Synthesis and SAR of C12-C13-oxazoline derivatives of epothilone A

The SAR of a series of new epothilone A derivatives with a 2-substituted-1,3-oxazoline moiety trans-fused to the C12-C13 bond of the deoxy macrocycle have been investigated with regard to tubulin polymerization induction and cancer cell growth inhibition. Significant differences in antiproliferative activity were observed between different analogs, depending on the nature of the substituent at the 2-position of the oxazoline ring. The most potent compounds showed comparable activity with the natural product epothilone A. Modeling studies provide a preliminary rationale for the observed SAR.

Multiasset Derivatives and Joint Distributions of Asset Prices

Several of multiasset derivatives like basket options or options on the weighted maximum of assets exhibit the property that their prices determine uniquely the underlying asset distribution. Related to that the question how to retrieve this distributions from the corresponding derivatives quotes will be discussed. On the contrary, the prices of exchange options do not uniquely determine the underlying distributions of asset prices and the extent of this non-uniqueness can be characterised. The discussion is related to a geometric interpretation of multiasset derivatives as support functions of convex sets. Following this, various symmetry properties for basket, maximum and exchange options are discussed alongside with their geometric interpretations and some decomposition results for more general payoff functions.

Correlation between Accurate Electron Density and Linear Optical Properties in Amino Acid Derivatives: L-Histidinium Hydrogen Oxalate

The accurate electron density and linear optical properties of L-histidinium hydrogen oxalate are discussed. Two high-resolution single crystal X-ray diffraction experiments were performed and compared with density functional calculations in the solid state as well as in the gas phase. The crystal packing and the hydrogen bond network are accurately investigated using topological analysis based on quantum theory of atoms in molecules, Hirshfeld surface analysis, and electrostatic potential mapping. The refractive indices are computed from couple perturbed Kohn-Sham calculations and measured experimentally. Moreover, distributed atomic polarizabilities are used to analyze the origin of the linear susceptibility in the crystal, in order to separate molecular and intermolecular causes. The optical properties are also correlated with the electron density distribution. This compound also offers the possibility to test the electron density building block approach for material science and different refinement schemes for accurate positions and displacement parameters of hydrogen atoms, in the absence of neutron diffraction data.

Polycyclic aromatic hydrocarbons (PAHs) and their polar derivatives (oxygenated PAHs, azaarenes) in soils along a climosequence in Argentina

We evaluated the effects of soil properties and climate on concentrations of parent and oxygenated polycyclic aromatic compounds (PAHs and OPAHs) and azaarenes (AZAs) in topsoil and subsoil at 20 sites along a 2100-km north (N)–south (S) transect in Argentina. The concentrations of Σ29PAHs, Σ15OPAHs and Σ4AZAs ranged 2.4–38 ng g− 1, 0.05–124 ng g− 1 and not detected to 0.97 ng g− 1, respectively. With decreasing anthropogenic influence from N to S, low molecular weight PAHs increasingly dominated. The octanol–water partitioning coefficients correlated significantly with the subsoil to topsoil concentration ratios of most compounds suggesting leaching as the main transport process. Organic C concentrations correlated significantly with those of many compounds typical for atmosphere–soil partitioning. Lighter OPAHs were mainly detected in the S suggesting biological sources and heavier OPAHs in the N suggesting a closer association with parent-PAHs. Decreasing alkyl-naphthalene/naphthalene and 9,10-anthraquinone (9,10-ANQ)/anthracene ratios from N to S indicated that 9,10-ANQ might have originated from low-temperature combustion.

Occurrence, gas/particle partitioning and carcinogenic risk of polycyclic aromatic hydrocarbons and their oxygen and nitrogen containing derivatives in Xi'an, central China

29 parent- and alkyl-polycyclic aromatic hydrocarbons (PAHs), 15 oxygenated-PAHs (OPAHs), 11 nitrated-PAHs (NPAHs) and 4 azaarenes (AZAs) in both the gaseous and particulate phases, as well as the particulate-bound carbon fractions (organic carbon, elemental carbon, char, and soot) in ambient air sampled in March and September 2012 from an urban site in Xi'an, central China were extracted and analyzed. The average concentrations (gaseous+particulate) of 29PAHs, 15OPAHs, 11NPAHs and 4AZAs were 1267.0±307.5, 113.8±46.1, 11.8±4.8 and 26.5±11.8ngm(-3) in March and 784.7±165.1, 67.2±9.8, 9.0±1.5 and 21.6±5.1ngm(-3) in September, respectively. Concentrations of 29PAHs, 15OPAHs and 11NPAHs in particulates were significantly correlated with those of the carbon fractions (OC, EC, char and soot). Both absorption into organic matter in particles and adsorption onto the surface of particles were important for PAHs and OPAHs in both sampling periods, with more absorption occurring in September, while absorption was always the most important process for NPAHs. The total carcinogenic risk of PAHs plus the NPAHs was higher in March. Gaseous compounds, which were not considered in most previous studies, contributed 29 to 44% of the total health risk in March and September, respectively.

Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice

The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P1 and S1P3, but not S1P2, receptor internalization as a result of receptor activation. Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNFα-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNFα-mediated downregulation of PECAM-1 mRNA expression. In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated. In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases.

Novel unsymmetrically functionalized BEDT–TTF derivatives: synthesis, crystal structure and electrochemical characterization

Novel functionalized bis(ethylenedithio)tetrathiafulvalene (BEDT–TTF) derivatives 4 and 5 have been synthesized in good yields from cyano precursor via a cross-coupling reaction. Their redox potentials have been studied by cyclic voltammetry in a dichloromethane solution; this indicated that they are slightly weaker electron donors than BEDT–TTF. Compound 4 has been studied by X–ray crystallography; this revealed that, in the crystal, the molecules were held together by some unconventional C–H···N and C–H···S hydrogen bonds.

Antisense derivatives of U7 and other small nuclear RNAs as tools to modify pre-mRNA splicing patterns

The importance of alternative splicing for the diversity of the proteome and the large number of genetic diseases that are due to splicing defects call for methods to modulate alternative splicing decisions. Although splicing can be modulated by antisense oligonucleotides, this approach is confronted with problems of efficient delivery and the need for repeated administrations of large amounts of the oligonucleotides. Therefore we have developed methods allowing us to modulate splicing with the help of modified derivatives of the U7 small nuclear RNA involved in histone RNA 3' end processing. Its nuclear accumulation as a stable ribonucleoprotein particle makes U7 snRNA especially useful for this purpose. In particular, U7 derivatives containing two tandem antisense sequences directed against targets upstream and downstream of an exon can induce the efficient and specific skipping of that exon. U7 expression cassettes have been successfully introduced into a great number of cell lines, primary cells or tissues with the help of lentiviral and adeno-associated viral vectors. Examples of these therapeutic strategies in the fields of β-thalassemia, Duchenne muscular dytrophy and HIV/AIDS are discussed.

FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P3 and phosphoinositide 3-kinase

Sphingosine-1-phosphate (S1P) is a key lipid regulator of a variety of cellular responses including cell proliferation and survival, cell migration, and inflammatory reactions. Here, we investigated the effect of S1P receptor activation on immune cell adhesion to endothelial cells under inflammatory conditions. We show that S1P reduces both tumor necrosis factor (TNF)-α- and lipopolysaccharide (LPS)-stimulated adhesion of Jurkat and U937 cells to an endothelial monolayer. The reducing effect of S1P was reversed by the S1P1+3 antagonist VPC23019 but not by the S1P1 antagonist W146. Additionally, knockdown of S1P3, but not S1P1, by short hairpin RNA (shRNA) abolished the reducing effect of S1P, suggesting the involvement of S1P3. A suppression of immune cell adhesion was also seen with the immunomodulatory drug FTY720 and two novel butterfly derivatives ST-968 and ST-1071. On the molecular level, S1P and all FTY720 derivatives reduced the mRNA expression of LPS- and TNF-α-induced adhesion molecules including ICAM-1, VCAM-1, E-selectin, and CD44 which was reversed by the PI3K inhibitor LY294002, but not by the MEK inhibitor U0126.In summary, our data demonstrate a novel molecular mechanism by which S1P, FTY720, and two novel butterfly derivatives acted anti-inflammatory that is by suppressing gene transcription of various endothelial adhesion molecules and thereby preventing adhesion of immune cells to endothelial cells and subsequent extravasation.

The sonic hedgehog signaling pathway and the development of pharyngeal arch Derivatives in Haplochromis piceatus, a Lake Victoria cichlid

Objectives Pharyngeal arches develop in the head and neck regions, and give rise to teeth, oral jaws, the hyoid bone, operculum, gills, and pharyngeal jaws in teleosts. In this study, the expression patterns of genes in the sonic hedgehog (shh), wnt, ectodysplasin A (eda), and bone morphogenetic protein (bmp) pathways were investigated in the pharyngeal arches of Haplochromis piceatus, one of the Lake Victoria cichlids. Furthermore, the role of the shh pathway in pharyngeal arch development in H. piceatus larvae was investigated. Methods The expression patterns of lymphocyte enhancer binding factor 1 (lef1), ectodysplasin A receptor (edar), shh, patched 1 (ptch1), bmp4, sp5 transcription factor (sp5), sclerostin domain containing 1a (sostdc1a), and dickkopf 1 (dkk1) were investigated in H. piceatus larvae by in situ hybridization. The role of the shh pathway was investigated through morphological phenotypic characterization after its inhibition. Results We found that lef1, edar, shh, ptch1, bmp4, dkk1, sostdc1a, and sp5 were expressed not only in the teeth, but also in the operculum and gill filaments of H piceatus larvae. After blocking the shh pathway using cyclopamine, we observed ectopic shh expression and the disappearance of ptch1 expression. After six weeks of cyclopamine treatment, an absence of teeth in the oral upper jaws and a poor outgrowth of premaxilla, operculum, and gill filaments in juvenile H. piceatus were observed. Conclusions These results suggest that the shh pathway is important for the development of pharyngeal arch derivatives such as teeth, premaxilla, operculum, and gill filaments in H. piceatus.