas. In order to better understand this phenomenon, we consider a system of oceanic flow from the Benguela area coupled with a simple biogeochemical model of Nutrient-Phyto-Zooplankton (NPZ) type. For the flow three different surface velocity fields are considered: one derived from satellite altimetry data, and the other two from a regional numerical model at two different spatial resolutions. We compute horizontal particle dispersion in terms of Lyapunov exponents, and analyzed their correlations with phytoplankton concentrations. Our modeling approach confirms that in the south Benguela there is a reduction of biological activity when stirring is increased. Two-dimensional offshore advection and latitudinal difference in primary production, also mediated by the flow, seem to be the dominant processes involved. We estimate that mesoscale processes are responsible for 30-50% of the offshore fluxes of biological tracers. In the northern area, other factors not taken into account in our simulation are influencing the ecosystem. We suggest explanations for these results in the context of studies performed in other eastern boundary upwelling areas. © 2013 Elsevier Ltd., I.H.-C. was supported by a FPI grant from MINECO to visit LEGOS. We acknowledge support from MINECO and FEDER through projects FISICOS (FIS2007-60327) and ESCOLA (CTM2012-39025-C02-01). V.G. thanks CNES funding through Hiresubcolor project.

An interesting series of new platinum complexes has been synthesized by the reaction of Na(2)ptCl(4) with 2-acetyl pyridine thiosemicarbazone, HAcTsc. The new complexes, [Pt(AcTsc)CI], [Pt(HAcTsc),]Cl-2 and [Pt(AcTsc)(2)], have been characterized by elemental analyses and spectroscopic studies. The crystal structure of the complex [Pt(AcTsc)CI] has been solved by single-crystal X-ray diffraction. The anion of HAcTsc coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine N and thiolato S atoms. Double intermolecular hydrogen bonds (NH-CI), pi-pi and weak Pt-Pt and Pt-pi contacts lead to aggregation and to a two-dimensional supramolecular assembly. The antibacterial and antifungal effect of the novel platinum(II) complexes and the related palladium(fl) complexes, [Pd(AcTsc)CI], [d(HAcTsc),]Cl, and [Pd(AcTsc),], were studied in vitro. The complexes were found to have a completely lethal effect on Gram+ bacteria, while the same complexes showed no bactericidal effect on Gram- bacteria. Additionally, the complexes [Pt(AcTsc),] and [Pd(AcTsc),] showed effective antifungal activity towards yeast. Among these compounds [33], the most effective in inducing antitumour and cytogenetic effects are the complexes [Pt(AcTsc)(2)] and [Pd(AcTsc)(2)] while the rest, display marginal cytogenetic and antitumour effects. (C) 2001 Elsevier Science BY All rights reserved. J Inorg Biochem

White light (WL) inhibited the stem elongation of etiolated pea (Pisum sativum L.) seedlings and the inhibition was partially reversed by the application of gibberellin A(1) (GA(1)), the active GA in shoot growth, The amount of GA(1) in the apical shoot was reduced to about 25% after 2 h of WL, and to a trace level after 4 h, The effect of light on GA(1) content was reversed when the plants were transferred again to the dark after 6 h of WL. The effect of light on the expression of GA 20-oxidase and GA 3 beta-hydroxylase genes, coding for the last steps of GA(1) biosynthesis, was also investigated. Contrary to expectations, the amounts of GA 20-oxidase and GA 3 beta-hydroxylase transcripts increased in the entire apical shoot of WL-irradiated seedlings, and this increase was negated in seedlings treated with GA(1) before WL irradiation, probably as a result of negative feed-back regulation. The effect of WL on GA 20-oxidase transcripts was mainly localized in the apex (hook) whereas the effect on GA 3 beta-hydroxylase transcripts was mainly localized in the subapical tissues, Red and far-red light also enhanced the GA 20-oxidase transcript level, but not that of GA 3 beta-hydroxylase, suggesting that different photoreceptors are involved in the regulation of these genes by WL, The results presented indicate that the inhibition of stem elongation by light is due, at least partially, to a decrease of GA(1) content by a still unknown mechanism. The increase of GA(8) upon WL irradiation raises the possibility that an inactivation activity may be involved in the control of the content of GA(1) by light

