The diastereomeric mixture of d/l-2,7-diaminooctanedioyl-bis(YRLRY-NH2) (BVD-74D, 2) was described in the literature as a high affinity Y4 receptor agonist. Here we report on the synthesis and pharmacological characterization of the pure diastereomers (2R,7R)- and (2S,7S)-2 and a series of homo- and heterodimeric analogues in which octanedioic acid was used as an achiral linker. To investigate the role of the Arg residues, one or two arginines were replaced by Ala. Moreover, N(ω)-(6-aminohexylaminocarbonyl)Arg was introduced as an arginine replacement (17). (2R,7R)-2 was superior to (2S,7S)-2 in binding and functional cellular assays and equipotent with 17. [(3)H]Propionylation of one amino group in the linker of (2R,7R)-2 or at the primary amino group in 17 resulted in high affinity Y4R radioligands ([(3)H]-(2R,7R)-10, [(3)H]18) with subnanomolar Kd values.

Ap alladium-catalyzed coupling between aryl halides and monocyclopropanated pyrroles or furans has been developed, leading to valuable six-membered N-and Oheterocycles.A st he key step,as elective cleavage of the nonactivated endocyclic CÀCb ond of the 2-heterobicyclo-[3.1.0]hexane framework is achieved. The developed method offers access to highly functionalized piperidines,p yridines, and pyrans that are challenging to access by traditional methods.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

An enantioselective three-step synthesis of the GABA uptake inhibitor (S)-(+)-homo-β-proline was developed. The basis for the synthesis was the enantioselective Cu-catalyzed cyclopropanation of N-Boc-pyrrole, a substrate that persistently has proved to be challenging in such transformations. The cyclopropanation can be performed on a 150 mmol scale, and the two subsequent steps (i.e., hydrogenation and in situ cyclopropane-opening/double-deprotection) toward the target molecule proceed smoothly in quantitative yield without loss of enantiopurity.

The first total synthesis of either enantiomer of Arteludovicinolide A and their biological evaluation is reported, featuring a new strategy for the asymmetric construction of γ-butyrolactones with stereogenic side chains in the 4-position. Starting from the renewable resource methyl 2-furoate, the sesquiterpene lactone was synthesized in 9 steps and 4.8% overall yield via an asymmetric cyclopropanation and two diastereoselective nucleophile additions making use of a donor-acceptor-cyclopropane-lactonization cascade. At noncytotoxic concentrations (≤10 μM) (+)-1 was found to have a 15 times higher anti-inflammatory activity (4.87 ± 1.1 μM) than previously reported for concentrations of ≥45 μM.

The increasing use of high-flux membranes for hemodialysis (HD) has raised concerns that these membranes may confer a higher risk of exposure to cytokine-inducing, bacterial substances (CIS) in the dialysate. Several studies, however, reported higher transfer of CIS through low-flux cellulosic than high-flux synthetic membranes. This surprising paradox was explained by adsorption of CIS to certain high-flux membranes. In order to investigate flux and membrane type independently, we studied two synthetic Polyflux (PF) membranes of the same type but with different flux properties and compared them to a cellulosic membrane (Cuprophan). Three different approaches were employed: (1) cytokine induction in whole blood during in vitro HD contaminated with bacterial filtrates, (2) removal of recombinant C5a, and (3) transfer of purified lipopolysaccharide (LPS). After 90 min recirculation of whole blood, the appearance of IL-6-inducing substances on the blood side was lowest with high-flux PF (1.1 ± 0.2 ng/ml), slightly higher with low-flux PF (1.9 ± 0.7 ng/ml) and highest with Cuprophan (4.1 ± 1 ng/ml). Recombinant C5a added to plasma on the blood side was markedly removed by high-flux PF (by 83%), to a lesser degree and only in the presence of ultrafiltration with low-flux PF (by 54%) and not significantly with Cuprophan (by 11%). Significant transfer of purified LPS from the dialysate onto the blood side was only observed with the cellulosic membrane. We conclude that in contrast to cellulosic membranes, certain synthetic membranes do not permit transfer of LPS. Cytokine induction on the blood side is further reduced by the use of high-flux membranes due to removal of activated complement factors.