Applications of the Pauson-Khand reaction in the synthesis of tricyclic sesquiterpene natural products

Within our laboratory, the syntheses of several related tricyclic sesquiterpene natural products have been completed, and, in all cases, the synthetic route employed the Pauson-Khand reaction (PKR) to generate the complex tricyclic core of each target.To further extend our studies within this area, we embarked upon synthesis of the[5,6,6]-fused tricyclic natural product α-duprezianene. Two main synthetic strategies towards construction of this complex and challenging target molecule have been investigated, and are described within.The first of these strategies focussed on direct formation of the central [5,6,6]-fused skeleton structure in a rapid and efficient fashion through the PKR. Initial synthetic endeavour thus focussed on the generation of suitable enyne intermediates to allow investigation of this key PKR. Towards this aim, a series of novel routes were proposed and investigated, ultimately delivering the requisite enyne intermediates.Regrettably, PKR of these enynes was unsuccessful and an alternative approach towards the target molecule was thus required.The second strategy towards formation of α-duprezianene involved initial construction of the related natural target sesquithuriferone. Indeed, formation of this target would provide a formal route to not only α-duprezianene, but also to a series of related sesquiterpene products. Once again, the PKR was employed in attempts to generate the [5,6,5]-fused tricyclic core of this target. In this regard, following investigation of several potential synthetic pathways, a robust and high yielding route was developed providing a formal total synthesis of sesquithuriferone. Key to this strategy was an extremely efficient PKR which furnished the [5,6,5]-skeletal core of sesquithuriferone in rapid fashion. In establishing this route, the original target α-duprezianene was also accessed in a formal manner. The success of this work serves to further reinforce the utility of the PKR within organic synthesis.Within our laboratory, the syntheses of several related tricyclic sesquiterpene natural products have been completed, and, in all cases, the synthetic route employed the Pauson-Khand reaction (PKR) to generate the complex tricyclic core of each target.To further extend our studies within this area, we embarked upon synthesis of the[5,6,6]-fused tricyclic natural product α-duprezianene. Two main synthetic strategies towards construction of this complex and challenging target molecule have been investigated, and are described within.The first of these strategies focussed on direct formation of the central [5,6,6]-fused skeleton structure in a rapid and efficient fashion through the PKR. Initial synthetic endeavour thus focussed on the generation of suitable enyne intermediates to allow investigation of this key PKR. Towards this aim, a series of novel routes were proposed and investigated, ultimately delivering the requisite enyne intermediates.Regrettably, PKR of these enynes was unsuccessful and an alternative approach towards the target molecule was thus required.The second strategy towards formation of α-duprezianene involved initial construction of the related natural target sesquithuriferone. Indeed, formation of this target would provide a formal route to not only α-duprezianene, but also to a series of related sesquiterpene products. Once again, the PKR was employed in attempts to generate the [5,6,5]-fused tricyclic core of this target. In this regard, following investigation of several potential synthetic pathways, a robust and high yielding route was developed providing a formal total synthesis of sesquithuriferone. Key to this strategy was an extremely efficient PKR which furnished the [5,6,5]-skeletal core of sesquithuriferone in rapid fashion. In establishing this route, the original target α-duprezianene was also accessed in a formal manner. The success of this work serves to further reinforce the utility of the PKR within organic synthesis

Mortality in intensive care: The impact of bacteremia and the utility of systemic inflammatory response syndrome

Background: The purpose of this study was to determine the impact of bacteremia on intensive care unit (ICU) mortality and to develop a bacteremia prediction tool using systemic inflammatory response syndrome (SIRS) criteria. Methods: Patients included those aged >18 years who had blood cultures taken in the ICU from January 1, 2011-December 31, 2013. Eligible patients were identified from microbiology records of the Glasgow Royal Infirmary, Scotland. Clinical and outcome data were gathered from ICU records. Patients with clinically significant bacteremia were matched to controls using propensity scores. SIRS criteria were gathered and used to create decision rules to predict the absence of bacteremia. The main outcome was mortality at ICU discharge. The utility of the decision tools was measured using sensitivity and specificity. Results: One hundred patients had a clinically significant positive blood culture and were matched to 100 controls. Patients with bacteremia had higher ICU mortality (odds ratio [OR], 2.35; P = .001) and longer ICU stay (OR, 17.0 vs 7.8 days; P ≤ .001). Of 1,548 blood culture episodes, 1,274 met ≥2 SIRS criteria (106 significant positive cultures and 1,168 negative cultures). There was no association between SIRS criteria and positive blood cultures (P = .11). A decision rule using 3 SIRS criteria had optimal predictive performance (sensitivity, 56%; specificity, 50%) but low accuracy. Conclusions: ICU patients with bacteremia have increased mortality and length of ICU stay. SIRS criteria cannot be used to identify patients at low risk of bacteremia

