Synthesis, properties and application of polyphenylene phosphonium salts

The central objective of this work was to generate weakly coordinating cations of unprecedented molecular size providing an inherently stable hydrophobic shell around a central charge. It was hypothesized that divergent dendritic growth by means of thermal [4+2] Diels-Alder cycloaddition might represent a feasible synthetic method to circumvent steric constraints and enable a drastic increase in cation size.rnThis initial proposition could be verified: applying the divergent dendrimer synthesis to an ethynyl-functionalized tetraphenylphosphonium derivative afforded monodisperse cations with precisely nanoscopic dimensions for the first time. Furthermore, the versatile nature of the applied cascade reactions enabled a throughout flexible design and structural tuning of the desired target cations. The specific surface functionalization as well as the implementation of triazolyl-moieties within the dendrimer scaffold could be addressed by sophisticated variation of the employed building block units (see chapter 3). rnDue to the steric screening provided by their large, hydrophobic and shape-persistent polyphenylene shells, rigidly dendronized cations proved more weakly coordinating compared to their non-dendronized analogues. This hypothesis has been experimentally confirmed by means of dielectric spectroscopy (see chapter 4). It was demonstrated for a series of dendronized borate salts that the degree of ion dissociation increased with the size of the cations. The utilization of the very large phosphonium cations developed within this work almost achieved to separate the charge carriers about the Bjerrum length in solvents of low polarity, which was reflected by approaching near quantitative ion dissociation even at room temperature. In addition to effect the electrolyte behavior in solution, the steric enlargement of ions could be visualized by means of several crystal structure analyses. Thus an insight into lattice packing under the effect of extraordinary large cations could be gathered. rnAn essential theme of this work focused on the application of benzylphosphonium salts in the classical Wittig reaction, where the concept of dendronization served as synthetic means to introduce an exceptionally large polyphenylene substituent at the -position. The straightforward influence of this unprecedented bulky group on the Wittig stereochemistry was investigated by NMR-analysis of the resulting alkenes. Based on the obtained data a valuable explanation for the origin of the observed selectivity was brought in line with the up-to-date operating [2+2] cycloaddition mechanism. Furthermore, a reliable synthesis protocol for unsymmetrically substituted polyphenylene alkenes and stilbenes was established by the design of custom-built polyphenylene precursors (see chapter 5).rnFinally, fundamental experiments to functionalize a polymer chain with sterically shielded ionic groups either in the pending or internal position were outlined within this work. Thus, inherently hydrophobic polysalts shall be formed so that future research can invesigate their physical properties with regard to counter ion condensation and charge carrier mobility.rnIn summary, this work demonstrates how the principles of dendrimer chemistry can be applied to modify and specifically tailor the properties of salts. The numerously synthesized dendrimer-ions shown herein represent a versatile interface between classic organic and inorganic electrolytes, and defined macromolecular structures in the nanometer-scale. Furthermore the particular value of polyphenylene dendrimers in terms of a broad applicability was illustrated. This work accomplished in an interdisciplinary manner to give answer to various questions such as structural modification of ions, the resulting influence on the electrolyte behavior, as well as the stereochemical control of organic syntheses via polyphenylene phosphonium salts. rn

4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ

The estrogen-related receptors (ERRα, ERRβ, and ERRγ) form a family of orphan nuclear receptors that share significant amino acid identity with the estrogen receptors, but for which physiologic roles remain largely unknown. By using a peptide sensor assay, we have identified the stilbenes diethylstilbestrol (DES), tamoxifen (TAM), and 4-hydroxytamoxifen (4-OHT) as high-affinity ligands for ERRγ. In direct binding assays, 4-OHT had a Kd value of 35 nM, and both DES and TAM displaced radiolabeled 4-OHT with Ki values of 870 nM. In cell-based assays, 4-OHT binding caused a dissociation of the complex between ERRγ and the steroid receptor coactivator-1, and led to an inhibition of the constitutive transcriptional activity of ERRγ. ERRα did not bind 4-OHT, but replacing a single amino acid predicted to be in the ERRα ligand-binding pocket with the corresponding ERRγ residue allowed high-affinity 4-OHT binding. These results demonstrate the existence of high-affinity ligands for the ERR family of orphan receptors, and identify 4-OHT as a molecule that can regulate the transcriptional activity of ERRγ.

Bioprospection of Petit Verdot grape pomace as a source of anti-inflammatory compounds.

The aim of this study was to evaluate the anti-inflammatory activity of Petit Verdot Extract and hexane, chloroform and ethyl acetate fractions obtained from grape pomace, in addition to identifying active compounds. The PVE and EAF reduced significantly paw edema and neutrophil migration when compared with control groups. The PVE reduced levels of TNF-α and IL1-β in the peritoneal fluid, whereas the EAF did not reduce cytokines significantly. Two hydroxybenzoic acids, two proanthocyanidins, three flavan-3-ol monomers and three anthocyanins were identified in the PVE and EAF by LC-MS/MS. The stilbene transresveratrol was identified only in the EAF. The phenolic compounds were quantified using HPLC-DAD analysis, except for the stilbenes, which were not sensible for the detection by the method. Since PVE and EAF showed significantly anti-inflammatory effects and high concentration of phenolic compounds, we concluded that Petit Verdot pomace could be an interesting source of anti-inflammatory bioactives.

Environmental factors correlated with the metabolite profile of Vitis vinifera cv. Pinot Noir berry skins along a European latitudinal gradient

Mature berries of Pinot Noir grapevines were sampled across a latitudinal gradient in Europe, from southern Spain to central Germany. Our aim was to study the influence of latitude-dependent environmental factors on the metabolite composition (mainly phenolic compounds) of berry skins. Solar radiation variables were positively correlated with flavonols and flavanonols and, to a lesser extent, with stilbenes and cinnamic acids. The daily means of global and erythematic UV solar radiation over long periods (bud break-veraison, bud break-harvest, and veraison-harvest), and the doses and daily means in shorter development periods (5–10 days before veraison and harvest) were the variables best correlated with the phenolic profile. The ratio between trihydroxylated and monohydroxylated flavonols, which was positively correlated with antioxidant capacity, was the berry skin variable best correlated with those radiation variables. Total flavanols and total anthocyanins did not show any correlation with radiation variables. Air temperature, degree days, rainfall, and aridity indices showed fewer correlations with metabolite contents than radiation. Moreover, the latter correlations were restricted to the period veraison-harvest, where radiation, temperature, and water availability variables were correlated, making it difficult to separate the possible individual effects of each type of variable. The data show that managing environmental factors, in particular global and UV radiation, through cultural practices during specific development periods, can be useful to promote the synthesis of valuable nutraceuticals and metabolites that influence wine quality.