Potent E‐Selectin Antagonists

In the search for drugs that could control excessive leukocyte extravasation, we now report on modifications of the already known potent E‐selectin antagonist 3 containing a cyclohexyllactic acid residue and a glucal‐derived building block. Thus, we describe the synthesis and biological evaluation of a series of derivatives 6 with modified glucal‐derived moieties (CH₂NR¹R² instead of CH₂OH in 3 ) to explore a hypothetical potential complementary interaction with E‐selectin. However, similar activity profiles of most derivatives 6 and compound 3 do not support such an interaction, but rather indicate topological‐structure changes of 6 (and 3 ) in the orientation of the neighboring fucose and galactose due to intramolecular steric interactions. The most potent E‐selectin antagonist 6v showed >50‐fold improved E‐selectin inhibition compared to the weak selectin ligand sialyl Lewis^x (sLe^x, 1 ; IC₅₀=1000 – 1500 μM ), but only a 2‐fold improvement compared to 3 . Compound 6x was tested in vivo in a murine model of acute inflammation and found to be as potent as 3 (ED₅₀=15 mg/kg).     

Explicit Universal Deformations of Even Galois Representations

We investigate the case of deformations of even Galois representations. Our methods are the group theoretic ones mainly developed by Nigel Boston to study odd representations. We present conditions for Borel and tame cases under which the universal deformation ring is isomorphic to ?_p[[T]] and where we compute the universal deformation explicitly. Furthermore we produce a family of examples of totally real S₃ extensions which satisfy the above conditions in the tame case and we give examples in the Borel case. Finally we study the change of the deformation space under enlarging the ramification and thus give an example of an even representation that is not twist-finite.     

Multi-attribute non-expected utility

In management applications of risk theory, planning and decision making are typically concerned with complex multi-dimensional attributes of risk and utility trade-offs between them. This paper presents a novel approach to multi-attribute non-expected utility which is especially designed to serve application and risk management purposes. It is based on a recently developed non-expected utility model that accommodates systematic violations of expected utility of various kinds observed in risky choice experiments. In the model, the possible outcomes of risky decisions are assumed to be multi-dimensional, that is, classified, measured, compared and assessed from different economic and non-economic perspectives simultaneously. Of the risk attributes to be jointly evaluated in a decision problem, each is supposed to be utility independent of the complementary set of all the other attributes also considered. Mutual utility independence and additive independence are particularly pronounced forms of utility independence. An order-preserving preference functional exists if the agent??s risk preferences satisfy familiar rationality requirements. The functional provides a consistently scaled, multi-linear representation in terms of single-attribute probability-dependent utility functions. Finally, the formalism is applied to explain observed trade-offs between monetary benefits obtained, and fatalities incurred, in the operation of large-scale industrial systems.     

Imidazole‐Peptide Foldamers: Parabolic Dependence of the Folding Process on the Water Content of the Solvent

Oligomers of azole peptides have been isolated from a multitude of marine organisms. Up to now, these azole‐containing dipeptide‐analogue oligomers have only been found as cyclic n‐mers (mostly tri‐ and tetramers) in nature. Herein, we show that imidazole‐containing pseudopeptides form helixlike secondary structures in different solvents. The screw sense of the helix can be determined by attaching a single chiral imidazole unit to the N terminus of the oligomer. Investigation by means of circular dichroism (CD) spectroscopy showed that the folding process of the helix depends on the water content of the solvent in a parabolic way. In a pure organic medium, the helix is stabilized by hydrogen bonds between the hydrogen atoms of the amide groups and the nitrogen atoms of the azole ring. In aqueous solution, the formation of the helix is driven by dispersion interactions. The formation of the helix is more pronounced in aqueous solution than in organic solvents.