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International audience; We describe how the Euclid detectors in the Near Infrared Spectrometer and Photometer (NISP) channel will be read out on board and present an analytic expression for the estimated fluence in each pixel with the associated quality factor of the fit per pixel. The method accounts for the Poisson like distribution of the data and includes the effects of noise correlations that arise after the coadding procedure of frames read non-destructively up the ramp during one exposure. The bias of the flux estimator presented in this paper is kept lower than 0.3% over a wide rang of scientifically interesting fluxes of Euclid. The associated error is by 6% lower than the commonly used formula derived in Rauscher et al. in the context of an equally weighted least squares fit. Moreover, the quality factor follows the very well known {χ }{{th}}2(x;n) distribution and thus provides a well behaved statistical tool to check the goodness of the ramp fit. The method is proposed in the context of a large amount of data per exposure, produced by the NISP detectors, that cannot be transferred to the ground for the subsequent processing. The method, which is validated using real and simulated test data, can be safely used by most near-infrared instruments which require very accurate measurements to be performed on board.

The remarkable selectivity of the β-L enantiomers of 2′,3′-dideoxycytidine analogues against the viral polymerases of HIV and HBV has stimulated our interest in targeting β-L enantiomers of anti-HCMV cytidine analogues. Indeed, Ara-C, FIAC and DMDC are cytidine analogues with β-D configuration that show significant potency as anti-HCMV agents but lack selectivity. β-L enantiomers have therefore been synthesized and evaluated together with four other nucleoside analogues, and the β-L. enantiomers were found not to be inhibitory to HCMV replication. However, the three α-L isomers, α-L-Ara-C, α-L-Xylo-C and α-L-FMAU, emerged with activity against HCMV and have provided new approaches for the treatment of viral diseases with nucleoside analogues possessing the unusual L-configuration.

A novel and efficient method for the oxidative glycosidation at the heterosubstituted benzylic positions with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is described. The reaction is stereospecific with 3-substituted isochromans and isothiochroman, as well as diastereoselective with non-3-substituted isochromans. The glycosidation with a mixture of α- and β-anomeric free sugars gives α-glycosides with absolute stereochemical control on the anomeric center. The synthetic utility of this novel methodology is demonstrated by a short, efficient, and stereoselective total synthesis of heteroanthracycline antitumor reagents

2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) induced oxidative coupling of isochromans or isothiochroman and alcohols proceeds in high yield with good regio- and stereochemical control.

Silaketals, in which reactive dienes and dienophiles are linked, can participate in intramolecular Diels-Alder reactions to produce products with a high degree of stereocontrol and with regiochemistry opposite to that predicted by bond polarization models.

2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) induced oxidative coupling of isochromans or isothiochroman and alcohols proceeds in high yield with good regio- and stereochemical control.

A novel and efficient method for the oxidative glycosidation at the heterosubstituted benzylic positions with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is described. The reaction is stereospecific with 3-substituted isochromans and isothiochroman, as well as diastereoselective with non-3-substituted isochromans. The glycosidation with a mixture of α- and β-anomeric free sugars gives α-glycosides with absolute stereochemical control on the anomeric center. The synthetic utility of this novel methodology is demonstrated by a short, efficient, and stereoselective total synthesis of heteroanthracycline antitumor reagents

On the 15th of June 2006, the PAMELA satellite-borne experiment was launched from the Baikonur cosmodrome and it has been collecting data since July 2006. The instrument allows precision studies of the charged cosmic radiation to be conducted over a wide energy range (100 MeV–100's GeV) with high statistics. The primary scientific goal is the measurement of the antiproton and positron energy spectrum in order to search for exotic sources, such as dark matter particle annihilations. PAMELA is also searching for primordial antinuclei (anti-helium), and testing cosmic-ray propagation models through precise measurements of the antiparticle energy spectrum and precision studies of light nuclei and their isotopes. Moreover, PAMELA is investigating phenomena connected with solar and earth physics. Results of the antiproton and positron data will be presented.

