Carbenoid-involved reactions integrated with scaffold-based screening generates a Nav1.7 inhibitor.

The discovery of selective Nav1.7 inhibitors is a promising approach for developing anti-nociceptive drugs. In this study, we present a novel oxindole-based readily accessible library (OREAL), which is characterized by readily accessibility, unique chemical space, ideal drug-like properties, and structural diversity.

Asymmetric Carbene Transfer: Enhancing Chemical Diversity for Drug Discovery.

The quest to explore chemical space is vital for identifying novel disease targets, impacting both the effectiveness and safety profile of therapeutic agents. The tangible chemical space, currently estimated at a conservative 10 synthesized compounds, pales in comparison to the theoretically conceivable diversity of 10 molecules. To bridge this vast gap, organic chemists are spearheading innovative methodologies that promise to broaden this limited chemical diversity.

Asymmetric Carbene-Alkyne Metathesis-Mediated Cascade: Synthesis of Benzoxazine Polychiral Polyheterocycles and Discovery of a Novel Pain Blocker.

This study introduces a novel approach for synthesizing Benzoxazine-centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene-alkyne metathesis-triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis-mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co-catalysis, ensuring precise stereo control as validated by X-ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo- and enantioselectivities, creating a unique library of BPCPHCs.

Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain.

Chronic pain is a growing global health problem affecting at least 10% of the world's population. However, current chronic pain treatments are inadequate. Voltage-gated sodium channels (Navs) play a pivotal role in regulating neuronal excitability and pain signal transmission and thus are main targets for nonopioid painkiller development, especially those preferentially expressed in dorsal root ganglial (DRG) neurons, such as Nav1.

Bifunctionality of dirhodium tetracarboxylates in metallaphotocatalysis.

Metallaphotocatalysis has been recognized as a pivotal catalysis enabling new reactivities. Traditional metallaphotocatalysis often requires two or more separate catalysts and exhibits flaw in cost and substrate-tolerance, thus representing an await-to-solve issue in catalysis. We herein realize metallaphotocatalysis with a bifunctional dirhodium tetracarboxylate ([Rh]) alone.

Silver-catalyzed pyrazole migration and cycloaddition reaction of diazo pyrazoleamides with ketimines.

A novel pyrazole migration and cycloaddition process is well developed AgOTf-catalyzed annulation reactions of α-diazo pyrazoleamides with ketimines. This protocol discloses efficient access to synthesize a series of spirooxindole-based β-lactams in good to excellent yields and the diastereoselectivity is switchable by tuning the substituents on the α-diazo pyrazoleamides.

Discovery and Development of a Selective Inhibitor of the ER Resident Chaperone Grp78.

A recent study illustrated that a fluorescence polarization assay can be used to identify substrate-competitive Hsp70 inhibitors that can be isoform-selective. Herein, we use that assay in a moderate-throughput screen and report the discovery of a druglike amino-acid-based inhibitor with reasonable specificity for the endoplasmic reticular Hsp70, Grp78. Using traditional medicinal chemistry approaches, the potency and selectivity were further optimized through structure-activity relationship (SAR) studies in parallel assays for six of the human Hsp70 isoforms.

Rh(PhCOO)(OAc)/Chiral Phosphoric Acid Cocatalyzed -Alkyl Imines-Involved Multicomponent Reactions Yielding -(Anthrancen-9-ylmethyl) Isoserines as Drug Intermediates.

-(Anthrancen-9-ylmethyl) isoserines are useful drug intermediates but short for efficient synthesis. We herein report the synthesis of -(anthrancen-9-ylmethyl) isoserines via a Rh(PhCOO)(OAc) and chiral phosphoric acid (CPA) synergistically catalyzed multicomponent reaction (MCR) of -alkyl imines, alcohols, and diazoesters. The method representing the first example of -alkyl imines-involved MCR is featured by high atom-economy, high diastereo- and enantioselectivities, and broad substrate scope.

Discovery of Novel Benzo[4,5]imidazo[1,2-]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A Adenosine Receptor Antagonists.

