Structural determination of oleanane-28,13β-olide and taraxerane-28,14β-olide fluoro-lactonization products from the reaction of oleanolic acid with Selectfluor.

The X-ray crystal structure data of 12-α-fluoro-3β-hy-droxy-olean-28,13β-olide methanol hemisolvate, 2CHFO·CHOH, (), and 12-α-fluoro-3β-hy-droxy-taraxer-28,14β-olide methanol hemisolvate, 2CHFO·CHOH, (), are described. The fluoro-lactonization of oleanolic acid using Selectfluor yielded a mixture of the six-membered δ-lactone () and the unusual seven-membered γ-lactone () following a 1,2-shift of methyl C-27 from C-14 to C-13.

Dual Action of Eeyarestatin 24 on Sec-Dependent Protein Secretion and Bacterial DNA.

Eeyarestatin 24 (ES24) is a promising new antibiotic with broad-spectrum activity. It shares structural similarity with nitrofurantoin (NFT), yet appears to have a distinct and novel mechanism: ES24 was found to inhibit SecYEG-mediated protein transport and membrane insertion in Gram-negative bacteria. However, possible additional targets have not yet been explored.

Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines.

The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines.

Eeyarestatin 24 impairs SecYEG-dependent protein trafficking and inhibits growth of clinically relevant pathogens.

Eeyarestatin 1 (ES1) is an inhibitor of endoplasmic reticulum (ER) associated protein degradation, Sec61-dependent Ca homeostasis and protein translocation into the ER. Recently, evidence was presented showing that a smaller analog of ES1, ES24, targets the Sec61-translocon, and captures it in an open conformation that is translocation-incompetent. We now show that ES24 impairs protein secretion and membrane protein insertion in Escherichia coli via the homologous SecYEG-translocon.

Negative Cooperativity in NAD(P)H Quinone Oxidoreductase 1 (NQO1).

NAD(P)H quinone oxidoreductase-1 (NQO1) is a homodimeric protein that acts as a detoxifying enzyme or as a chaperone protein. Dicourmarol interacts with NQO1 at the NAD(P)H binding site and can both inhibit enzyme activity and modulate the interaction of NQO1 with other proteins. We show that the binding of dicoumarol and related compounds to NQO1 generates negative cooperativity between the monomers.

Eeyarestatin Compounds Selectively Enhance Sec61-Mediated Ca Leakage from the Endoplasmic Reticulum.

Eeyarestatin 1 (ES1) inhibits p97-dependent protein degradation, Sec61-dependent protein translocation into the endoplasmic reticulum (ER), and vesicular transport within the endomembrane system. Here, we show that ES1 impairs Ca homeostasis by enhancing the Ca leakage from mammalian ER. A comparison of various ES1 analogs suggested that the 5-nitrofuran (5-NF) ring of ES1 is crucial for this effect.

Draft Genome Sequences of UV4 and UV4/95, Toluene Dioxygenase-Expressing Producers of -1,2-Dihydrodiols.

Here, we present draft genome sequences of strains UV4 and UV4/95, which demonstrate an ability to conduct a wide range of industrially important biotransformations of arenes, alkenes, and phenols.

Transition metal-free, visible-light mediated synthesis of 1,10-phenanthroline derived ligand systems.

A broad range of 1,10-phenanthroline substrates was efficiently C-H functionalised, providing rapid, gram-scale access to substituted heteroaromatic cores of broad utility. Furthermore, this C-H functionalisation pathway was extended to the synthesis of previously inaccessible, ultra-soluble, 2,9-bis-triazinyl-1,10-phenanthroline (BTPhen) ligands for advanced nuclear fuel cycles.

Hydrophilic 2,9-bis-triazolyl-1,10-phenanthroline ligands enable selective Am(iii) separation: a step further towards sustainable nuclear energy.

The first hydrophilic, 1,10-phenanthroline derived ligands consisting of only C, H, O and N atoms for the selective extraction of Am(iii) from spent nuclear fuel are reported herein. One of these 2,9-bis-triazolyl-1,10-phenanthroline (BTrzPhen) ligands combined with a non-selective extracting agent, was found to exhibit process-suitable selectivity for Am(iii) over Eu(iii) and Cm(iii), providing a clear step forward.

Exploring electronic effects on the partitioning of actinides(iii) from lanthanides(iii) using functionalised bis-triazinyl phenanthroline ligands.

The first examples of 4,7-disubstituted 2,9-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzo-triazin-3-yl)-1,10-phenanthroline (CyMe-BTPhen) ligands are reported herein. Evaluating the kinetics, selectivity and stoichiometry of actinide(iii) and lanthanide(iii) radiotracer extractions has provided a mechanistic insight into the extraction process. For the first time, it has been demonstrated that metal ion extraction kinetics can be modulated by backbone functionalisation and a promising new CHON compliant candidate ligand with enhanced metal ion extraction kinetics has been identified.

Deubiquitinases regulate the activity of caspase-1 and interleukin-1β secretion via assembly of the inflammasome.

IL-1β is a potent pro-inflammatory cytokine produced in response to infection or injury. It is synthesized as an inactive precursor that is activated by the protease caspase-1 within a cytosolic molecular complex called the inflammasome. Assembly of this complex is triggered by a range of structurally diverse damage or pathogen associated stimuli, and the signaling pathways through which these act are poorly understood.

Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response.

Selective small-molecule inhibitors represent powerful tools for the dissection of complex biological processes. ES(I) (eeyarestatin I) is a novel modulator of ER (endoplasmic reticulum) function. In the present study, we show that in addition to acutely inhibiting ERAD (ER-associated degradation), ES(I) causes production of mislocalized polypeptides that are ubiquitinated and degraded.

Novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2): crystal structures, biochemical activity, and intracellular effects of imidazoacridin-6-ones.

Imidazoacridin-6-ones are shown to be potent nanomolar inhibitors of the enzyme NQO2. By use of computational molecular modeling, a reliable QSAR was established, relating inhibitory potency with calculated binding affinity. Further, crystal structures of NQO2 containing two of the imidazoacridin-6-ones have been solved.

Eeyarestatin 1 interferes with both retrograde and anterograde intracellular trafficking pathways.

Background: The small molecule Eeyarestatin I (ESI) inhibits the endoplasmic reticulum (ER)-cytosol dislocation and subsequent degradation of ERAD (ER associated protein degradation) substrates. Toxins such as ricin and Shiga/Shiga-like toxins (SLTx) are endocytosed and trafficked to the ER. Their catalytic subunits are thought to utilise ERAD-like mechanisms to dislocate from the ER into the cytosol, where a proportion uncouples from the ERAD process, recovers a catalytic conformation and destroys their cellular targets.

How much human milk do infants consume? Data from 12 countries using a standardized stable isotope methodology.

The WHO has developed new growth curves based on breast-fed infants. Recommendations for energy intake have been adopted based on measurements of total energy expenditure. Data on human milk (HM) intake are needed to estimate the energy intake from this food source.

Inhibitors of NQO1: identification of compounds more potent than dicoumarol without associated off-target effects.

The enzyme NAD(P)H quinone oxidoreductase (NQO1) can function both as a detoxifying enzyme as well as chaperone protein. The latter property has been extensively characterized by the use of dicoumarol which inhibits the chaperone properties of NQO1 in cells. However, the use of this compound is compromised by its multiple "off-target" effects.

Pharmacological inhibitors of NAD(P)H quinone oxidoreductase, NQO1: structure/activity relationships and functional activity in tumour cells.

NAD(P)H quinone oxidoreductase (NQO1) has multiple functions in the cell including an ability to act as a detoxifying enzyme and as a protein chaperone. The latter property is particularly important in oncology as one of the client proteins of NQO1 is p53. The inhibitor, dicoumarol, is classically used to probe the biological properties of NQO1, but interpretation of enzyme function is compromised by the multiple "off-target" effects of this agent.

Nutritional knowledge, attitudes, and practices of women living with HIV in eastern Uganda.

HIV and AIDS have posed various medical, nutritional, social and economic problems, female-headed households being the most affected. Poor nutritional knowledge and dietary practices common among the most affected households significantly contribute to the rapid progression of HIV. However, very little data exist concerning these aspects of nutrition among women living with HIV and AIDS in resource-limited settings, such as Uganda.

Triazoloacridin-6-ones as novel inhibitors of the quinone oxidoreductases NQO1 and NQO2.

A range of triazoloacridin-6-ones functionalized at C5 and C8 have been synthesized and evaluated for ability to inhibit NQO1 and NQO2. The compounds were computationally docked into the active site of NQO1 and NQO2, and calculated binding affinities were compared with IC(50) values for enzyme inhibition. Excellent correlation coefficients were demonstrated suggesting a predictive QSAR model for this series of structurally similar analogues.

Eeyarestatin I inhibits Sec61-mediated protein translocation at the endoplasmic reticulum.

Production and trafficking of proteins entering the secretory pathway of eukaryotic cells is coordinated at the endoplasmic reticulum (ER) in a process that begins with protein translocation via the membrane-embedded ER translocon. The same complex is also responsible for the co-translational integration of membrane proteins and orchestrates polypeptide modifications that are often essential for protein function. We now show that the previously identified inhibitor of ER-associated degradation (ERAD) eeyarestatin 1 (ES(I)) is a potent inhibitor of protein translocation.

Synthesis and biological evaluation of coumarin-based inhibitors of NAD(P)H: quinone oxidoreductase-1 (NQO1).

The synthesis is reported here of two novel series of inhibitors of human NAD(P)H quinone oxidoreductase-1 (NQO1), an enzyme overexpressed in several types of tumor cell. The first series comprises substituted symmetric dicoumarol analogues; the second series contains hybrid compounds where one 4-hydroxycoumarin system is replaced by a different aromatic moiety. Several compounds show equivalent or improved NQO1 inhibition over dicoumarol, both in the presence and in the absence of added protein.

Feeding and nutritional characteristics of infants on PMTCT programs.

Objectives: To compare feeding and nutritional characteristics of infants born to mothers on the prevention of mother to child transmission (PMTCT) programs with infants not in the program.

Design: A hospital-based case-control study was used.

Setting: The study was conducted in Nsambya hospital, Kampala, Uganda.

Arene cis-dihydrodiols: useful precursors for the preparation of analogues of the anti-tumour agent, 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC).

The synthesis of 6-epi-COTC, a diastereoisomer of Streptomyces metabolite 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC), is described. The anti-cancer activities of the novel analogue, in racemic and enantiomerically pure forms, are presented.

Food security status in households of people living with HIV/AIDS (PLWHA) in a Ugandan urban setting.

Because HIV/AIDS negatively impacts on the food security status of households, it is crucial to identify how households respond to these impacts, in order to identify positive food security entry points and design strategies that can effectively alleviate food insecurity among the households of people living with HIV/AIDS (PLWHA). A cross-sectional study was thus undertaken to establish how HIV affected households in an urban Ugandan setting in terms of response to food shortages and the interrelations between the practice of agriculture by PLWHA households within and around town, food security, access to food aid and dietary diversity among these households. Data for this cross-sectional study were collected using quantitative methods from 144 randomly recruited households of PLWHA (aged 15-49 years) residing in Jinja town in Eastern Uganda.