Synthesis of 1-deoxysphingosine derivatives with conformationally restricted pyrrolidinediol head groups

[structure: see text] A family of cyclic 1-deoxysphingolipid derivatives of structure 4 has been designed and synthesized, which may serve as tumorigenesis suppressors for various cancers. Compound 4 is a second-generation analogue developed from sphingosine (1), in which a hydroxyl substituent is moved from C1 to C5 and a methylene is added for conformational rigidity between the C2-nitrogen substituent and C4. The synthetic chemistry for pyrrolidine ring closure at C3-C4 features ring-closing metathesis followed by hydroboration-oxidation.     

Zur Herstellung von reinem Gold und Probirsilber

Ohne Zusammenfassung     

Determining the scope of the organolanthanide-catalyzed, sequential intramolecular amination/cyclization reaction: formation of substituted quinolizidines, indolizidines, and pyrrolizidines

The scope of the lanthanide-mediated, intramolecular amination/cyclization reaction was determined for the formation of substituted quinolizidines, indolizidines, and pyrrolizidines. A methyl group was installed at diverse positions in the substrates to determine the sense and magnitude of diastereoselection. High diastereoselectivity (>20:1) was achieved for the formation of some quinolizidines and indolizidines. The sense of relative asymmetric induction was contrary to previously studied systems, and although some questions remain, a rationalization for these results is put forward.     

Pyridine Syntheses. II. Condensation Routes Toward Streptonigrin Ring C

Alternative complimentary syntheses of penta-substituted pyridine rings with full regiochemical control of substituents were studied as a method for the synthesis of Streptonigrin ( 1 ). Various α-substituted acetophenones 2 were reacted with enones 3 in acetic acid/ammonium acetate and air to afford penta-substituted pyridines 4 . α-Substituents that could provide a source of exocyclic nitrogen at position 3 of these Steptonigrin ring-C models proved to be the limiting factor. However, an inverse “3+2+1” cyclocondensation of α-cyanochalcone 5c with 2-furyl ethyl ketone ( 6b ) afforded the desired model 6-(2-furyl)-5-methyl2,4-diphenyl-3-pyridinecarbonitrile ( 4g ) in 75% yield.     

Measurement of inclusive neutron spectra at the ISR

With a total absorption counter, inclusive neutron spectra have been measured at four ISR energies and at angles of 20, 66 and 119 mrad. The spectra show scaling behavior in the variables x and p⊥. Pion exchange is found to be important at large x values.     

Dielectric relaxation phenomena of rigid polar liquid molecules under giga hertz electric field

The dielectric relaxation phenomena of rigid polar liquid molecules chloral and ethyltrichloroacetate (j) in benzene, n-hexane and n-heptane (i) under 4.2, 9.8 and 24.6 GHz electric fields at 30°C are studied to show the possible existence of double relaxation times τ ₂ and τ ₁ for rotations of the whole and the flexible parts of molecules. The probability of showing double relaxation is more in aliphatic solvents indicating their nonrigidity. The symmetric and asymmetric distribution parameters γ and δ are obtained from X _ij ^′ /X _0ij and X _ij ^″ /X _0ij and w _j →0 where X _ij ^′ and X _ij ^″ are real and imaginary parts of the complex orientational susceptibility X _i ^* and X _0ij is the low frequency susceptibility which is real. X _ij ’s are involved with the measured dielectric relative permittivities ε _ij ^′ , ε _in ^″ , ε _0ij and ε _∞ij of solutions. The theoretical weighted contributions c ₁ and c ₂ towards dielectric dispersions by Fröhlich’s method are compared with the experimental ones obtained from the graphical variation of X _ij ^′ /X _0ij and X _ij ^″ /X _0ij with weight fractions w _j ’s at w _j → 0. The measured dipole moments μ ₂ and μ ₁ of the whole and the flexible part of a polar molecule in terms of the linear coefficients β’s of X _ij ^′ ’s with w _j ’s and the estimated τ ₂ and τ ₁ reveal their associations with aliphatic solvents. The theoretical dipole moments μ _theo’s from the available bond angles and bond moments of the substituent polar groups of the molecules with the estimated μ’s suggest the mesomeric, inductive and electromeric effects in them under GHz electric field.     