The blockade of A adenosine receptor (AAR) activates immunostimulatory response through regulating signaling in tumor microenvironment. Thus, AAR has been proposed as a promising target for cancer immunotherapy. In this work, we designed a new series of benzo[4,5]imidazo[1,2-]pyrazin-1-amine derivatives bearing an amide substitution at 3-position to obtain potent antitumor antagonist .

Discovery of an eIF4A Inhibitor with a Novel Mechanism of Action.

Increased protein synthesis is a requirement for malignant growth, and as a result, translation has become a pharmaceutical target for cancer. The initiation of cap-dependent translation is enzymatically driven by the eukaryotic initiation factor (eIF)4A, an ATP-powered DEAD-box RNA-helicase that unwinds the messenger RNA secondary structure upstream of the start codon, enabling translation of downstream genes. A screen for inhibitors of eIF4A ATPase activity produced an intriguing hit that, surprisingly, was not ATP-competitive.

Brønsted Acid Catalyzed Enantioselective Assembly of Spirochroman-3,3-oxindoles.

An enantioselective cyclization of diazoindolinones with -hydroxymethyl chalcones has been established by a cooperative dirhodium complex and chiral phosphonic acid catalysis under mild conditions. This reaction is the first example of catalytic asymmetric intramolecular Michael-type trapping of oxonium ylide enabled by phosphoric acid through a dual H-bonding activation model, which provides an efficient access to the chiral spirochroman-3,3-oxindoles, with vicinal quaternary and tertiary stereocenters, in good to excellent yields and enantioselectivities.

A one-step, atom economical synthesis of thieno[2,3-]pyrimidin-4-amine derivatives via a four-component reaction.

A NaHPO-catalyzed four-component reaction between a ketone, malononitrile, S and formamide has been realized for the first time. This reaction provides a concise approach to thieno[2,3-]pyrimidin-4-amines, previously requiring 5 steps. The utility of this reaction was validated by preparing a multi-targeted kinase inhibitor and an inhibitor of the NRF2 pathway with excellent atom- and step-economy.

Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes.

Post-translational modifications (PTMs) regulate enzyme structure and function to expand the functional proteome. Many of these PTMs are derived from cellular metabolites and serve as feedback and feedforward mechanisms of regulation. We have identified a PTM that is derived from the glycolytic by-product, methylglyoxal.

One-Step Synthesis of Thieno[2,3-]pyrimidin-4(3)-ones via a Catalytic Four-Component Reaction of Ketones, Ethyl Cyanoacetate, S and Formamide.

Thieno[2,3-]pyrimidin-4(3)-ones are important pharmacophores that previously required a three step synthesis with two chromatography steps. We herein report a green approach to the synthesis of this pharmacologically important class of compounds via a catalytic four-component reaction using a ketone, ethyl cyanoacetate, S and formamide. The reported reaction is characterized by step economy, reduced catalyst loading and easy purification.

A sustainable catalytic enantioselective synthesis of norstatine derivatives.

Norstatine derivatives are of important value in pharmaceutical science. However, their catalytic asymmetric synthesis is rare. We developed a sustainable method via chiral phosphoric acid (CPA)-[Rh(OAc)] co-catalyzed multi-component reactions (MCR) of diazoacetates with alcohol/water and imines.

Catalytic asymmetric synthesis of 2,5-dihydrofurans using synergistic bifunctional Ag catalysis.

We report a bifunctional Ag catalyst promoted intramolecular capture of oxonium ylides with alkynes for the enantioselective synthesis of 2,5-dihydrofurans. This represents unprecedented synergistic catalysis of a bifunctional Ag catalyst. Mechanistic studies revealed that [(R)-3,5-DM-BINAP](AgSbF) (9) is likely to be the active catalytic species and that the reaction involves second order kinetics with respect to 9, suggesting that two molecules of 9 are involved in the intramolecular trapping of a Ag-associated oxonium ylide with a Ag-activated alkyne.

An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol.

