Intranasal Delivery of a Methyllanthionine-Stabilized Galanin Receptor-2-Selective Agonist Reduces Acute Food Intake

The regulatory (neuro)peptide galanin is widely distributed in the central and peripheral nervous systems, where it mediates its effects via three G protein-coupled receptors (GAL1-3R). Galanin has a vast diversity of biological functions, including modulation of feeding behavior. However, the clinical application of natural galanin is not practicable due to its rapid in vivo breakdown by peptidases and lack of receptor subtype specificity. Much effort has been put into the development of receptor-selective agonists and antagonists, and while receptor selectivity has been attained to some degree, most ligands show overlapping affinity. Therefore, we aimed to develop a novel ligand with specificity to a single galanin receptor subtype and increased stability. To achieve this, a lanthionine amino acid was enzymatically introduced into a galanin-related peptide. The residue’s subsequent cyclization created a conformational constraint which increased the peptide’s receptor specificity and proteolytic resistance. Further exchange of certain other amino acids resulted in a novel methyllanthionine-stabilized galanin receptor agonist, a G1pE-T3N-S6A-G12A-methyllanthionine[13–16]-galanin-(1–17) variant, termed M89b. M89b has exclusive specificity for GAL2R and a prolonged half-life in serum. Intranasal application of M89b to unfasted rats significantly reduced acute 24 h food intake inducing a drop in body weight. Combined administration of M89b and M871, a selective GAL2R antagonist, abolished the anorexigenic effect of M89b, indicating that the effect of M89b on food intake is indeed mediated by GAL2R. This is the first demonstration of in vivo activity of an intranasally administered lanthipeptide. Consequently, M89b is a promising candidate for clinical application as a galanin-related peptide-based therapeutic.

An overview of the obtaining of biomass-derived gamma-valerolactone from levulinic acid or esters without H2 supply

Gamma-valerolactone (GVL) is a highly reactive keto-lactone and a promising platform biomolecule, used as an additive for food and fuels, green solvent, and fuels precursor, among others. Its production from biomass usually involves hydrogenation and subsequent cyclization of levulinic acid or its esters. The process of conventional hydrogenation requires high pressures and temperatures, an external hydrogen source, and scarce noble/precious materials as catalysts. However, it could be produced under mild conditions, using bifunctional metal-acid catalysts with high metal dispersion and meso or microporosity, high surface area, temperatures lower than 200 °C, pressures ≤ 1MPa, and secondary alcohols (such as isopropanol) as hydrogen donors. The catalytic transfer hydrogenation followed by cyclization (CTHC) of levulinic acid (LA) and its esters (LE) to produce GVL using secondary alcohols as H donor is a great alternative. Variables involved in CTHC such as raw material, time, temperature, and type of catalyst, mainly transition metals and their combinations, are reviewed in this work.

An overview of the obtaining of biomass-derived gamma-valerolactone from levulinic acid or esters without H2 supply

Gamma-valerolactone (GVL) is a highly reactive keto-lactone and a promising platform biomolecule, used as an additive for food and fuels, green solvent, and fuels precursor, among others. Its production from biomass usually involves hydrogenation and subsequent cyclization of levulinic acid or its esters. The process of conventional hydrogenation requires high pressures and temperatures, an external hydrogen source, and scarce noble/precious materials as catalysts. However, it could be produced under mild conditions, using bifunctional metal-acid catalysts with high metal dispersion and meso or microporosity, high surface area, temperatures lower than 200 °C, pressures ≤ 1MPa, and secondary alcohols (such as isopropanol) as hydrogen donors. The catalytic transfer hydrogenation followed by cyclization (CTHC) of levulinic acid (LA) and its esters (LE) to produce GVL using secondary alcohols as H donor is a great alternative. Variables involved in CTHC such as raw material, time, temperature, and type of catalyst, mainly transition metals and their combinations, are reviewed in this work.

Aldol Addition-Cyclization Reaction Cascade on a Platform of Chiral Ni(II) Complex of Glycine Schiff Base

Using platform of a new type of chiral Ni(II) complex of glycine Schiff base we designed addition-cyclization reaction cascade to explore aspects of kinetic/thermodynamic formation of the corresponding (S)(2S,3S)/(S)(2S,3R) diastereomers. It was found that the final lactone products reflect the thermodynamic stereocontrol due to much greater rates of the reversible aldol addition vs. subsequent cyclization step. The observed 4/1 (S)(2S,3S)/(S)(2S,3R) diastereoselectivity in the reactions of new type of (S)-Ni(II) complexes constitute an improvement over the previously reported 1.7/1 ratio.