The evolution of a quinoline based FLAP inhibitor, L-674,636, into a novel quinoline-indole hybrid compound: MK0591, is described. The new series of compounds are more potent, particularly in binding to FLAP, in inhibiting LTB4 biosynthesis in stimulated human PMN, and in the human whole blood assay.

We examine the annihilation of positrons on polycyclic aromatic hydrocarbon (PAH) molecules in interstellar medium conditions. We estimate the annihilation rates of positrons on PAHs by a semi-empirical approach. We show that PAHs can play a significant role in the overall galactic positron annihilation picture and use the annihilation rates and INTEGRAL galactic emission measurements to constrain the amount of PAHs present in the ISM. We find an upper limit of 4.6 x 10^-7 for the PAH abundance., Comment: Accepted in MNRAS, 10 pages, 5 figures

Silaketals, in which reactive dienes and dienophiles are linked, can participate in intramolecular Diels-Alder reactions to produce products with a high degree of stereocontrol and with regiochemistry opposite to that predicted by bond polarization models.

Intramolecular radical cyclisation reactions of substrates possessing a silaketal tether proceed predominantly via an endo mode in moderate to good yield to give 7, 8 or 9 membered ring products. The products, which are protected diols, can then be deprotected using standard conditions.

Deregulated expression of members of the IAP (inhibitor of apoptosis) family has been identified in a wide variety of neoplastic cells, and synthetic IAP antagonists represent a promising novel class of chemotherapeutic agents. Early work focused on the ability of these compounds to block the caspase-inhibitory function of XIAP (X-linked IAP). However, recent studies have shown that IAP antagonists, although primarily designed to target XIAP, trigger ubiquitin-mediated degradation of two related proteins, c-IAP (cellular IAP) 1 and c-IAP2, and through this process potentiates the death of tumour cells via autocrine cellular-signalling pathways. In this context, the relative contribution of XIAP as a target of this class of compounds is unclear. In the present study, we examine the involvement of XIAP using a recently described synthetic IAP antagonist, AEG40730, and through comparison of a human XIAP-depleted tumour cell line with its isogenic wild-type control line. Treatment with nanomolar concentrations of AEG40730 resulted in the loss of both XIAP and c-IAP1 proteins, albeit with different kinetics. Although XIAP-deficient HCT116 cells retained some sensitivity to external apoptotic stimuli, the results suggest that IAP antagonists, such as AEG40730, exert their apoptosis-enhancing effects through XIAP in addition to the c-IAPs. These results indicate that IAP antagonists can target multiple IAPs to augment distinct pro-apoptotic signalling pathways, thereby revealing the potential for these compounds in cancer therapy and underscoring the promise of IAP-targeted therapies.

Several inflammatory diseases, including asthma, arthritis and psoriasis are associated with the production of leukotrienes by neutrophils, mast cells and macrophages. The initial enzymatic step in the formation of leukotrienes is the oxidation of arachidonic acid by 5-lipoxygenase (5-LO) to leukotriene A4. Osteosarcoma cells transfected with 5-LO express active enzyme in broken cell preparations, but no leukotriene metabolites are produced by these cells when stimulated with the calcium ionophore A23187, indicating that an additional component is necessary for cellular 5-LO activity. A new class of indole leukotriene inhibitor has been described that inhibits the formation of cellular leukotrienes but has no direct inhibitory effect on soluble 5-LO activity. We have now used these potent agents to identify and isolate a novel membrane protein of relative molecular mass 18,000 which is necessary for cellular leukotriene synthesis.

