Reprogramming macrophage polarization with a small molecule G3I: Enhancing tumor suppression and inflammation control.

Glycogen synthase kinase-3β (GSK-3β) is a ubiquitously expressed serine/threonine kinase that plays a pivotal role in regulating innate and adaptive immunity by modulating the production of pro- and anti-inflammatory cytokines. To investigate specific regulators of GSK-3β in innate immunity, we developed small molecule inhibitors that are tightly interact with three ATP-binding sites of GSK-3β through a systematic Fragment-based de novo design (FBDND). Among the leading candidates, G3I was found to modulate early macrophage polarization by downregulating the expression of mRNAs of M2-like markers such as CD206, Arg-1, CCL18 and upregulating the markers for M1-like macrophages such as CD86 and CCR7.

NiH-Catalyzed Enantio- and Regioselective Hydroarylation of Unactivated Alkenes Enabled by Outer-Sphere Electron Transfer with Diaryliodonium Salts.

Asymmetric hydroarylation of unactivated alkenes provides a direct route to enantiomerically enriched C─C bonds in aryl-containing compounds, a key transformation in pharmaceutical and natural product synthesis. While recent advances have achieved high regio- and enantioselectivity with terminal alkenes, controlled hydroarylation of unactivated internal alkenes remains challenging. Here, we report a nickel-hydride-catalyzed protocol that overcomes this limitation through a mechanistic paradigm shift.

Synergistic optimizations of efficacy and membrane permeability of IRAK4 inhibitors: identifying new lead compounds for anti-inflammatory therapeutics.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a pivotal role in immune signalling and cytokine regulation, making it a compelling target for the treatment of inflammatory and autoimmune diseases. We initiated a drug discovery campaign based on the -diphenylpyrimidine-2,4-diamine (DPDA) scaffold, employing an integrated strategy that combined structure-based design, three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, and biochemical evaluation. This approach emphasised the optimisation of membrane permeability by controlling the 1-octanol/water partition coefficient (Log), while also enforcing configurational constraints to enhance IRAK4-specific binding.

Transformation of Pyridines into 2D and 3D Fused Bicyclic Heterocycles.

Skeletal editing of heteroarenes in complex molecules represents a transformative synthetic strategy that transcends the limitations of conventional peripheral functionalization, enabling the profound structural diversification of molecular frameworks. Here, we demonstrate a powerful metal-free approach for converting pyridines into planar (2D) and three-dimensional (3D) fused bicyclic heterocycles through a precisely orchestrated process of nucleophilic addition, 6π-electrocyclic ring opening/ring closure, and fused ring formation. This methodology exploits the unique reactivity of -pyridinium salts with hydrazine nucleophiles, accommodating diverse functional groups in a sequential one-pot protocol.

Photocatalytic 1,3-oxyheteroarylation of aryl cyclopropanes with azine -oxides.

Cyclopropanes, valuable C3 building blocks in organic synthesis, possess high strain energy and inherent stability. We present an efficient, environmentally benign 1,3-oxyheteroarylation of aryl cyclopropanes using azine -oxides as bifunctional reagents under visible light irradiation. This metal-free method yields β-pyridyl ketones under mild conditions.

Reductive deaminative cross-coupling of alkyl bistriflimides enabled by electrocatalysis.

We present a versatile nickel-electrocatalytic deaminative cross-coupling platform for the efficient construction of C(sp)-C(sp) and C(sp)-C(sp) bonds from readily available alkyl bistriflimides. This methodology involves the assembly of two leaving groups on alkyl amines to form alkyl bistriflimides, followed by their effective coupling with a wide range of alkyl halides, alkyl pseudohalides, aryl halides, and alkenyl halides under electrochemical reductive conditions. Moreover, the successful application of electrochemical reductive relay cross-coupling and transition metal-free cross-electrophile coupling further demonstrates the versatility of alkyl bistriflimides as valuable building blocks in organic synthesis.

Divergent Enantioselective Access to Diverse Chiral Compounds from Bicyclo[1.1.0]butanes and α,β-Unsaturated Ketones under Catalyst Control.

Achieving structural and stereogenic diversity from the same starting materials remains a fundamental challenge in organic synthesis, requiring precise control over the selectivity. Here, we report divergent catalytic methods that selectively yield either cycloaddition or addition/elimination products from bicyclo[1.1.

Harnessing the potential of acyl triazoles in bifunctional cobalt-catalyzed radical cross-coupling reactions.

Persistent radicals facilitate numerous selective radical coupling reactions. Here, we have identified acyl triazole as a new and versatile moiety for generating persistent radical intermediates through single-electron transfer processes. The efficient generation of these persistent radicals is facilitated by the formation of substrate-coordinated cobalt complexes, which subsequently engage in radical cross-coupling reactions.

Traceless Nucleophile Strategy for C5-Selective C-H Sulfonylation of Pyridines.