Synthesis and characterization of enantiopure planar–chiral phosphorus-linked diferrocenes

In the course of an ongoing synthetic project on cyclic diferrocenylphosphines, we obtained a group of planar–chiral diferrocenyl compounds useful as precursors for subsequent cyclization. Here we report the crystal structures of two symmetric compounds [(FcA)2(Ph)P], one of which contains four stereogenic centres (two C chiral and two planar chiral centres), i.e. 1,1′-(phenylphosphanediyl)bis{(2S p)-2-[(1R)-1-(acetyloxy)ethyl]ferrocene}, [Fe2(C5H5)2(C24H25O4P)], and the other phosphine sulfide is a purely planar–chiral compound (two planar chiral centres), i.e. bis[(2S p)--2-ethenylferrocen-1-yl]phenylphosphane sulfide, [Fe2(C5H5)2(C20H17PS)]. Owing to the stereocentres present, reactions performed on [(FcA)2(Ph)P]-type compounds strongly favour one ferrocene unit over the other due to diastereoselectivity. Furthermore, we present four related structures where the ferrocene units are not identical [(FcA)(FcB)(Ph)P]. These are {(2S p)-2-[(1R)-1-(acetyloxy)ethyl]ferrocen-1-yl}[(2S p)-2-ethenylferrocen-1-yl]phenyl-(S)-phosphine sulfide, [Fe2(C5H5)2(C22H21O2PS)], [(2S p)-2-ethenylferrocen-1-yl]{(2S p)-2-[(1R)-1-hydroxyethyl]ferrocen-1-yl}phenyl-(S)-phosphine sulfide, [Fe2(C5H5)2(C20H19OPS)], {(2S p)-2-[(1R)-1-(acetyloxy)ethyl]ferrocen-1-yl}{(2S p)-2-[(1R)-1-hydroxyethyl]ferrocen-1-yl}phenyl-(R)-phosphine sulfide, [Fe2(C5H5)2(C22H23O3PS)], and {(2S p)-2-[(1R)-1-benzylamino)ethyl]ferrocen-1-yl}[(2S p)-2-ethenylferrocen-1-yl]phenyl-(S)-phosphine sulfide, [Fe2(C5H5)2(C27H26NPS)]. All of the structures are accessible in one step from known precursors.

Understanding Cu(II)-based systems for C(sp3)–H bond functionalization: insights on the synthesis of aza-heterocycles

Herein we report the synthesis of imidazo[1,5-a]pyridine heterocycles via a Cu(II)-mediated functionalization of α’-C(sp3)–H bonds of pyridinylaldimines and subsequent cyclization. This strategy exploits the inherent directing ability of heteroleptic aldimine...

Thiomonosaccharide Derivatives from D-Mannose

Sulfur-containing monosaccharide derivatives can be highly valuable for obtaining compounds with biological activities. In this work, a synthetic route starting from D-mannose has been designed. After a convenient hydroxyl protection and anomeric carbon functionalization in a cyano group, a new carbohydrate analogue has been obtained with sulfur in the ring. The heteroatoms have been introduced by an SN2 mechanism, with subsequent cyclization. Structural identification has been performed by different spectroscopic techniques.

Iodothiophenes and Related Compounds as Coupling Partners in Copper-Mediated N-Arylation of Anilines

N-Arylation of various 2-acylated anilines with different electron-rich heteroaryl iodides (2- and 3-iodothiophenes, 2- and 3-iodobenzothiophenes­, 2-iodobenzofuran) was achieved by using activated copper and potassium carbonate in dibutyl ether at reflux. The reactivity of the different heteroaryl iodides and anilines employed was discussed and rationalized on the basis of their electronic features. Subsequent cyclization by aromatic electrophilic substitution easily took place in the case of C2-free (benzo)thienyl or C3-free (benzo)furyl derivatives­, affording original tri- and tetracycles. The antiproliferative activity of most of them was evaluated in A2058 melanoma cells and revealed four chlorinated tetracycles as effective growth inhibitors.

Synthesis of Pyrroles Through the CuH-Catalyzed Coupling of Enynes and Nitriles

<p>Herein, we describe an efficient method to prepare polysubstituted pyrroles via a copper-hydride (CuH)-catalyzed enyne-nitrile coupling reaction. This protocol accommodates both aromatic and aliphatic substituents and a broad range of functional groups, providing a variety of N-H pyrroles in good yields and with high regioselectivity. We propose that the Cu-based catalyst promotes both the initial reductive coupling and subsequent cyclization steps. Density functional theory (DFT) calculations were performed to elucidate the reaction mechanism.</p>