Recently, we have shown that ionophore activation of human leukocytes results in leukotriene synthesis and a translocation of 5-lipoxygenase from the cytosol to cellular membrane. This membrane translocation was postulated to be an important early activation step for the enzyme. 3-[1-(p-Chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2, 2- dimethylpropanoic acid (MK886) is a potent and specific inhibitor of leukotriene biosynthesis in vivo and in intact cells, but has no direct effect on 5-lipoxygenase activity in cell-free systems. In this report, we show that MK886 can both prevent and reverse the membrane translocation of 5-lipoxygenase, in conjunction with the inhibition of leukotriene synthesis. Similar compounds of the indole class could also inhibit the membrane translocation of 5-lipoxygenase in a rank order of potency that correlated with their potencies for leukotriene synthesis inhibition. In contrast L-656,224, a direct 5-lipoxygenase inhibitor, had no effect on the translocation of the enzyme. Attempts to demonstrate the effects of MK886 on the association of 5-lipoxygenase with membrane in cell-free preparations failed due to a nonspecific Ca2+-dependent sedimentation of the enzyme. The mechanism of action of MK-886 is therefore to block translocation, prevent subsequent activation of 5-lipoxygenase, and hence block cellular leukotriene biosynthesis.

International audience; We use the recent model for the distribution of interstellar gas in the Galactic bulge developed by Ferrière et al. (2007) together with the Galprop numerical code to compute the Galactic diffuse gamma-ray emission due to cosmic rays. We then compare our computed Galactic diffuse gamma-ray sky with the previous results obtained with Galprop. Based on the differences between the models of gas of [1] and that commonly employed in Galprop, we investigate what observational constraints GLAST/LAT could provide by simulating one year of GLAST/LAT sky survey.

We present a map of 511 keV electron-positron annihilation emission, based on data accumulated with the SPI spectrometer aboard ESA's INTEGRAL gamma-ray observatory, that covers approximately 95% of the celestial sphere. 511 keV line emission is significantly detected towards the galactic bulge region and, at a very low level, from the galactic disk. The bulge emission is highly symmetric and is centred on the galactic centre with an extension of 8 deg. The emission is equally well described by models that represent the stellar bulge or halo populations. The disk morphology is only weakly constrained by the present data, being compatible with both the distribution of young and old stellar populations. The 511 keV line flux from the bulge and disk components is 1.05e-3 ph cm-2 s-1 and 0.7e-3 ph cm-2 s-1, respectively, corresponding to a bulge-to-disk flux ratio in the range 1-3. Assuming a positronium fraction of 0.93 this translates into annihilation rates of 1.5e43 s-1 and 3e42 s-1, respectively. The ratio of the bulge luminosity to that of the disk is in the range 3-9. We find no evidence for a point-like source in addition to the diffuse emission, down to a typical flux limit of 1e-4 ph cm-2 s-1. We also find no evidence for the positive latitude enhancement that has been reported from OSSE measurements; our 3 sigma upper flux limit for this feature is 1.5e-4 ph cm-2 s-1. The disk emission can be attributed to the beta+ decay of the radioactive species 26Al and 44Ti. The bulge emission arises from a different source which has only a weak or no disk component. We suggest that Type Ia supernovae and/or low-mass X-ray binaries are the prime candidates for the source of the galactic bulge positrons. Light dark matter annihilation could also explain the observed 511 keV bulge emission characteristics., accepted for publication in A&A

We reexamine in detail the various processes undergone by positrons in the ISM from their birth to their annihilation using the most recent results of positron interaction cross sections with H, H2 and He. The positrons' lives are divided into two phases: the 'in-flight' phase and the thermal phase. The first phase is treated with a Monte Carlo simulation that allows us to determine the fraction of positrons that form positronium and annihilate as well as the characteristics of the annihilation emission as a function of the medium conditions. The second phase is treated with a binary reaction rate approach, with cross sections adopted from experimental measurement or theoretical calculations. An extensive search and update of the knowledge of positron processes was thus undertaken. New reaction rates and line widths have been obtained. We investigate the treatment of the complicated interactions between positrons and interstellar dust grains. New reaction rates and widths of the line resulting from the annihilation inside and outside of the grain have been obtained. The final results of our calculations showed that dust is only important in the hot phase of the ISM, where it dominates all other processes. Combining the new calculations, we have constructed annihilation spectra for each phase of the ISM, considering various grain contents, as well as an overall combined spectrum for the ISM as a whole., 16 pages, 6 figures. accepted in Astronomy and Astrophysics