Compounds of formula [Pt(diam)(Soa)]NO3, 3, and [Pt(diam)(Sob)]NO3, 4, (Soa, (methylsulfinyl)acetate; Sob, 2-(methylsulfinyl)benzoate; diam, chelating diamines: 1,2-ethylenediamine, en; (+/-)-, R,R-, S,S-, and meso-1,2-diaminocyclohexane, dach; 1,1-bis(aminomethyl)cyclohexane, damch) have been synthesized. IR, NMR, and FAB-mass spectroscopy suggest that the Soa and Sob anions are chelated to Pt through the S atom and the carboxylate group. Such a mode of coordination was confirmed for compounds 3 by the X-ray crystal structure determination of [Pt(en)(Soa)]NO3. This compound crystallizes in space group R3 (No. 146) with cell constants a = 15.139(3) angstrom and c = 12.886(2) angstrom. The structure was refined using 1001 independent reflections with I > 3sigma(I), giving a final R value of 0.018. In the complex cation Pt is in a square planar environment with en (Pt-N, 2.019(8) and 2.055(8) angstrom) and Soa (Pt-S, 2.184(2) angstrom, and Pt-O, 2.025(6) angstrom) chelated to Pt. The reactivities of 3 and 4 toward Cl-, 5'-GMP, and 9-methylguanine have been investigated by H-1 NMR spectroscopy at 40-degrees-C and complex concentration 10(-2) mol L-1 in D2O. Compounds 3 react readily with Cl- by displacement of the carboxylate group, yielding [PtCl(diam)(Soa-S)] (with monodentate S-coordinated Soa) which reacts with excess chloride to give [PtCl2-(diam)] at a very slow rate (for the en derivative formation of [PtCl2(en)] 24 h, but the concentration of the intermediates with S-coordinated monodentate Sob remains very low throughout the course of the reaction, indicating that the Sob chelate ring is more inert toward ring opening. Reactions of 3 and 4 toward 5'-GMP are rather fast: formation of [Pt(dach)(GMP)2]2- is complete in 3 and 1 h respectively (Pt/GMP = 1/2). These reactions proceed via the formation of intermediates with one N(7)-bound GMP and one monodentate Soa, coordinated to Pt via the S atom, or Sob probably bound to Pt via the O (sulfinyl) atom. Reactions with 9-methylguanine are slower and occur with a similar mechanism. The first step of the reaction of 5 with 2 mol of GMP is displacement of Cl by GMP. Formation of [Pt(en)(GMP)2]2- is complete in 75 min. Complexes 3 and 4 are moderately cytotoxic toward L1210 leukemia cells; the dach and damch derivatives are cytotoxic also against the L1210 cisplatin-resistant line. The cytotoxicities of the dach complexes depend not only on the absolute configuration of the diamine, but also on the configuration of the leaving group.

This study reports on new proteolytically stable, pharmacologically active endomorphin analogues, incorporating Dmt(1), Achc(2), pFPhe(4), or beta MePhe(4) unnatural amino acids. Consistent with earlier results, it was found that the analogues carrying anti and Achc2 residues displayed the highest p-opioid receptor affinities, depending upon the configuration of the incorporated Achc(2). Combination of such derivatives with pFPhe(4) or beta MePhe(4) yielded further compounds with variable binding potencies. Combined application of Dmt(1), cis-(1S,2R)Achc(2), and pFPhe(4) (compound 16) resulted in the most potent analogue. Ligand stimulated [S-35]GTP gamma S binding assays indicated that the analogues retained their agonist activities and opioid receptor specificities. NMR and molecular modeling studies of the analogues containing beta MePhe(4) or pFPhe(4) confirmed the predominance of bent structures, however, it is apparent that bent structures are energetically more favored than random/extended structures for all studied compounds.

