Characterization of Protein Kinase ULK3 Regulation by Phosphorylation and Inhibition by Small Molecule SU6668.

Serine/threonine protein kinase ULK3 is implicated in a variety of cellular processes, including autophagy, cell division, and execution of the Sonic hedgehog pathway. However, very little about how its biological activity could be controlled is known. This study focuses on unraveling biochemical insights into the mechanism of inhibition and activation of ULK3. We identify novel phosphorylation sites in ULK3 and show that autophosphorylation has no impact on the kinase activity of the protein. We further demonstrate that phosphorylation of two residues in the kinase domain of ULK3 by an as yet unidentified kinase may completely abolishes its catalytic activity. We show that a low-molecular weight inhibitor SU6668, designed as an ATP competitive inhibitor for tyrosine kinases, binds in the ATP pocket of ULK3 yet inhibits ULK3 kinase activity in a partially ATP noncompetitive manner. Finally, we demonstrate that the ULK3 kinase domain, annotated in silico, is not sufficient for its kinase activity, and additional amino acids in the 271-300 region are required.

Enantioselective Construction of Acyclic Quaternary Carbon Stereocenters: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Amide Enolates.

We report a divergent and modular protocol for the preparation of acyclic molecular frameworks containing newly created quaternary carbon stereocenters. Central to this approach is a sequence composed of a (1) regioselective and -retentive preparation of allyloxycarbonyl-trapped fully substituted stereodefined amide enolates and of a (2) enantioselective palladium-catalyzed decarboxylative allylic alkylation reaction using a novel bisphosphine ligand.

Electrophilic amination: the case of nitrenoids.

Among the numerous approaches and reagents employed for electrophilic amination, nitrenoids have long stayed out of the limelight. Here, we systematically review the discovery, structural features and chemical reactivity of these promising reagents. We highlight advances in applying the chemistry of nitrenoids as well as outline current limitations and future directions.

Iron Triad-Based Bimetallic M-N-C Nanomaterials as Highly Active Bifunctional Oxygen Electrocatalysts.

The use of precious metal electrocatalysts in clean electrochemical energy conversion and storage applications is widespread, but the sustainability of these materials, in terms of their availability and cost, is constrained. In this research, iron triad-based bimetallic nitrogen-doped carbon (M-N-C) materials were investigated as potential bifunctional electrocatalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). The synthesis of bimetallic FeCo-N-C, CoNi-N-C, and FeNi-N-C catalysts involved a precisely optimized carbonization process of their respective metal-organic precursors. Comprehensive structural analysis was undertaken to elucidate the morphology of the prepared M-N-C materials, while their electrocatalytic performance was assessed through cyclic voltammetry and rotating disk electrode measurements in a 0.1 M KOH solution. All bimetallic catalyst materials demonstrated impressive bifunctional electrocatalytic performance in both the ORR and the OER. However, the FeNi-N-C catalyst proved notably more stable, particularly in the OER conditions. Employed as a bifunctional catalyst for ORR/OER within a customized zinc-air battery, FeNi-N-C exhibited a remarkable discharge-charge voltage gap of only 0.86 V, alongside a peak power density of 60 mW cm-2. The outstanding stability of FeNi-N-C, operational for about 55 h at 2 mA cm-2, highlights its robustness for prolonged application.

Direct synthesis of amides from carboxylic acids and amines using B(OCH2CF3)3.

B(OCH2CF3)3, prepared from readily available B2O3 and 2,2,2-trifluoroethanol, is as an effective reagent for the direct amidation of a variety of carboxylic acids with a broad range of amines. In most cases, the amide products can be purified by a simple filtration procedure using commercially available resins, with no need for aqueous workup or chromatography. The amidation of N-protected amino acids with both primary and secondary amines proceeds effectively, with very low levels of racemization. B(OCH2CF3)3 can also be used for the formylation of a range of amines in good to excellent yield, via transamidation of dimethylformamide.

Borate esters as convenient reagents for direct amidation of carboxylic acids and transamidation of primary amides.

Simple borates serve as effective promoters for amide bond formation with a variety of carboxylic acids and amines. With trimethyl or tris(2,2,2-trifluoroethyl) borate, amides are obtained in good to excellent yield and high purity after a simple work-up procedure. Tris(2,2,2-trifluoroethyl) borate can also be used for the straightforward conversion of primary amides to secondary amides via transamidation.

An alternative approach to aldol reactions: gold-catalyzed formation of boron enolates from alkynes.

A new method for enolate generation via the gold-catalyzed addition of boronic acids to alkynes is reported. The formation of boron enolates from readily accessible ortho-alkynylbenzeneboronic acids proceeds rapidly with 2 mol % PPh(3)AuNTf(2) at ambient temperature. The enolates undergo aldol reaction with an aldehyde present in the reaction mixture to give cyclic boronate esters, which can be subsequently transformed into phenols, biaryls, or dihydrobenzofurans via oxidation, Suzuki-Miyaura, or intramolecular Chan-Lam coupling, respectively. A combined gold/boronic acid catalyzed aldol condensation reaction of an alkynyl aldehyde was also successfully achieved.

A phenotypic approach to probing cellular outcomes using heterobivalent constructs.

Various conjugation techniques are used to affect the intracellular delivery of bioactive small molecules. However, the ability to track changes in the phenotype when applying these tools remains poorly studied. We addressed this issue by having prepared a focused library of heterobivalent constructs based on Rho kinase inhibitor HA-100. By comparing the induction of the phenotype of interest, cell viability and cellular uptake, we demonstrate that various conjugates indeed lead to divergent cellular outcomes.

Direct amidation of unprotected amino acids using B(OCH2CF3)3.

A commercially available borate ester, B(OCH2CF3)3, can be used to achieve protecting-group free direct amidation of α-amino acids with a range of amines in cyclopentyl methyl ether. The method can be applied to the synthesis of medicinally relevant compounds, and can be scaled up to obtain gram quantities of products.