A novel small molecule NJH-13 induces pyroptosis via the Ca driven AKT-FOXO1-GSDME signaling pathway in NSCLC by targeting TRPV5.

Introduction: Pyroptosis represents a mode of programmed necrotic cell death (PCD), mediated by members of gasdermin family (GSDMs), such as GSDME. It is emerging as a promising approach for combating cancer. Notably, GSDME is the key modulator for the switch between apoptosis and pyroptosis in cells.

Cascade Annulation for Synthesizing Chromenopyrrolones from -Hydroxyphenyl Enaminones and 2-Halo--alkyloxyacetamides.

A cascade cyclization reaction comprising two halogenation reactions and a Michael addition was developed for the synthesis of chromeno[2,3-]pyrrole-3-ones . Additionally, another cascade cyclization reaction, which involves a halogenation reaction followed by two intramolecular Michael additions, was established for the synthesis of chromeno[2,3-]pyrrole-2-ones . Both types of compounds were synthesized from -hydroxyphenyl enaminones and 2-halo--alkyloxyacetamides through a process that facilitated the intramolecular formation of C-C, C-O, and C-N bonds to effectively establish two fused rings in a single operation.

Cascade [3 + 2]/[4 + 2] Cycloaddition of Enaminones with Vinylene Carbonate for the Synthesis of Functionalized Pyrrolo[2,1-]isoquinoline Derivatives.

We developed a protocol for the synthesis of functionalized pyrrolo[2,1-]isoquinoline derivatives (PIQDs) from enaminones using vinylene carbonate . This strategy involved [3 + 2] and [4 + 2] cycloadditions via heating a mixture of substrates with vinylene carbonate and DCE at 60 °C, catalyzed by [Cp*RhCl] and oxidized with Cu(OAc) and AgSbF promoted by NaOAc. As we increased the reaction temperature to 110 °C under the same conditions, we synthesized PIQDs through sequential C-H activation, alkene insertion, migratory insertion, C-N reductive elimination, β-O elimination, and finally dehydration.

Radical Cascade Reaction of Heterocyclic Ketene Aminals with Thiocyanates Promoted by Visible Light: Synthesis of Functionalized Fused 2-Iminothiazolines.

Herein, a visible-light-promoted radical cascade cyclization of heterocyclic ketene aminals (HKAs) and thiocyanates was developed to access functionalized fused 2-iminothiazolines. This novel cascade reaction can be realized under only visible-light irradiation without the help of external photocatalysts, oxidants, and additives. These multicomponent cascade reactions demonstrate excellent selectivity for the -isomers and ensure the formation of the products only in their isomeric form.

Cycloaddition and Skeleton Rearrangement of Heterocyclic Ketene Aminals (HKAs) with 1-Diazonaphthalen-2(1)-ones for the Synthesis of Functionalized 1,2,3-Triazoles.

We developed a protocol for the synthesis of highly functionalized 5,6-dihydro-imidazo[1,2-][1,2,3]triazole derivatives - (DHITs) from 1-diazonaphthalen-2(1)-one derivatives with heterocyclic ketene aminals (HKAs). This strategy involved cycloaddition and skeletal rearrangement entailing the heating of a mixture of substrates with HKAs - and THF without any catalyst. As a result, a series of DHITs - were produced by cleaving one bond (1 C═N bond) and forming three bonds (1 N-N and 2 C-N bonds) in a single step.

Divergent Synthesis of 2-Chromonyl-3-hydrazono-chromones and 2-Alkoxy-3-hydrazono-chromones through Switchable Annulation Reactions of -Hydroxyphenylenaminones with Aryldiazonium Salts.

An unprecedented selective chromone annulation reaction controlled by solvent for the divergent synthesis of two types of 2,3-disubstituted chromone skeletons has been developed. A variety of 2-chromonyl-3-hydrazono-chromones and 2-alkoxy-3-hydrazono-chromones were constructed efficiently from readily available -hydroxyphenylenaminones (-HPEs) and aryldiazonium salts at room temperature. This strategy is highly chemoselective and features mild reaction conditions, broad substrate scope, broad functional group tolerance, easy gram-scale preparation, and simple filtration to obtain the pure products without tedious column chromatography.

Rh(III)-Catalyzed [3 + 2] Annulation/Pinacol Rearrangement Reaction of Enaminones with Iodonium Ylides: Direct Synthesis of 2-Spirocyclo-pyrrol-3-ones.