IL-17B Can Impact on Endothelial Cellular Traits Linked to Tumour Angiogenesis

IL-17B is a member of the IL-17 cytokine family which have been implicated in inflammatory response and autoimmune diseases such as rheumatoid arthritis. The founding member of this family, IL-17 (or IL-17A), has also been implicated in promoting tumour angiogenesis through the induction of other proangiogenic factors. Here we examine the potential of recombinant human IL-17B to contribute to the angiogenic process. In vitro rhIL-17B was able to inhibit HECV endothelial cell-matrix adhesion and cellular migration and also, at higher concentrations, could substantially reduce tubule formation compared to untreated HECV cells in a Matrigel tubule formation assay. This data suggests that IL-17B may act in an antiangiogenic manner

Potential implication of Paxillin in cancer establishment within the bone environment

Background: Bone metastases are a common feature of advanced prostatic malignancies. They are characterised by a unique prevalence of osteoblastic phenotype and a poor prognosis. Paxillin is a 68-kDa signal transduction adaptor and scaffold protein that contains motifs involved in the mediation of protein–protein interactions. The state of paxillin phosphorylation is central to determining a cell's ability to adhere, detach and migrate and hence has been linked to processes such as wound repair and tumour metastasis. The current study explored the impact of paxillin suppression on prostate and breast cancer cell function and their responsiveness to hepatocyte growth factor (HGF) and bone matrix extract (BME) in order to assess its potential to influence bone colonization and homing. Materials and Methods: Hammerhead ribozyme transgenes were used to knockdown the expression of paxillin in breast and prostate cancer cell lines. The impact on the cell growth, migration, adhesion and invasion was assessed using in vitro functional assays. In order to explore potential mechanisms, focal adhesion kinase (FAK) inhibitor was also used. Results: Knockdown of paxillin expression was observed in all tested cell lines following transfection with the ribozyme transgene. The knockdown of paxillin increased proliferation and invasiveness of LNCaP cells, with no effect on their attachment abilities. The opposite, however, is true for PC-3 cells where, following knockdown, cellular attachment was significantly reduced, while no significant changes in growth and invasiveness were detected. In the MDA-MB-231 breast cancer knockdown model, cells had little difference in proliferative rates and generally increased attachment and reduced invasive abilities. Treatments with HGF and BME had differential effects on targeted cells when compared to controls. Conclusion: These data suggest that paxillin appears to influence major cell functions in a diverse range of prostate and breast cancer models. The responsiveness of cells to environmental factors such as HGF or BME may be influenced by paxillin status, although this seems to be dependent on cell type

Unveiling Dust-enshrouded Star Formation in the Early Universe: a Sub-mm Survey of the Hubble Deep Field

The advent of sensitive sub-mm array cameras now allows a proper census of dust-enshrouded massive star-formation in very distant galaxies, previously hidden activity to which even the faintest optical images are insensitive. We present the deepest sub-mm survey of the sky to date, taken with the SCUBA camera on the James Clerk Maxwell Telescope and centred on the Hubble Deep Field. The high source density found in this image implies that the survey is confusion-limited below a flux density of 2 mJy. However, within the central 80 arcsec radius independent analyses yield 5 reproducible sources with S(850um) > 2 mJy which simulations indicate can be ascribed to individual galaxies. We give positions and flux densities for these, and furthermore show using multi-frequency photometric data that the brightest sources in our map lie at redshifts z~3. These results lead to integral source counts which are completely inconsistent with a no-evolution model, and imply that massive star-formation activity continues at redshifts > 2. The combined brightness of the 5 most secure sources in our map is sufficient to account for 30 - 50% of the previously unresolved sub-mm background, and we estimate statistically that the entire background is resolved at about the 0.3 mJy level. Finally we discuss possible optical identifications and redshift estimates for the brightest sources. One source appears to be associated with an extreme starburst galaxy at z~1, whilst the remaining four appear to lie in the redshift range 2 < z < 4. This implies a star-formation density over this redshift range that is at least five times higher than that inferred from the ultraviolet output of HDF galaxies.Comment: 19 pages, 6 figures (to appear as a Nature Article

