Regio- and Enantioselective -Heterocyclic Carbene-Catalyzed Annulation of Aminoindoles Initiated by Friedel-Crafts Alkylation.

Chiral indoles annulated on the benzene ring are unique and significant in natural and medicinal compounds. However, accessing these enantioenriched molecules has often been overlooked. The present study introduces an organocatalytic protocol to access these compounds efficiently, demonstrated by substrate scope, functional group tolerance, and using only 1 mol % of a chiral conjugated acid catalyst.

Organocatalytic desymmetrization provides access to planar chiral [2.2]paracyclophanes.

Planar chiral [2.2]paracyclophanes consist of two functionalized benzene rings connected by two ethylene bridges. These organic compounds have a wide range of applications in asymmetric synthesis, as both ligands and catalysts, and in materials science, as polymers, energy materials and dyes.

Access to Spirooxindole-Fused Cyclopentanes via a Stereoselective Organocascade Reaction Using Bifunctional Catalysis.

The present study reports an asymmetric organocascade reaction of oxindole-derived alkenes with 3-bromo-1-nitropropane efficiently catalyzed by the bifunctional catalyst. Spirooxindole-fused cyclopentanes were produced in moderate-to-good isolated yields (15-69%) with excellent stereochemical outcomes. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spirooxindole compounds.

Stereoselective -Heterocyclic-Carbene-Catalyzed Formal [4 + 2] Cycloaddition: Access to Chiral Heterocyclic Cyclohexenones.

The present study reports an asymmetric NHC-catalyzed formal [4 + 2] cycloaddition of heterocyclic alkenes containing a polarized double bond with an azolium-dienolate intermediate generated from α-bromo-α,β-unsaturated aldehydes without external oxidation of the Breslow intermediate. Heterocyclic cyclohexenones were produced in good isolated yields (typically about 90%) with good stereochemical outcomes (in most cases, dr > 20/1, and ee = 70-99%). The synthetic utility of the protocol was exemplified by the scope of heterocyclic alkenes.

Lengthening the Guanidine-Aryl Linker of Phenylpyrimidinylguanidines Increases Their Potency as Inhibitors of FOXO3-Induced Gene Transcription.

Increased FOXO3 nuclear localization is involved in neuroblastoma chemoresistance and tumor angiogenesis. Accordingly, FOXO3 inhibition is a promising strategy for boosting antitumor immune responses and suppressing FOXO3-mediated therapy resistance in cancer cells. However, no FOXO3 inhibitors are currently available for clinical use.

Enantioselective Construction of Spirooxindole-Fused Cyclopentanes.

The present study reports an asymmetric organocatalytic cascade reaction of oxindole derivates with α,β-unsaturated aldehydes efficiently catalyzed by simple chiral secondary amine. Spirooxindole-fused cyclopentanes were produced in excellent isolated yields (up to 98%) with excellent enantiopurities (up to 99% ) and moderate to high diastereoselectivities. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spiro compounds.

Modulating FOXO3 transcriptional activity by small, DBD-binding molecules.

FOXO transcription factors are critical regulators of cell homeostasis and steer cell death, differentiation and longevity in mammalian cells. By combined pharmacophore-modeling-based in silico and fluorescence polarization-based screening we identified small molecules that physically interact with the DNA-binding domain (DBD) of FOXO3 and modulate the FOXO3 transcriptional program in human cells. The mode of interaction between compounds and the FOXO3-DBD was assessed NMR spectroscopy and docking studies.

Decarboxylative Organocatalytic Allylic Amination of Morita-Baylis-Hillman Carbamates.

The present study reports the organocatalytic enantioselective allylic amination of Morita-Baylis-Hillman carbamates efficiently catalyzed by a chiral amine in the presence of a Brønsted acid. Chiral allylic amines were produced in high yields (up to 98 %) and enantioselectivities (up to 97 % ee). This method provides an efficient and easily performed route to prepare α-methylene-β-lactams, and other optically active β-lactams, such as the cholesterol-lowering drug Ezetimibe.

Molecular basis of the 14-3-3 protein-dependent activation of yeast neutral trehalase Nth1.

The 14-3-3 proteins, a family of highly conserved scaffolding proteins ubiquitously expressed in all eukaryotic cells, interact with and regulate the function of several hundreds of partner proteins. Yeast neutral trehalases (Nth), enzymes responsible for the hydrolysis of trehalose to glucose, compared with trehalases from other organisms, possess distinct structure and regulation involving phosphorylation at multiple sites followed by binding to the 14-3-3 protein. Here we report the crystal structures of yeast Nth1 and its complex with Bmh1 (yeast 14-3-3 isoform), which, together with mutational and fluorescence studies, indicate that the binding of Nth1 by 14-3-3 triggers Nth1's activity by enabling the proper 3D configuration of Nth1's catalytic and calcium-binding domains relative to each other, thus stabilizing the flexible part of the active site required for catalysis.