The functionalization of pyridines is crucial for the rapid construction and derivatization of agrochemicals, pharmaceuticals, and materials. Conventional functionalization approaches have primarily focused on the ortho- and para-positions, while achieving precise meta-selective functionalization, particularly at the C5 position in substituted pyridines, remains a formidable challenge due to the intrinsic electronic properties of pyridines. Herein, we present a new strategy for meta- and C5-selective C-H sulfonylation of N-amidopyridinium salts, which employs a transient enamine-type intermediate generated through a nucleophilic addition to N-amidopyridinium salts.

Insight into C4 Selectivity in the Light-Driven C-H Fluoroalkylation of Pyridines and Quinolines.

Given the prevalence of pyridine motifs in FDA-approved drugs, selective fluoroalkylation of pyridines and quinolines is essential for preparing diverse bioisosteres. However, challenges are often faced with conventional Minisci reactions in achieving precise regioselectivity owing to competing reaction sites of pyridine and the limited availability of fluoroalkyl radical sources. Herein, we present a light-driven, C4-selective fluoroalkylation of azines utilizing N-aminopyridinium salts and readily available sulfinates.

1,3-Difunctionalization of [1.1.1]propellane through iron-hydride catalyzed hydropyridylation.

Current methodologies for the functionalization of [1.1.1]propellane primarily focus on achieving 1, 3-difunctionalized bicyclo[1.

Nickel/photoredox-catalyzed three-component silylacylation of acrylates chlorine photoelimination.

The extensive utility of organosilicon compounds across a wide range of disciplines has sparked significant interest in their efficient synthesis. Although catalytic 1,2-silyldifunctionalization of alkenes provides a promising method for the assembly of intricate organosilicon frameworks with atom and step economy, its advancement is hindered by the requirement of an external hydrogen atom transfer (HAT) agent in photoredox catalysis. Herein, we disclose an efficient three-component silylacylation of α,β-unsaturated carbonyl compounds, leveraging a synergistic nickel/photoredox catalysis with various hydrosilanes and aroyl chlorides.

Concurrent Optimizations of Efficacy and Blood-Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson's Disease Therapeutics.

The elevated activity of leucine-rich repeat kinase 2 (LRRK2) is implicated in the pathogenesis of Parkinson's disease (PD). The quest for effective LRRK2 inhibitors has been impeded by the formidable challenge of crossing the blood-brain barrier (BBB). We leveraged structure-based de novo design and developed robust three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict BBB permeability, enhancing the likelihood of the inhibitor's brain accessibility.

Nickel-Catalyzed Hydrofluorination in Unactivated Alkenes: Regio- and Enantioselective C-F Bond Formation.

Catalytic formation of a regio- and enantioselective C-F bond chiral center from readily available alkenes is a crucial goal, yet it continues to pose significant challenges in organic synthesis. Here, we report the regioselective formation of C-F bonds facilitated by NiH catalysis and a coordination directing strategy that enables precise hydrofluorination of both terminal and internal alkenes. Notably, we have optimized this methodology to achieve high enantioselectivity in creating aliphatic C-F stereogenic centers especially with β,γ-alkenyl substrates, using a tailored chiral Bn-BOx ligand.

Unraveling the Potential of Vinyl Ether as an Ethylene Surrogate in Heteroarene C─H Functionalization via the Spin-Center Shift.

Despite the simplicity and abundance of ethylene, its practical application presents significant hurdles due to its nature as a highly flammable gas. Herein, a strategic use of easily handled vinyl ether is reported as a latent ethylene surrogate achieved via a spin-center shift (SCS) pathway, enabling the successful three-component reaction that bridges heteroarenes and various coupling partners, including sulfinates, thiols, and phosphine oxides. Through a photoredox catalytic process, α-oxy radicals are generated by combining various radicals with phenyl vinyl ether, which are subsequently added to N-heteroarenes.

NiH-catalyzed C-N bond formation: insights and advancements in hydroamination of unsaturated hydrocarbons.

The formation of C-N bonds is a fundamental aspect of organic synthesis, and hydroamination has emerged as a pivotal strategy for the synthesis of essential amine derivatives. In recent years, there has been a surge of interest in metal hydride-catalyzed hydroamination reactions of common alkenes and alkynes. This method avoids the need for stoichiometric organometallic reagents and overcomes problems associated with specific organometallic compounds that may impact functional group compatibility.

Photocatalytic Enantioselective Hydrosulfonylation of α,β-Unsaturated Carbonyls with Sulfonyl Chlorides.