A novel Rh(III)-catalyzed cascade alkenyl C-H activation/[3 + 2] annulation/pinacol rearrangement reaction of enaminones with iodonium ylides has been developed. This methodology provides a new and straightforward synthetic strategy to afford highly functionalized 2-spirocyclo-pyrrol-3-ones in satisfactory yield from readily available starting materials under mild conditions. Moreover, gram-scale reactions and further derivatization experiments are implemented to demonstrate the potential utility of this developed approach.

Hydroxyl-Directed Rh(III)-Catalyzed C-H Functionalization: Access to Benzo[]chromenes.

A cascade oxidative annulation reaction of heterocyclic ketene aminals (HKAs) with internal alkynes catalyzed by [Cp*RhCl] and oxidized by Cu(OAc)·HO was developed to efficiently synthesize highly functionalized benzo[]chromene derivatives in good to excellent yields. The reaction proceeded by the sequential cleavage of C(sp)-H/O-H and C(sp)-H/C(sp)-H bonds. These multicomponent cascade reactions were highly regioselective.

Cu-Catalyzed Decarboxylative Annulation of -Phenylglycines with Maleimides: Synthesis of 1-Pyrrolo[3,4-]quinoline-1,3(2)-diones.

A novel protocol for the construction of functionalized 1-pyrrolo[3,4-]quinoline-1,3(2)-diones (PQLs, ) from -phenylglycines and maleimides was developed. The cascade reaction was enabled by heating a mixture of the two substrates in the presence of di--butyl peroxide (DTBP) as an oxidant and anhydrous CuBr as a catalyst in chlorobenzene. Consequently, a diverse series of PQLs were synthesized in moderate-to-good yields (43-73%).

Synthesis of benzo[][1,5]diazocin-6(5)-one derivatives the Cu-catalysed oxidative cyclization of 2-aryl-1-indoles with 1,1-enediamines.

A novel protocol for the synthesis of highly functionalized benzo[][1,5]diazocin-6(5)-one derivatives (BDCOs, 4 and 5) from 2-aryl-1-indoles and 1,1-enediamines was developed a complex cascade of reactions including regioselective free radical oxidation, the 1,2-addition of imine, imine-enamine tautomerization, intramolecular cyclization, and ring expansion. The cascade reaction was enabled by refluxing a mixture of two substrates in the presence of di--butyl peroxide (DTBP) as an oxidant and anhydrous CuI as a catalyst in toluene under argon protection. Consequently, a series of BDCOs (4 and 5) were synthesized with high regioselectivity in good yield.

Cu-Catalyzed Oxidative [3 + 2] Annulation of 2-(Pyridine-2-yl)acetates with Maleimides: Synthesis of 1-Pyrrolo[3,4-]indolizine-1,3-diones.

A novel protocol for the construction of highly functionalized indolizine derivatives, that is, 1-pyrrolo[3,4-]indolizine-1,3-diones (PIZDOs, ) from 2-(pyridine-2-yl)acetates and maleimides via a regioselective oxidative [3 + 2] annulation was developed. The cascade oxidative reaction was enabled by heating a mixture of the two substrates in the presence of AgCO as an oxidant and Cu(OAc)·HO as a catalyst in chlorobenzene. Consequently, a series of PIZDOs were synthesized with high regioselectivity in moderate yields.

Multicomponent Cascade Reaction of 3-Cyanochromones: Highly Site-Selective Synthesis of 2-(1-Imidazol-1-yl)-4-chromen-4-one Derivatives.

A method for the synthesis of 2-(1-imidazol-1-yl)-4-chromen-4-one derivatives (IMCMs) from 3-cyanochromones and α-isocyanoacetates via a one-pot cascade reaction involving a 1,2-addition, Michael reaction, ring-closing, tautomerization, ring-opening, and [3 + 2] cyclization was enabled by refluxing a mixture of the starting materials in THF in the presence of AgCO as a catalyst. The cascade reaction resulted in the formation of five bonds and the cleavage of two bonds, including a triple bond, in one pot. This protocol enabled not only the synthesis of functionalized imidazoles (i.

Cu-Catalyzed decarboxylative annulation of -substituted glycines with 3-formylchromones: synthesis of functionalized chromeno[2,3-]pyrrol-4(1)-ones.