Polypyrrole Nanospheres with Magnetic and Cell‐Targeting Capabilities

The preparation of polypyrrole/Fe₃O₄ nanospheres by a facile mini‐emulsion polymerization method is investigated using poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), and hyaluronic acid as surfactants. Hyaluronic acid is deemed the most suitable surfactant since it results in well‐dispersed nanospheres of 80–100 nm, and offers the advantages of biocompatibility, cell adhesive property, and the availability of functional groups for attachment of other molecules. These polypyrrole/Fe₃O₄ nanospheres are magnetic and can be further functionalized with a cancer antibody, herceptin. Our results show that this combination of hyaluronic acid and herceptin results in high specific uptake of the nanospheres by cancer cells.

     

Degradable self-assembling dendrons for gene delivery: experimental and theoretical insights into the barriers to cellular uptake

This paper uses a combined experimental and theoretical approach to gain unique insight into gene delivery. We report the synthesis and investigation of a new family of second-generation dendrons with four triamine surface ligands capable of binding to DNA, degradable aliphatic-ester dendritic scaffolds, and hydrophobic units at their focal points. Dendron self-assembly significantly enhances DNA binding as monitored by a range of experimental methods and confirmed by multiscale modeling. Cellular uptake studies indicate that some of these dendrons are highly effective at transporting DNA into cells (ca. 10 times better than poly(ethyleneimine), PEI). However, levels of transgene expression are relatively low (ca. 10% of PEI). This indicates that these dendrons cannot navigate all of the intracellular barriers to gene delivery. The addition of chloroquine indicates that endosomal escape is not the limiting factor in this case, and it is shown, both experimentally and theoretically, that gene delivery can be correlated with the ability of the dendron assemblies to release DNA. Mass spectrometric assays demonstrate that the dendrons, as intended, do degrade under biologically relevant conditions over a period of hours. Multiscale modeling of degraded dendron structures suggests that complete dendron degradation would be required for DNA release. Importantly, in the presence of the lower pH associated with endosomes, or when bound to DNA, complete degradation of these dendrons becomes ineffective on the transfection time scale-we propose this explains the poor transfection performance of these dendrons. As such, this paper demonstrates that taking this kind of multidisciplinary approach can yield a fundamental insight into the way in which dendrons can navigate barriers to cellular uptake. Lessons learned from this work will inform future dendron design for enhanced gene delivery.     

Fecal microbiota transplantation ameliorates atherosclerosis in mice with C1q/TNF-related protein 9 genetic deficiency

Despite the strong influence of the gut microbiota on atherosclerosis, a causal relationship between atherosclerosis pathophysiology and gut microbiota is still unverified. This study was performed to determine the impact of the gut microbiota on the pathogenesis of atherosclerosis caused by genetic deficiency. To elucidate the influence of the gut microbiota on atherosclerosis pathogenesis, an atherosclerosis-prone mouse model (C1q/TNF-related protein 9-knockout (CTRP9-KO) mice) was generated. The gut microbial compositions of CTRP9-KO and WT control mice were compared. Fecal microbiota transplantation (FMT) was performed to confirm the association between gut microbial composition and the progression of atherosclerosis. FMT largely affected the gut microbiota in both CTRP9-KO and WT mice, and all transplanted mice acquired the gut microbiotas of the donor mice. Atherosclerotic lesions in the carotid arteries were decreased in transplanted CTRP9-KO mice compared to CTRP9-KO mice prior to transplantation. Conversely, WT mice transplanted with the gut microbiotas of CTRP9-KO mice showed the opposite effect as that of CTRP9-KO mice transplanted with the gut microbiotas of WT mice. Here, we show that CTRP9 gene deficiency is related to the distribution of the gut microbiota in subjects with atherosclerosis. Transplantation of WT microbiotas into CTRP9-KO mice protected against the progression of atherosclerosis. Conversely, the transplantation of CTRP9-KO microbiotas into WT mice promoted the progression of atherosclerosis. Treating atherosclerosis by restoring gut microbial homeostasis may be an effective therapeutic strategy.Subject terms: Atherosclerosis, Experimental models of disease, Mechanisms of disease