Xenon difluoride induced aryl iodide reductive elimination: a simple access to difluoropalladium(II) complexes

Palladium(II) aryliodo complexes bearing chelating diphosphine ligands react with XeF2, giving iodoarene and rare palladium(II) difluoro complexes. The reaction is general with regard to the aryl group, with even C6F5-I undergoing facile reductive elimination from a Pd center.     

On the electronic effects of OH groups. Synthesis and investigation of tetrahydroxylated azabicycloheptanes

Two stereoisomeric 2,3,5,6-tetrahydroxyazabicyclo[2.2.1]heptanes were synthesised and their base strengths determined. The 2,3,5,6-exo-isomer 1 and the 2,3-exo-5,6-endo-isomer 2 were prepared from the Diels-Alder adduct of Boc-pyrrole and tosylacetylene by a route involving osmium catalyzed dihydroxylation and protection, tosyl group reduction and repeated dihydroxylation. Deprotection gave 1, while 2 was obtained by conversion of the diol into the ditriflate, followed by nucleophilic inversion with KNO(2) and deprotection. Synthesis of the 2,3,5,6-endo-isomer by a similar strategy was attempted but failed. The pK(a) of 1 and 2 was determined to be 7.0 and 6.4 respectively. This means that the change in base strength as a result of stereoisomerism of an OH is smaller in the [2.2.1]-azabicyclic system than in the piperidines. This is explained by a difference in charge-dipole interactions in the two systems.     

Follow-up of stable isotope analysis of organic versus conventional milk

Analysis of the stable isotope ratio of carbon (δ ¹³C) and α-linolenic acid (C18:3ω3) content in milk fat is a useful indicator of organic milk production. Referring to corresponding measurements, further analyses of stable isotope ratios were performed in 120 samples of conventionally and organically produced whole milk collected from German retailers during a period of 18 months. Conventional milk predominantly exhibited higher δ ¹⁵N values than organic milk, the latter of which never exceeded a maximum δ ¹⁵N threshold value of 5.50‰. Measurements of δ ³⁴S did not differ significantly between organic and conventional milk. Because δ ¹³C, in general, is related to maize consumption, δ ¹³C in milk protein and δ ¹³C in milk fat were equally suited for authentication of organic milk. Thus, a high correlation (r = 0.99) was established between δ ¹³C in milk protein and lipids. Although occurring on different levels in organic and conventional milk, the relatively constant fractionation of carbon isotopes between protein and fat will allow for the advanced detection of adulteration in processed milk products, such as fraudulent combinations of organic milk fat and conventional skim milk. In addition to the strong correlation between C18:3ω3 and δ ¹³C_protein (r = −0.91), a mutual dependence was identified between both δ ¹³C_protein and δ ¹⁵N (r = 0.66) and C18:3ω3 and δ ¹⁵N (r = −0.61). Thus, multi-variable analyses are useful to increase robustness and reduce the number of exceptions in organic milk authentication. Future work involving multivariate statistical analysis can possibly further improve milk authentication in various respects including differentiating between brands of retail milk.     

Fluorescence response of human HER2+ cancer- and MCF-12F normal cells to 200MHz ultrasound microbeam stimulation: a preliminary study of membrane permeability variation

Targeted mechanical cell stimulation has been extensively studied for a better understanding of its effect on cellular mechanotransduction signaling pathways and structures by utilizing a variety of mechanical sources. In this work, an ultrasound-driven single cell stimulation method is thus proposed, and a preliminary study is carried out by comparing the fluorescence intensities representing a change in cell membrane permeability between MDA-MB-435 human HER2+ cancer cells (∼40-50 μm in diameter) and MCF-12F normal cells (∼50-60 μm) in the presence of ultrasound. A 200 MHz single element zinc oxide (ZnO) transducer is employed to generate ultrasound microbeam (UM) whose beamwidth and depth of focus are 9.5 and 60 μm, comparable to typical cell size. The cells in tetramethyl rhodamine methyl ester (TMRM) are interrogated with 200 MHz sinusoidal bursts. The number of cycles per burst is 5 and the pulse repetition frequency (PRF) is 1 kHz. The temporal variation of fluorescence intensity in each cell is measured as a function of input voltage to the transducer (16, 32, and 47 V), and its corresponding fluorescence images are obtained via a confocal microscope. A systematic method for visualizing UM’s focus by adding Rhodamine B to the immersion medium is also proposed to enhance the precision in aiming the beam at an individual cell.Both types of cells exhibit a decrease in the intensity upon UM irradiation. In particular, normal cells show more fluorescence reduction (down to 0.7 in normalized intensity) than cancer cells (∼0.9) under the same excitation condition of the transducer. With UM being turned off, the normalized intensity level in normal cells is slowly increased to 1.1. The cell images taken before and after UM exposure indicate that the intensity reduction is more pronounced in those cells after exposure. Hence the results show the potential of UM as a non-invasive in vitro stimulation tool for facilitating targeted drug delivery and gene transfection as well as for studying cellular mechanotransduction.     