LEUKOTRIENES, the biologically active metabolites of arachidonic acid, have been implicated in a variety of inflammatory responses, including asthma, arthritis and psoriasis1,2. Recently a compound, MK-886, has been described that blocks the synthesis of leukotrienes in intact activated leukocytes, but has little or no effect on enzymes involved in leukotriene synthesis, including 5-lipoxygenase, in cell-free systems3. A membrane protein with a high affinity for MK-886 and possibly representing the cellular target for MK-886 has been isolated from rat and human leukocytes4. Here, we report the isolation of a complementary DNA clone encoding the MK-886-binding protein. We also demonstrate that the expression of both the MK-886-binding protein and 5-lipoxygenase is necessary for leukotriene synthesis in intact cells. Because the MK-886-binding protein seems to play a part in activating this enzyme in cells, it is termed the five-lipoxygenase activating protein (FLAP).

The role of the U.S. military has expanded significantly under the National Security Strategy, "Engagement and Enlargement." Most of its new missions come under the heading Military Operations Other Than War (MOOTW), and the variety of tasks and diverse cast of organizations with whom the military must operate has strained its ability to execute smartly in recent conflicts. MOOTW are difficult and complex. The most critical challenge facing the Joint Task Force (JTF) commander, however, is conducting MOOTW while still being able to deter or, if necessary, fight and win wars. Training for war fighting continues to be a major part of maintaining this readiness, but if the military is to be prepared to conduct operations across the spectrum of conflict, as I believe it must, today's leaders need to develop new doctrine and a new way of organizing the JTF as well. The JTF organization of today and tomorrow must be prepared to cooperate with and support humanitarian relief organizations and other agencies to accomplish many different types of peace keeping missions. At the same time it has to plan for and organize itself to make an orderly and rapid transition to war fighting. The Civil-Military Operations Center is a concept which holds promise for enabling the JTF to balance MOOTW with possible war fighting missions. It was used with some success in Operation PROVIDE HOPE, and with further refinement in JTF exercises it should greatly improve the military's ability to operate comfortably with civilian groups in lesser intensity scenarios without hindering the potential transition to combat. Properly integrated, the CMOC can bo the tool that helps today's operational commander keep peace and win wars.

Combinations of structural elements found in (methoxyalkyl)thiazole 1a and methoxytetrahydropyran 2a with a naphthalenic lignan lactone produce the potent 5-lipoxygenase (5-LO) inhibitors 3 and 4. While the nature of link Y-Z has a major effect on the in vitro activity of compounds 1 and 2, inhibitors 3 and 4 retain their potencies with either an oxymethylene (Y = O, Z = CH2) or a methyleneoxy (Y = CH2, Z = O) link. Compound 4b inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 14 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 1.5 nM) as well as in human whole blood (IC50 = 50 nM). Compound 4b is a selective 5-LO inhibitor showing no significant inhibition of human 15-lipoxygenase or porcine 12-lipoxygenase or binding to human 5-lipoxygenase-activating protein up to 10 microM and inhibits leukotriene biosynthesis by a direct, nonredox interaction with 5-LO. Compound 15, the open form of lactone 4b, is well absorbed in the rat and is transformed into the active species 4b. In addition, 15 is orally active in the rat pleurisy model (ED50 = 0.6 mg/kg) and in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.3 mg/kg).