A novel protocol was developed for preparing functionalized chromeno[2,3]pyrrol-4(1)-ones 3 (CMPOs) from 3-formylchromones with -substituted glycine derivatives. The method entailed decarboxylative annulation of the acyl group of 3-formylchromones by simply heating a mixture of substrates 1-2 and toluene oxidized by 2-di--butyl peroxide (DTBP) and catalyzed by CuBr. As a result, a series of CMPOs 3 were produced a cascade reaction.

An Environmentally Benign Multicomponent Cascade Reaction of 3-Formylchromones, 2-Naphthols, and Heterocyclic Ketal Aminals: Site-Selective Synthesis of Functionalized Morphan Derivatives.

A novel protocol has been developed for the preparation of highly functionalized 2-azabicyclo[3.3.1]nonane (morphan) derivatives by the interesting three-component cascade reaction of 3-formylchromones, 2-naphthol, and heterocyclic ketal aminals (HKAs) in the ionic liquid [BMIM]PF promoted by the organic base EtN.

Multicomponent Cascade Reaction of 3-Formylchromones: Highly Selective Synthesis of Functionalized 9-Azabicyclo[3.3.1]nonane Derivatives.

A novel protocol for the preparation of functionalized 9-azabicyclo[3.3.1]nonane (ABCN) derivatives from 3-formylchromones, enaminones, and heterocyclic ketene aminals (HKAs) through an unprecedented cascade reaction has been developed by simply refluxing the mixture of the substrates -.

Multi-component cascade reaction of 3-formylchromones: highly selective synthesis of 4,5-dihydro-[4,5'-bipyrimidin]-6(1)-one derivatives.

A novel protocol for the construction of highly functionalized bipyrimidine derivatives 4 and 5 from 3-formyl-chromones, ethyl 2-(pyridine-2-yl)acetate derivatives, and amidine hydrochlorides via an interesting and considerably complex multi-component cascade reaction was developed. The cascade reaction was manifested by refluxing a mixture of the three substrates in acetonitrile or DMF along with Cs2CO3. A series of 4,5-dihydro-[4,5'-bipyrimidin]-6(1H)-ones (DBPMOs) 4 was constructed regioselectively in suitable to excellent yields.

An Environmentally Benign Cascade Reaction of 1,1-Enediamines (EDAMs) for Site-Selective Synthesis of Highly Functionalized 2,10-Dihydro-1-imidazo[1',2':1,6]pyrido[2,3-]indoles and Pyrroles.

A novel protocol for the synthesis of pyrido[2,3-]indoles (α-carbolines, ) from ()-3-(2-oxo-2-phenylethylidene) indolin-2-one derivatives and 1,1-enediamine (EDAM) via an unexpected cascade reaction in ethanol was developed. Pyrido[2,3-]indole derivatives were obtained by the same reaction, albeit by stirring the mixture for a longer period of time (about 48 h). As a result, two kinds of functionalized α-carbolines and were synthesized by the facile reaction of the ()-3-(2-oxo-2-phenylethylidene)indolin-2-one derivatives and 2-(nitromethylene)imidazolidine under basic conditions (CsCO) in ethanol.

Cu(II)/Iodine(III) Oxide Dimerization of Heterocyclic Ketene Aminals: Tandem TEMPO Oxidation for the Highly Selective Synthesis of Functionalized 2-Pyrrolo[1,2-]imidazol-7(3)-ones.

This study aimed to develop a novel protocol for the synthesis of 2-pyrrolo[1,2-]imidazol-7(3)-ones (PIDOs) from heterocyclic ketene aminals (HKAs) through an unprecedented cascade reaction by refluxing. Consequently, a series of PIDOs was produced through an amazing oxidative dimerization, followed by sequential cleavage of the C-N and C-C bonds in dimeric HKAs. This formation of PIDOs was accompanied by the formation and cleavage of many bonds.

Cascade reaction of isatins with nitro-substituted enamines: highly selective synthesis of functionalized (Z)-3-(1-(arylamino)-2-oxoarylidene)indolin-2-ones.

A novel protocol for the construction of functionalized (Z)-3-(1(-arylamino)-2-oxoarylidene)indolin-2-ones (AOIDOs) from isatins 1 with nitro-substituted enamines 2via an unprecedented cascade reaction catalyzed by sulfamic acid is developed. The AOIDOs are prepared by simply refluxing a mixture of isatins with a wide variety of nitro-substituted enamines. Interestingly, the AOIDOs 3 were formed through the novel cascade reaction involving a unique cleavage of two C-N bonds of the nitro-substituted enamines.

