Methylene Homologues of Artemisone: An Unexpected Structure-Activity Relationship and a Possible Implication for the Design of C10-Substituted Artemisinins.

We sought to establish if methylene homologues of artemisone are biologically more active and more stable than artemisone. The analogy is drawn with the conversion of natural O- and N-glycosides into more stable C-glycosides that may possess enhanced biological activities and stabilities. Dihydroartemisinin was converted into 10β-cyano-10-deoxyartemisinin that was hydrolyzed to the α-primary amide. Reduction of the β-cyanide and the α-amide provided the respective methylamine epimers that upon treatment with divinyl sulfone gave the β- and α-methylene homologues, respectively, of artemisone. Surprisingly, the compounds were less active in vitro than artemisone against P. falciparum and displayed no appreciable activity against A549, HCT116, and MCF7 tumor cell lines. This loss in activity may be rationalized in terms of one model for the mechanism of action of artemisinins, namely the cofactor model, wherein the presence of a leaving group at C10 assists in driving hydride transfer from reduced flavin cofactors to the peroxide during perturbation of intracellular redox homeostasis by artemisinins. It is noted that the carba analogue of artemether is less active in vitro than the O-glycoside parent toward P. falciparum, although extrapolation of such activity differences to other artemisinins at this stage is not possible. However, literature data coupled with the leaving group rationale suggest that artemisinins bearing an amino group attached directly to C10 are optimal compounds. A brief critique is made of proteomic studies purporting to demonstrate the alkylation of intraparasitic proteins by alkyne- and azide-tagged artemisinins and synthetic peroxides in relation to mechanism of action

(Z)-(1,2-Dichloro­vin­yl)diphenyl­phosphine oxide

The title compound, C14H11Cl2OP, was synthesized by the reaction of diphenyl­phosphine oxide with 1,2-dichloro­ethyne under CuI catalysis. The reaction provided the Z isomer regioselectively. Two O—P—C bond angles [114.3 (1) and 112.5 (1)°] are significantly larger than the C—P—C [107.7 (1), 105.6 (1) and 106.6 (1)°] and another O—P—C angle [109.5 (1)°], indicating significant distortion of the tetra­hedral configuration of the P atom. In the crystal, mol­ecules are linked by weak inter­molecular C—H⋯O hydrogen bonds into centrosymmetric dimers, which are connected by further C—H⋯O inter­actions into chains along [101]

Methods development for Analysis of Partially Deglycosylated Proteins and Application to an HIV Envelope Protein Vaccine Candidate

The work presented herein describes the first comprehensive analysis of a partially deglycosylated HIV vaccine candidate envelope protein (Env). The Env, JRFL gp140 ΔCF, with 27 potential glycosylation sites, was partially deglycosylated with PNGase F as part of a strategy to generate a more immunogenic HIV vaccine, and the resulting protein’s glycosylation was characterized in a unique workflow using two different glycosidases, Endo H and Endo F3. This unique analysis protocol provided for coverage on 26 of the 27 glycosylation sites, and the data showed that the biochemical treatment with PNGase F resulted in a highly heterogeneous glycoprotein product that had been partially deglycosylated at most of the glycosylation sites. The protocols described in this work could be useful for characterizing the glycosylation site occupancy of other native or biochemically deglycosylated proteins

STAT4 deficiency reduces obesity-induced insulin resistance and adipose tissue inflammation

Signal transducer and activator of transcription (STAT) 4 is one of the seven members of the STAT family. STAT4 has a prominent role in mediating interleukin-12-induced T-helper cell type 1 lineage differentiation. T cells are key players in the maintenance of adipose tissue (AT) inflammation. The role of STAT4 in obesity and AT inflammation is unknown. We sought to determine the role of STAT4 in AT inflammation in obesity-induced insulin resistance. We studied STAT4-null mice on the C57Bl6/J background. We have found that STAT4(-/-)C57Bl6/J mice develop high-fat diet-induced obesity (DIO) similar to wild-type controls, but that they have significantly improved insulin sensitivity and better glucose tolerance. Using flow cytometry and real-time PCR, we show that STAT4(-/-) mice with DIO produce significantly reduced numbers of inflammatory cytokines and chemokines in adipocytes, have reduced numbers of CD8(+) cells, and display increased alternative (M2) macrophage polarization. CD8(+) cells, but not CD4(+) cells, from STAT4(-/-) mice displayed reduced in vitro migration. Also, we found that adipocyte inflammation is reduced and insulin signaling is improved in STAT4(-/-) mice with DIO. We have identified STAT4 as a key contributor to insulin resistance and AT inflammation in DIO. Targeting STAT4 activation could be a novel approach to reducing AT inflammation and insulin resistance in obesity

3-Chloro-4-hydroxy­furan-2(5H)-one

In the title compound, C4H3ClO3, mol­ecules are linked via O—H⋯O hydrogen bonds into an infinite chain with graph-set motif C(6) along the c axis

A comparison of the galaxy peculiar velocity field with the PSCz gravity field-- A Bayesian hyper-parameter method

We constructed a Bayesian hyper-parameter statistical method to quantify the difference between predicted velocities derived from the observed galaxy distribution in the \textit{IRAS}-PSC$z$ redshift survey and peculiar velocities measured using different distance indicators. In our analysis we find that the model--data comparison becomes unreliable beyond 70 \hmpc because of the inadequate sampling by \textit{IRAS} survey of prominent, distant superclusters, like the Shapley Concentration. On the other hand, the analysis of the velocity residuals show that the PSC$z$ gravity field provides an adequate model to the local, \le 70 \hmpc, peculiar velocity field. The hyper-parameter combination of ENEAR, SN, A1SN and SFI++ catalogues in the Bayesian framework constrains the amplitude of the linear flow to be $\beta=0.53 \pm 0.014$. For an rms density fluctuations in the PSC$z$ galaxy number density $\sigma_8^{\rm gal}=0.42\pm0.03$, we obtain an estimate of the growth rate of density fluctuations $f\sigma_{8}(z\sim0) = 0.42 \pm 0.033$, which is in excellent agreement with independent estimates based on different techniques.Comment: 14 pages, 32 figures, MNRAS in press, matched the MNRAS published versio

Coordination cages as permanently porous ionic liquids

Porous materials are widely used in industry for applications that include chemical separations and gas scrubbing. These materials are typically porous solids, although the liquid state can be easier to manipulate in industrial settings. The idea of combining the size and shape selectivity of porous domains with the fluidity of liquids is a promising one and porous liquids composed of functionalized organic cages have recently attracted attention. Here we describe an ionic-liquid, porous, tetrahedral coordination cage. Complementing the gas binding observed in other porous liquids, this material also encapsulates non-gaseous guests—shape and size selectivity was observed for a series of isomeric alcohols. Three gaseous chlorofluorocarbon guests, trichlorofluoromethane, dichlorodifluoromethane and chlorotrifluoromethane, were also shown to be taken up by the liquid coordination cage with an affinity that increased with their size. We hope that these findings will lead to the synthesis of other porous liquids whose guest-uptake properties may be tailored to fulfil specific functions