The inhibitor of apoptosis proteins (IAPs) are important regulators of cell death. Over-expression of IAPs, including XIAP, cIAP1 and cIAP2, predicts poor patient outcome in several types of cancer. XIAP binds to and inhibits caspases 3, 7 and 9. Inhibition of IAP function can enhance cell death in tumor cells. Inhibition of IAPs is being explored clinically with XIAP anti-sense (AEG35156) and small molecule inhibitor (HGS1029) strategies. We describe small molecule inhibitors of the IAPs that have been designed to bind to the homologous BIR3 domains on the IAPs, which is the site of binding of second mitochondria-derived activator of caspase (SMAC). Structure-activity trends of IAP inhibitors were evaluated for binding potency and selectivity towards IAP BIR domains and analyzed for their ability to sensitize cancer cells to death alone or in conjunction with the agonistic TRAIL receptor 1 monoclonal antibody, mapatumumab, or chemotherapeutic agents. Bridging selected compounds at various sites led to compounds with binding affinities for IAPs in the picomolar range. In cellular assays, IAP inhibitor compounds caused rapid and robust loss of cIAP1, consistent with stimulation of E3 ligase activity. In vitro cytotoxicity assays demonstrated sensitization of tumor cell lines to co-treatment with mapatumumab or chemotherapy at low nanomolar concentrations. In vitro ADME studies were conducted in multiple species to select stable molecules which were negative in CYP and hERG binding assays. Selected compounds had high protein binding in plasma from multiple species. IV administration in mice resulted in Cmax values in excess of the EC50 required for cancer cell death in vitro. Efficacy of lead compounds was demonstrated against several xenograft tumor models as single agents and in combination with either mapatumumab or conventional chemotherapeutics. This led to the identification of a highly potent compound series from which a clinical development candidate, HGS1029, was selected. Solid tumor and lymphoid malignancies Phase 1 cancer trials with HGS1029 have been initiated. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 139.

MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)-indol-2-yl]-2,2-dimethyl propanoic acid, previously L-686,708) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human and elicited rat polymorphonuclear leukocytes (PMNLs) (IC50 values 3.1 and 6.1 nM, respectively) and in human, squirrel monkey, and rat whole blood (IC50 values 510, 69, and 9 nM, respectively). MK-0591 had no effect on rat 5-lipoxygenase. MK-0591 has a high affinity for 5-lipoxygenase activating protein (FLAP) as evidenced by an IC50 value of 1.6 nM in a FLAP binding assay and inhibition of the photoaffinity labelling of FLAP by two different photoaffinity ligands. Inhibition of activation of 5-lipoxygenase was shown through inhibition of the translocation of the enzyme from the cytosol to the membrane in human PMNLs. MK-0591 was a potent inhibitor of LT biosynthesis in vivo, first, following ex vivo challenge of blood obtained from treated rats and squirrel monkeys, second, in a rat pleurisy model, and, third, as monitored by inhibition of the urinary excretion of LTE4 in antigen-challenged allergic sheep. Inhibition of antigen-induced bronchoconstriction by MK-0591 was observed in inbred rats pretreated with methysergide, Ascaris-challenged squirrel monkeys, and Ascaris-challenged sheep (early and late phase response). These results indicate that MK-0591 is a potent inhibitor of LT biosynthesis both in vitro and in vivo indicating that the compound will be suitable for assessing the role of leukotrienes in pathological situations.Key words: leukotriene, 5-lipoxygenase, leukotriene inhibitor, bronchoconstriction, inflammation, 5-lipoxygenase activating protein.

A binding assay has been developed to measure the affinity of leukotriene synthesis inhibitors for 5-lipoxygenase-activating protein (FLAP), using human leukocyte membranes as the source of FLAP and a radioiodinated leukotriene synthesis inhibitor, 125I-L-691,831, as ligand. Linearity of specific binding of radiolabeled ligand was demonstrated with increasing protein and ligand concentrations. Saturation analysis of radioligand binding showed a Kd of 6 nM and a Bmax that, depending on the membrane preparation, varied between 8 and 53 pmol/mg of protein. An excellent correlation was shown between affinity for FLAP in the binding assay and inhibition of leukotriene synthesis in human polymorphonuclear leukocytes for compounds from two structurally distinct classes, namely indoles and quinolines. A large number of membrane-active compounds did not compete with 125I-L-691,831 binding to FLAP. In addition, direct 5-lipoxygenase inhibitors and a selection of eicosanoids were unable to compete for FLAP binding. This study validates a selective binding assay for leukotriene synthesis inhibitors whose protein target is FLAP.