The influence of replacing the d-phenylalanine residue with substituted and unsubstituted azoles on the structure and biological activity of the antibiotic gramicidinS was investigated against a representative panel of Gram-positive and Gram-negative bacteria strains. Substituted triazole derivatives, obtained using a convergent synthetic strategy, are as active as gramicidinS, provided that any substituent on the triazole moiety is not too large. The unsubstituted triazole derivative was biologically less active than the parent natural product, gramicidinS. In general for the triazole series, the hemolytic activity could be correlated with the antibacterial activity, that is, the higher the antibacterial activity, the higher the toxicity towards blood cells. Interestingly, its imidazole counterpart showed high antibacterial activity, combined with significantly diminished hemolytic activity. Turning circles! A series of substituted and unsusbstituted azole derivatives of gramicidinS were synthesised, analysed and tested against a range of bacteria and against erythrocytes. The compound where R=H and X=N exhibited high antibacterial and lower hemolytic activities, while a considerable loss of antibacterial activity was observed for the triazole derivative (R=H; X=CH). © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Competition between virus genotypes in insect hosts is a key element of virus fitness, affecting their long-term persistence in agro-ecosystems. Little information is available on virus competition in insect hosts or during serial passages from one cohort of hosts to the next. Here we report on the competition between two genotypes of Spodoptera exigua nucleopolyhedrovirus (SeMNPV), when serially passaged as mixtures in cohorts of 4th instar S. exigua larvae. One of the genotypes was a SeMNPV wild-type isolate, SeUS1, while the other was a SeMNPV recombinant (SeMNPV-XD1) having a greater speed of kill than SeUS1. SeXD1 lacks a suite of genes, including the ecdysteroid UDP-glucosyl transferase (egt) gene. SeXD1 expresses the green fluorescent protein (GFP) gene, enabling the identification of SeXD1 in cell culture and in insects. The relative proportion of SeUS1 and SeXD1 in successive passages of mixed infections in various ratios was determined by plaque assays of budded virus from infected larvae and by polymerase chain reactions and restriction enzyme analyses. The SeUS1 genotype outcompeted recombinant SeXD1 over successive passages. Depending on the initial virus genotype ratio, the recombinant SeXD1 was no longer detected after 6–12 passages. A mathematical model was developed to characterize the competition dynamics. Overall, the ratio SeUS1/XD1 increased by a factor 1.9 per passage. The findings suggest that under the experimental conditions recombinant SeXD1 is displaced by the wild-type strain SeUS1, but further studies are needed to ascertain that this is also the case when the same baculoviruses would be used in agro-ecosystems

It has recently been shown that some growth factors (GFs) have strong interactions with nonproteoglycan extracellular matrix proteins. Relevant here, the 12th-14th type three repeats of fibronectin (FN III12-14) have been shown to bind insulin-like growth factor binding-protein-3, fibroblast growth factor (FGF)-2, and vascular endothelial growth factor (VEGF)-A with high affinity. Since FN III12-14 is known to bind GFs from different families, we hypothesized that this domain could be highly promiscuous in its GF-binding capacity. We used biochemical approaches and surface plasmon resonance to investigate such interactions with recombinant FN III12-14. We found that FN III12-14 binds most of the GFs from the platelet-derived growth factor (PDGF)/VEGF and FGF families and some GFs from the transforming growth factor-β and neurotrophin families, with K(D) values in the nanomolar range, without inhibiting GF activity. Overall, 25 new binding interactions were identified. In a clinically relevant fibrin matrix, a fibrin-binding variant of FN III12-14 was highly effective as a GF delivery system. For instance, in matrices functionalized with FN III12-14, PDGF-BB-induced sprouting of human smooth muscle cell spheroids was greatly enhanced. We show that FN III12-14 is a highly promiscuous ligand for GFs and also holds great potential in clinical healing applications.

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.

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)

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

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.

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.

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.

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.