This research explores the enantioselective hydrosulfonylation of various α,β-unsaturated carbonyl compounds via the use of visible light and redox-active chiral Ni-catalysis, facilitating the synthesis of enantioenriched α-chiral sulfones with remarkable enantioselectivity (exceeding 99 % ee). A significant challenge entails enhancing the reactivity between chiral metal-coordinated carbonyl compounds and moderate electrophilic sulfonyl radicals, aiming to minimize the background reactions. The success of our approach stems from two distinctive attributes: 1) the Cl-atom abstraction employed for sulfonyl radical generation from sulfonyl chlorides, and 2) the single-electron reduction to produce a key enolate radical Ni-complex.

Nucleophilic C4-selective (hetero) arylation of pyridines for facile synthesis of heterobiaryls.

The synthesis of heterobiaryl compounds holds significant value in organic chemistry due to their extensive range of applications. Herein, we report a highly efficient strategy for conducting C4-selective (hetero) arylation of pyridines using -aminopyridinium salts. The reaction proceeds readily at room temperature in the presence of a base, thus eliminating the requirement for catalysts or oxidants.

Regio- and Enantioselective Catalytic δ-C-H Amidation of Dioxazolones Enabled by Open-Shell Copper-Nitrenoid Transfer.

Controlling regio- and enantioselectivity in C-H functionalization reactions is of paramount importance due to their versatile synthetic utilities. Herein, we describe a new approach for the asymmetric δ-C(sp)-H amidation catalysis of dioxazolones using a Cu(I) precursor with a chiral bisoxazoline ligand to access six-membered lactams with high to excellent regio- and enantioselectivity (up to >19:1 rr and >99:1 er). Combined experimental and computational mechanistic studies unveiled that the open-shell character of the postulated Cu-nitrenoids enables the regioselective hydrogen atom abstraction and subsequent enantio-determining radical rebound of the resulting carbon radical intermediates.

Energy-transfer-induced [3+2] cycloadditions of N-N pyridinium ylides.

Photocycloaddition is a powerful reaction to enable the conversion of alkenes into high-value synthetic materials that are normally difficult to obtain under thermal conditions. Lactams and pyridines, both prominent in pharmaceutical applications, currently lack effective synthetic strategies to combine them within a single molecular structure. Here we describe an efficient approach to diastereoselective pyridyl lactamization via a photoinduced [3+2] cycloaddition, based on the unique triplet-state reactivity of N-N pyridinium ylides in the presence of a photosensitizer.

Unlocking the Potential of β-Fragmentation of Aminophosphoranyl Radicals for Sulfonyl Radical Reactions.

Exploiting β-scission in aminophosphoranyl radicals for radical-mediated transformations has been a longstanding challenge. In this study, we investigated the untapped potential of β-fragmentation in aminophosphoranyl radicals by leveraging the unique properties of the P-N bond and the substituents of P(III) reagents. Our approach carefully considers factors such as cone angle and electronic properties of phosphine and employs density functional theory (DFT) calculations to probe structural and molecular orbital influence.

Photoinduced Electron Transfer from Xanthates to Acyl Azoliums: Divergent Ketone Synthesis via N-Heterocyclic Carbene Catalysis.

Considering the prevalence of alcohols and carboxylic acids, their fragment cross-coupling reactions could hold significant implications in organic synthesis. Herein, we report a versatile method for synthesizing a diverse range of ketones from alcohols and carboxylic acid derivatives via N-heterocyclic carbene (NHC) catalysis. Mechanistic investigations revealed that photoexcited xanthates and acyl azoliums undergo single electron transfer (SET) under photocatalyst-free conditions, generating NHC-derived ketyl radicals and alkyl radicals.

Penile length and circumference: are they related to nose size?

Background: We investigated the relationship between the size of the penis and that of the nose.

Methods: We retrospectively analyzed 1,160 patients whose nose and penis sizes were measured. These participants were selected from a subset of 1,531 patients who visited the Dr.

Nickel-Catalyzed Kinetic Resolution of Racemic Unactivated Alkenes via Enantio-, Diastereo-, and Regioselective Hydroamination.

Kinetic resolution is a powerful strategy for the isolation of enantioenriched compounds from racemic mixtures, and the development of selective catalytic processes is an active area of research. Here, we present a nickel-catalyzed kinetic resolution of racemic α-substituted unconjugated carbonyl alkenes via the enantio-, diastereo-, and regioselective hydroamination. This protocol affords both chiral α-substituted butenamides and syn-β -amino acid derivatives with high enantiomeric purity (up to 99 % ee) and selectivity factor up to >684.

Deconstructive Pyridylation of Unstrained Cyclic Amines through a One-Pot Umpolung Approach.

A one-pot umpolung method for the ring-opening pyridylation of unstrained cyclic amines was developed using -amidopyridinium salts. This process involves the formation of electron donor-acceptor complexes between bromide and -amidopyridinium salts, ultimately leading to the functionalization of pyridines. This protocol is compatible with a range of 5- or 6-membered cyclic amines and pyridines, thereby providing a powerful synthon for preparing C4-functionalized pyridines under visible-light conditions in the absence of an external photocatalyst.