An 18-kDa leukocyte membrane protein, termed 5-lipoxygenase-activating protein (FLAP), has recently been shown to be the target of two structurally distinct classes of leukotriene biosynthesis inhibitors. These classes of inhibitors are based on indole and quinoline structures and are represented by MK-886 and L-674,573, respectively. A novel class of hybrid structure based on the indole and quinoline classes of inhibitors, termed quindoles, has recently been developed. These compounds, exemplified by L-689,037, are potent inhibitors of leukotriene biosynthesis, both in vitro and in vivo. In the present study, we have developed and characterized a potent radioiodinated photoaffinity analogue of L-689,037, termed [125I]L-691,678. This compound was used in immunoprecipitation studies with FLAP antisera to show that the quindole series of leukotriene biosynthesis inhibitors interact directly with FLAP. In addition, we show that MK-886, L-674,573, and L-689,037 specifically compete, in a concentration-dependent manner, with both [125I]L-691,678 and [125I]L-669,083, a photoaffinity analogue of MK-886, for binding to FLAP. These results suggest that these three classes of leukotriene biosynthesis inhibitors share a common binding site on FLAP, providing further evidence that FLAP represents a suitable target for structurally diverse classes of leukotriene biosynthesis inhibitors.

Two approaches toward developing anti-leukotriene therapy have led to clinical candidates at the present time. Specific potent leukotriene antagonists (MK-571 [2], MK-679 and ICI-204,219 [3]) have entered clinical trials for asthma and display efficacy in early studies of induced bronchoconstriction (allergen or exercise). These results are encouraging in supporting the thesis of leukotriene-induced pathology in asthma. Inhibitors of leukotriene biosynthesis inhibit the entire cascade of lipoxygenase products, removing simultaneously the contracti1e and oedemagenic peptido-leukotrienes as well as the chemotactic proinflammatory dihydroxy-leukotrienes. The therapeutic implications of such treatment are significant in diseases where an inflammatory response is also associated with, or causes, the pathological effect. Two agents have been examined in clinical trials to date. A-64077 (zileuton) is a 5-lipoxygenase enzyme inhibitor from Abbott [1]. It is an N-hydroxy area derivative which has demonstrated tolerability and efficacy in humans [4]. MK-886 [5], from Merck, is a novel-mechanism agent which acts at an independent site from 5-lipoxygenase, on the 5-lipoxygenase-activating protein, FLAP.

The peptide leukotrienes LTC4, D4 and E4 collectively account for the biological activity known as slow-reacting substance of anaphylaxis (SRS-A). These metabolites of arachidonic acid are thought to play a role in lung pathophysiology. A role in asthma is postulated as a result of their potent bronchoconstrictor activity both in vitro (Dahlen et al. 1980; Drazen et al. 1980; Hanna et al. 1981; Piper et al. 1981; Jones et al. 1982; Peters et al. 1984) and in vivo (Manning et al. 1990; Holroyde et al. 1981; Griffin et al. 1983; Weiss et al. 1982; Barnes et al. 1984). Increased production of leukotrienes has been demonstrated following antigen challenge of the airways of allergic patients in vivo (Creticos et al. 1984; Ishihara et al. 1985; Isono et al. 1985) and in vitro (Dalhen et al. 1983).