Vascular endothelial cells as targets for photochemical internalization (PCI)

Cancer treatment can be exerted by targeting both cancer cells and the vasculature supplying solid tumors. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, but recent data on contrast‐enhanced MRI have indicated that the method also reduces blood perfusion in HT1080 fibrosarcoma xenografts. The present report aims to investigate if PCI may exert direct cytotoxic effects on endothelial cells. PCI of saporin was performed on endothelial human umbilical vein endothelial cell (HUVEC) and fibrosarcoma cells (HT1080) using two PCI‐relevant photosensitizers, TPPS_2a and AlPcS_2a. A 22‐ and 13‐fold higher photosensitizer uptake was detected in the endothelial cells compared with the HT1080 cells for AlPcS_2a and TPPS_2a, respectively. PCI of saporin was, however, found more effective in HT1080 cells. For HT1080 cells, PCI with saporin increased cell killing 1.9‐fold over photodynamic therapy alone, but under the same conditions, only increased HUVEC cell killing by 1.6‐ and 1.3‐fold with AlPcS_2a and TPPS_2a, respectively. Saporin uptake was higher in HUVECs than in the HT1080 cells, hence did not reflect the cell line differences in PCI efficacy. This is the first report on PCI‐mediated kill of endothelial cells and lays the foundation for further preclinical evaluation of the PCI technology as an antivascular strategy to ablate tumors.     

Polymer electrolyte membranes by in situ polymerization of poly(ethylene carbonate‐co‐ethylene oxide) macromonomers in blends with poly(vinylidene fluoride‐co‐hexafluoropropylene)

Salt‐containing membranes based on polymethacrylates having poly(ethylene carbonate‐co‐ethylene oxide) side chains, as well as their blends with poly(vinylidene fluoride‐co‐hexafluoropropylene) (PVDF‐HFP), have been studied. Self‐supportive ion conductive membranes were prepared by casting films of methacrylate functional poly(ethylene carbonate‐co‐ethylene oxide) macromonomers containing lithium bis(trifluorosulfonyl)imide (LiTFSI) salt, followed by irradiation with UV‐light to polymerize the methacrylate units in situ. Homogenous electrolyte membranes based on the polymerized macromonomers showed a conductivity of 6.3 × 10^?6 S cm^?1 at 20 °C. The preparation of polymer blends, by the addition of PVDF‐HFP to the electrolytes, was found to greatly improve the mechanical properties. However, the addition led to an increase of the glass transition temperature (T_g) of the ion conductive phase by ～5 °C. The conductivity of the blend membranes was thus lower in relation to the corresponding homogeneous polymer electrolytes, and 2.5 × 10^?6 S cm^?1 was recorded for a membrane containing 10 wt % PVDF‐HFP at 20 °C. Increasing the salt concentration in the blend membranes was found to increase the T_g of the ion conductive component and decrease the propensity for the crystallization of the PVDF‐HFP component. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 45: 79–90, 2007     

Antibody–Prodrug Conjugates with KSP Inhibitors and Legumain-Mediated Metabolite Formation

Many antibody–drug conjugates (ADCs) have failed to achieve a sufficient therapeutic window in clinical studies either due to target-mediated or off-target toxicities. To achieve an additional safety level, a new class of antibody–prodrug conjugates (APDCs) directed against different targets in solid tumors is here described. The tumor-associated lysosomal endopeptidase legumain with a unique cleavage sequence was utilized for APDC metabolism. Legumain-activatable APDCs were as potent as their cathepsin B-activatable analogues. The peptide sequence susceptible to legumain cleavage was optimized for further discrimination of the formation of active metabolites within tumor cells versus healthy tissues, leveraging different tissue-specific legumain activities. Optimized APDCs with slow legumain-mediated conversion reduced preclinically the levels of active metabolite in healthy organs while retaining high activity against different TWEAKR- and B7H3-expressing tumors.     

Solutions for biomedical grid computing—Case studies from the D-Grid project Services@MediGRID

The project Services@MediGRID consortium established a tool set of grid-based biomedical services since 2008. The services are related to genetic analysis, genome data visualization, and pharmacokinetic modeling. Furthermore, business concepts for these services have been examined which are supported by an accounting and billing service. While the tools cover a whole service chain for biomedicine, the business concepts are rather heterogeneous. However, the overall addressed target market areas show promising potential. In addition, a structured coaching process reduces friction in the technology transfer from grid computing to biomedicine. This should be considered for similar future endeavors.