A library of natural products and their derivatives was screened for inhibition of protein tyrosine phosphatase (PTP) 1B, which is a validated drug target for the treatment of obesity and type II diabetes. Of those active in the preliminary assay, the most promising was compound containing a novel pyrrolopyrazoloisoquinolone scaffold derived by treating radicicol () with hydrazine. This nitrogen-atom augmented radicicol derivative was found to be PTP1B selective relative to other highly homologous nonreceptor PTPs.

A high throughput substrate binding assay reveals hexachlorophene as an inhibitor of the ER-resident HSP70 chaperone GRP78.

Glucose-regulated protein 78 (GRP78) is the ER resident 70 kDa heat shock protein 70 (HSP70) and has been hypothesized to be a therapeutic target for various forms of cancer due to its role in mitigating proteotoxic stress in the ER, its elevated expression in some cancers, and the correlation between high levels for GRP78 and a poor prognosis. Herein we report the development and use of a high throughput fluorescence polarization-based peptide binding assay as an initial step toward the discovery and development of GRP78 inhibitors. This assay was used in a pilot screen to discover the anti-infective agent, hexachlorophene, as an inhibitor of GRP78.

Diastereoselective synthesis of isochromans via the Cu(ii)-catalysed intramolecular Michael-type trapping of oxonium ylides.

A highly diastereoselective approach for the rapid construction of an isochroman skeleton was achieved by the copper(ii)-catalyzed transformation of alcohol-tethered enones and diazo compounds. This transformation was proposed to proceed through the intramolecular Michael-type trapping of an in situ generated oxonium ylide intermediate. The copper(ii) catalyst may play a dual role in catalyzing diazo decomposition as well as activating the enone unit.

An epigenetic modifier induces production of (10'S)-verruculide B, an inhibitor of protein tyrosine phosphatases by Phoma sp. nov. LG0217, a fungal endophyte of Parkinsonia microphylla.

Incorporation of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), to a culture broth of the endophytic fungus Phoma sp. nov. LG0217 isolated from Parkinsonia microphylla changed its metabolite profile and resulted in the production of (10'S)-verruculide B (1), vermistatin (2) and dihydrovermistatin (3).

Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin.

The ATPase p97 is a ubiquitin targeted segregase that uses the energy of ATP binding and hydrolysis to extract ubiquitylated substrates from biological membranes, from other proteins, or from protein complexes to carry out myriad tasks in eukaryotes. Increased p97 activity has been linked to a poor prognosis in cancer patients, making p97 an anti-neoplastic target. In the present study, we show that dehydrocurvularin (DHC) and its chlorinated variants are covalent inhibitors of p97, interfering with its ATPase activity.

Pd(II)-catalyzed formal [4+1] cycloaddition reactions of diazoacetates and aryl propargyl alcohols to form 2,5-dihydrofurans.

A Pd(II)-catalyzed formal [4+1] cycloaddition of aryl diazoacetates and aryl propargyl alcohols is reported to afford 2,5-dihydrofuran derivatives as the dominant product over other traditional ones. The auto-tandem catalytic process is proposed to occur via Pd(II)-catalyzed intermolecular oxonium ylide formation and subsequent intramolecular trapping of the ylide with Pd(II)-activated alkynes.

Successively recycle waste as catalyst: a one-pot Wittig/1,4-reduction/Paal-Knorr sequence for modular synthesis of substituted furans.

A one-pot tandem Wittig/conjugate reduction/Paal-Knorr reaction is reported for the synthesis of di- or trisubstituted furans. This novel sequence first demonstrates the possibility of successively recycling waste from upstream steps to catalyze downstream reactions.

Ruthenium(II)/chiral Brønsted acid co-catalyzed enantioselective four-component reaction/cascade aza-Michael addition for efficient construction of 1,3,4-tetrasubstituted tetrahydroisoquinolines.

An elegant synergistic catalytic system comprising a ruthenium complex with a chiral Brønsted acid was developed for a four-component Mannich/cascade aza-Michael reaction. The ruthenium-associated ammonium ylides successfully trapped with in situ generated imines indicates a stepwise process of proton transfer in the ruthenium-catalyzed carbenoid N-H insertion reaction. The different decomposition abilities of various ruthenium complexes towards diazo compounds were well explained by the calculated thermodynamic data.