Previous studies involving transfection of cDNAs for 5-lipoxygenase-activating protein (FLAP) and 5-lipoxygenase into osteosarcoma cells have shown that both these proteins are essential for leukotriene synthesis (Dixon, R. A. F., Diehl, R. E., Opas, E., Rands, E., Vickers, P. J., Evans, J. F., Gillard, J. W., and Miller, D. K. (1990) Nature 343, 282-284). In the present study we show that FLAP is present in a variety of cells known to produce leukotrienes, but is absent from a number of cells which do not synthesize leukotrienes. Furthermore, differentiation of the human promyelocytic HL-60 cell line towards granulocytic cells following exposure to dimethylsulfoxide is associated with the concurrent induction of both FLAP and 5-lipoxygenase and an increased capacity to synthesize leukotrienes. Cellular leukotriene synthesis in this system is functionally dependent on FLAP as shown by its inhibition by the leukotriene biosynthesis inhibitor MK-886, a compound which specifically binds to FLAP.

Following the intravenous administration of thromboxane (TX) B2, the stable hydration product of TXA2, to human and nonhuman primates the most abundant urinary metabolites are 2,3-dinor-TXB2 and 11-dehydro-TXB2. However, it is not known whether fractional conversion of TXB2 to its enzymatic metabolites is an accurate representation of TXA2 metabolism. Thus, we have compared the metabolic disposition of synthetic TXA2 and TXB2 via the beta-oxidation and 11-OH-dehydrogenase pathways in vivo in the monkey. TXA2 or TXB2 (20 ng/kg) was intravenously administered to four cynomolgus monkeys pretreated with aspirin in order to suppress endogenous TXA2 production. Urinary TXB2, 2,3-dinor-TXB2 and 11-dehydro-TXB2 were measured before, during and up to 24 h after thromboxane administration by means of reversed-phase high-performance liquid chromatography radioimmunoassay. Aspirin treatment suppressed urinary 2,3-dinor-TXB2 and 11-dehydro-TXB2 by approx. 75%. A similar fractional conversion of TXA2 and TXB2 into 2,3-dinor-TXB2 and 11-dehydro-TXB2 was found. These results suggest that TXA2 is hydrolyzed to TXB2 prior to enzymatic degradation and that metabolites of the latter represent reliable indices of TXA2 biosynthesis. Due to the variability in the conversion of thromboxanes into 2,3-dinor-TXB2 and 11-dehydro-TXB2, the measurement of both metabolites seems to represent a more reliable index of acute changes in TXA2 production.

Chinizarindichjnon (Ic) und seine Substitutionsprodukte (Ia) und (Ib) konnen mit konjugierten Dienen im Sinne einer Diels-Alder-Reaktion zu (III), (IV), (V) bzw. (VI) reagieren.

Preparation d'alcoxy (ou aryloxy) chloro dialkyl silanes a partir de dialkyl dichloro silanes et d'alcools primaires, secondaires ou tertiaires. Ces composes reagissent ensuite avec la triethylamine pour donner des alcoxy (ou aryloxy) dialkyl lauryloxy silanes. On etudie les possibilites de deprotection et de sililation rattachees a ces composes

Stereoselective bromination of anomeric glycosyl acetates was achieved with trimethylsilyl bromide under mild conditions and in the presence of various protecting groups commonly employed in carbohydrate chemistry.

1-Methoxy-l ,3-cyclohexadien (I) reagiert mit Naphthazarin (II) zum Cycloaddukt (III), das in Gegenwart von Base mit Sauerstoff zu (IV) oxidiert wird.

L-670,596 ((−)6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of 125I-labeled PTA-OH to human platelets (IC50, 5.5 × 10−9 M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 × 10−7 M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA2,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED50 values, 0.04 and 0.03 mg/kg i.v., respectively), U-44069 induced renal vasoconstriction in the pig (ED50, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1–5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.Key words: thromboxane A2, thromboxane antagonist, prostaglandin endoperoxides, platelet aggregation.

The development of a general strategy for the control ofregiochemistry in the Diels-Alder reactions of substituted naphthazarins is described. Application of this strategy to the synthesis of(±)-daunomycinone ( 2 ) employs two successive regiochemically controlled Diels-Alder reactions and leads to a ten-step, regiospecific synthesis of(±)- 2 in 36% overall yield (Scheme 4).

tert -Butylmethoxyphenylsilyl ethers, which can be formed from primary, secondary or tertiary alcohols and tert -butylmethoxyphenylsilyl bromide, are selectively cleaved by fluoride in the presence of other silyl ethers.

