Designing of Supported Organocatalysts from Carboxylic Acids for the Mannich-Type Synthesis of β-Amino Carbonyl Compounds

<div><p></p><p>New supported acidic organocatalysts were prepared by the impregnation of three carboxylic acids (CF₃COOH, CCl₃COOH and CH₃COOH) on silica support at room temperature in diethyl ether. The catalysts were characterized by SEM, EDX, TGA, FT-IR and powder XRD analysis. These solid acids were observed as highly efficient reusable catalysts at room temperature for the selective synthesis of β-amino carbonyl compounds via Mannich-type reactions of acetophenone, arylamine and arylaldehydes in CH₂Cl₂ solution and solvent-free grinding method within short time. The more acidic two catalysts could be recycled up to five cycles with a small loss in catalytic activity.</p></div

Studies on –SO₃H functionalized Brønsted acidic imidazolium ionic liquids (ILs) for one-pot, two-step synthesis of 2-styrylquinolines

<p>Four task-specific –SO₃H functionalized imidazolium ionic liquids (ILs) were investigated for Brønsted acidities by Hammett functions. After knowing their thermal stabilities, the catalytic activity was observed for the preparation of 2-styrylquinolines by following consecutive Friedländer and Knoevenagel reactions in solvent-free thermal energy. The acidity order ([Dsim][OOCCF₃] > [Dsim][OTs] > [Dsim][OOCCl₃] > [Msim][OOCCF₃]) of three ILs was consistent with their activity order observed in the acid-catalyzed synthesis of 2-styrylquinolines under solvent-free conditions at 90° C, with the exception of [Dsim][OTs]. The best catalytic activity was shown by 25 mol% of [Dsim][OOCCF₃] IL. The less acidic IL required 50 mol% to give good yield of 2-styrylquinolines under the optimized condition.</p

A key GPCR phosphorylation motif discovered in arrestin2⋅CCR5 phosphopeptide complexes

The two non-visual arrestins, arrestin2 and arrestin3, bind hundreds of GPCRs with different phosphorylation patterns, leading to distinct functional outcomes. Structural information on these interactions is available only for very few GPCRs. Here, we have characterized the interactions between the phosphorylated human CC chemokine receptor 5 (CCR5) and arrestin2. We identified several new CCR5 phosphorylation sites necessary for stable arrestin2 complex formation. Structures of arrestin2 in the apo form and complexes with CCR5 C-terminal phosphopeptides, together with NMR, biochemical, and functional assays, revealed three phosphoresidues in a pXpp motif that are essential for arrestin2 binding and activation. The identified motif appears responsible for robust arrestin2 recruitment in many other GPCRs. An analysis of receptor sequences and available structural and functional information provides hints on the molecular basis of arrestin2/arrestin3 isoform specificity. Our findings demonstrate how multi-site phosphorylation controls GPCR⋅arrestin interactions and provide a framework to probe the intricate details of arrestin signaling

Exceptional Thermo-Mechano-Fluorochromism and Nanomechanical Analysis of Mechanically Responsive J and H Type Polymorphic Systems

Mechanically responsive organic crystals with thermo-mechano-fluorochromic behavior are relatively scarce. A polymorphic J and H aggregate system with such mechanosalient properties has potential importance for the understanding of structure-mechanochromic luminescence. Herein, we not only carefully investigated the nanomechanical properties of a polymorphic organic fluorophore of (biphenyl-4-ylmethylidene) propanedinitrile but also demonstrated their exceptional thermo-mechanochromic luminescence. Both the polymorphs were characterized using single crystal X-ray diffraction, solid-state UV, SSFL, nanoindentation, Hirshfeld surfaces, energy frameworks, powder X-ray diffraction, and differential scanning calorimetry thermograms. Relatively weak π–π stacking interactions present in the crystal structures govern the hypsochromic shift on mechanical grinding. Density functional theory calculations provide tremendous support to shed light on the origin of the distinct photophysical properties of the two polymorphs

Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution

Abstract The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. Its activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. GPR109A continues to be a target for developing potential therapeutics in dyslipidemia with minimized flushing response. Here, we present cryo-EM structures of the GPR109A in complex with dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures elucidate the binding mechanism of agonists, molecular basis of receptor activation, and insights into biased signaling elicited by some of the agonists. The structural framework also allows us to engineer receptor mutants that exhibit G-protein signaling bias, and therefore, our study may help in structure-guided drug discovery efforts targeting this receptor

Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody

Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a primary determinant of β-arrestin (βarr) recruitment and trafficking. For several GPCRs such as the vasopressin receptor subtype 2 (V2R), agonist-stimulation first drives the translocation of βarrs to the plasma membrane, followed by endosomal trafficking, which is generally considered to be orchestrated by multiple phosphorylation sites. We have previously shown that mutation of a single phosphorylation site in the V2R (i.e., V2RT360A) results in near-complete loss of βarr translocation to endosomes despite robust recruitment to the plasma membrane, and compromised ERK1/2 activation. Here, we discover that a synthetic intrabody (Ib30), which selectively recognizes activated βarr1, efficiently rescues the endosomal trafficking of βarr1 and ERK1/2 activation for V2RT360A. Molecular dynamics simulations reveal that Ib30 enriches active-like βarr1 conformation with respect to the inter-domain rotation, and cellular assays demonstrate that it also enhances βarr1-β2-adaptin interaction. Our data provide an experimental framework to positively modulate the receptor-transducer-effector axis for GPCRs using intrabodies, which can be potentially integrated in the paradigm of GPCR-targeted drug discovery