A Submillimetre Survey of the Hubble Deep Field: Unveiling Dust-Enshrouded Star Formation in the Early Universe

The advent of sensitive sub-mm array cameras now allows a proper census of dust-enshrouded massive star-formation in very distant galaxies, previously hidden activity to which even the deepest optical images are insensitive. We present the deepest sub-mm survey, taken with the SCUBA camera on the James Clerk Maxwell Telescope (JCMT) and centred on the Hubble Deep Field (HDF). The high source density on this image implies that the survey is confusion-limited below a flux density of 2 mJy. However within the central 80 arcsec radius independent analyses yield 5 reproducible sources with S(850um) > 2 mJy which simulations indicate can be ascribed to individual galaxies. These data lead to integral source counts which are completely inconsistent with a no evolution model, whilst the combined brightness of the 5 most secure sources in our map is sufficient to account for 30-50% of the previously unresolved sub-mm background, and statistically the entire background is resolved at about the 0.3 mJy level. Four of the five brightest sources appear to be associated with galaxies which lie in the redshift range 2 < z < 4. With the caveat that this is a small sample of sources detected in a small survey area, these submm data imply a star-formation density over this redshift range that is at least five times higher than that inferred from the rest-frame ultraviolet output of HDF galaxies.Comment: to appear in the proceedings of `The Birth of Galaxies', Xth Rencontres de Blois, 4 pages, 1 postscript figure, uses blois.sty (included

Conformationally rigid pyrazoloquinazoline α-amino acids: one- and two-photon induced fluorescence

The synthesis and photophysical properties of a new class of α-amino acid bearing a rigid pyrazoloquinazoline chromophore are described. Confromational constraint of the amino acid side-chains resulted in high emission quantum yields, while the demonstration of two-photon-induced fluorescence via near-IR excitation signifies their potential for sensitive bioimaging applications

Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis.

With the functional demonstration of a role in erythrocyte invasion by Plasmodium falciparum parasites, implications in the aetiology of common conditions that prevail in individuals of African origin, and a wealth of pharmacological knowledge, the stimulatory G protein (Gs) signal transduction pathway presents an exciting target for anti-malarial drug intervention. Having previously demonstrated a role for the G-alpha-s gene, GNAS, in severe malaria disease, we sought to identify other important components of the Gs pathway. Using meta-analysis across case-control and family trio (affected child and parental controls) studies of severe malaria from The Gambia and Malawi, we sought evidence of association in six Gs pathway candidate genes: adenosine receptor 2A (ADORA2A) and 2B (ADORA2B), beta-adrenergic receptor kinase 1 (ADRBK1), adenylyl cyclase 9 (ADCY9), G protein beta subunit 3 (GNB3), and regulator of G protein signalling 2 (RGS2). Our study amassed a total of 2278 cases and 2364 controls. Allele-based models of association were investigated in all genes, and genotype and haplotype-based models were investigated where significant allelic associations were identified. Although no significant associations were observed in the other genes, several were identified in ADORA2A. The most significant association was observed at the rs9624472 locus, where the G allele (approximately 20% frequency) appeared to confer enhanced risk to severe malaria [OR = 1.22 (1.09-1.37); P = 0.001]. Further investigation of the ADORA2A gene region is required to validate the associations identified here, and to identify and functionally characterize the responsible causal variant(s). Our results provide further evidence supporting a role of the Gs signal transduction pathway in the regulation of severe malaria, and request further exploration of this pathway in future studies