Both thromboxane A2 (TXA2) and its precursor prostaglandin H2 (PGH2) are labile and share a common receptor. The affinities of these two compounds for their putative common receptor are unknown. We compared the potencies of TXA2 and PGH2 to aggregate human platelets and bind to the TXA2/PGH2 receptor. TXA2 was more potent than PGH2 in initiating aggregation in platelet-rich plasma, EC50 of 66 +/- 15 nM and 2.5 +/- 1.3 microM, respectively. In washed platelets, however, PGH2 was more potent than TXA2 with EC50 values of 45 +/- 2 nM and 163 +/- 21 nM, respectively. The affinity of these two compounds in washed platelets was determined in radioligand competition binding assays employing [125I]-PTA-OH. The Kd values for PGH2 and TXA2 were 43 nM and 125 nM, respectively. The results demonstrate that the affinity of PGH2 for the platelet TXA2/PGH2 receptor is greater than previously thought. The data raise the possibility that PGH2 may significantly contribute to the responses attributed to TXA2 in vivo.

A scheme is presented which outlines the possible mode of biogenesis of alkaloids so far reported from the proteaceous plants Bellendena montana and Agastachys odorata (both from Tasmania), Darlingia darlingiana and D. ferruginea (from Queensland) and Knightia deplanchei and K. strobilina (from New Caledonia).

The synthesis, cell growth-inhibitory activity, in vivo antileukemic activity, and extent of DNA binding of the alpha- and beta-anomeric 7-O-(3-amino-3,5-dideoxy-D-ribofuranosyl)daunomycinones and their trifluoroacetamides are described. These compounds are unique in that they are the first reported furanoside analogues of the antitumor antibiotics daunorubicin and adriamycin. Continuing analysis of structure-activity relationships amongst natural and semisynthetic anthracyclines fails to reveal a predictable relationship between in vivo antitumor activity and the in vitro properties of DNA complexation and cell growth inhibition.

Developments are reported which establish a basis for the precision alignment of the segmented optical elements of a large, multipanel telescope. The apparatus described in this paper employs a form of Young's double slit interferometer and a CCD photodetector array to obtain a measure of the step as well as the gap between adjacent mirror segments. A simple adjunct to this arrangement can also provide a means for measuring the relative angle between the normals at the edges of adjoining mirror segments. Despite the preliminary nature of the developments reported herein, the sensor is based on well-known principles and the critical criteria for establishing a viable sensor system have been established experimentally. The parameters of adjacent mirror segment step, gap, and relative angle can all be measured with but a single sensor.© (1983) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Boresighting involves precisely transferring angular coordinates from one point to another. This frequently arises in correlating directional information between systems such as optical telescopes or high-gain microwave antennas that are physically separated by a truss or support. Generally, the separating truss is not rigid to the accuracies required for precise alignment because of thermal, aerodynamic, and vibrational distortions typical of many practical environments. This paper presents a relatively simple concept for optically boresighting between any two points, in three degrees of angular freedom, and independent of the rigid body. Analyses and laboratory investigations indicate that sub-microradian accuracies, data rates exceeding 100 Hz, and dynamic ranges of approximately milliradians are feasible between points separated by over 10 meters.

The synthesis, cell growth-inhibitory activity, in vivo antileukemic activity, and extent of DNA binding of the alpha- and beta-anomeric 7-O-(3-amino-3,5-dideoxy-D-ribofuranosyl)daunomycinones and their trifluoroacetamides are described. These compounds are unique in that they are the first reported furanoside analogues of the antitumor antibiotics daunorubicin and adriamycin. Continuing analysis of structure-activity relationships amongst natural and semisynthetic anthracyclines fails to reveal a predictable relationship between in vivo antitumor activity and the in vitro properties of DNA complexation and cell growth inhibition.