Multicomponent Cascade Reaction by Metal-Free Aerobic Oxidation for Synthesis of Highly Functionalized 2-Amino-4-coumarinyl-5-arylpyrroles.

A novel approach has been constructed for the synthesis of two types of 2-amino-4-coumarinyl-5-arylpyrroles (ACAPs, and ) through a cascade reaction and a metal-free catalyzed aerobic oxidation reaction of arylglyoxal monohydrates , 1,1-enediamines (EDAMs) and , and 4-hydroxy-2-chromen-2-ones via multicomponent reactions to produce the target compounds with good to excellent yields. Specifically, hydroxyl-substituted 2-amino-4-coumarinyl-5-arylpyrroles, that is, 2-amino-4-coumarinyl-5-aryl-6-hydroxylpyrroles (ACAHPs) , were obtained by metal-free aerobic oxidation in 1,4-dioxane at simple reflux for approximately 10 h. As a result, ACAHPs have been produced without metal catalysts or traditional oxidizing agents.

Multicomponent Tether Catalysis Synthesis of Highly Functionalized 4-(Pyridin-2-ylmethyl)-2-aminopyrroles via Cascade Reaction Is Accompanied by Decarboxylation.

A multicomponent tether catalysis protocol for the synthesis of 4-(pyridin-2-ylmethyl)-2-aminopyrroles (PMAPs) was constructed by simply refluxing a mixture of ethyl 2-(pyridin-2-yl)acetates and various types of arylglyoxal monohydrates and different heterocyclic ketene aminals in EtOH solvent. Based on this reaction, a series of highly functionalized PMAPs were obtained through a novel cascade reaction accompanied by a decarboxylation mechanism. As a result, the pyridin-2-ylmethyl was successfully introduced in the target compounds, and a library of PMAPs were easily constructed using the cascade reaction described in this study.

Cascade Reaction of 1,1-Enediamines with 2-Benzylidene-1-indene-1,3(2)-diones: Selective Synthesis of Indenodihydropyridine and Indenopyridine Compounds.

A concise and environmentally friendly route for the synthesis of diverse indenodihydropyridines () via a cascade reaction of 1,1-eneamines () with benzylidene-1-indene-1,3(2)-diones (BIDs) () in ethanol media was developed. The targeted compounds were efficiently obtained by only filtration without any further post-treatment. In the one-step cascade reaction, C-C and C-N bonds were constructed.

Three-Component Cascade Reaction of 1,1-Enediamines, ,-Dimethylformamide Dimethyl Acetal, and 1,3-Dicarbonyl Compounds: Selective Synthesis of Diverse 2-Aminopyridine Derivatives.

A novel approach has been developed for the synthesis of three kinds of highly functionalized 2-aminopyridine derivatives (APDs) through a three-component reaction of 1,1-enediamines (EDAMs) , ,-dimethylformamide dimethyl acetal (DMF-DMA) , and 1,3-dicarbonyl compounds - via a base-promoted cascade reaction, producing the desired products in good to excellent yields. This method represents a route to obtain a novel class of APDs in a concise, rapid, and practical manner. This approach is particularly attractive because of the following features: low cost, mild temperature, atom economy, high yields, and potential biological activity of the product.

Cascade Reaction of Morita-Baylis-Hillman Acetates with 1,1-Enediamines or Heterocyclic Ketene Aminals: Synthesis of Highly Functionalized 2-Aminopyrroles.

A new strategy for the construction of two kinds of fully substituted pyrroles, including 2-aminopyrroles and bicyclic pyrroles from Morita-Baylis-Hillman (MBH) acetates with 1,1-enediamines (EDAMs), or heterocyclic ketene aminals (HKAs) via base-promoted tandem Michael addition, elimination, and aromatization sequence has been developed, affording the expected products in moderate to excellent yields. This methodology is a highly efficient, concise way to access 2-aminopyrroles or bicyclic pyrroles with diversity in molecular structures from accessible building blocks under moderate reaction conditions.

Highly Selective Synthesis of 2-Amino-4,6-diarylpyridine Derivatives by the Cascade Reaction of 1,1-Enediamines with α,β-Unsaturated Ketones.

A general and concise method was developed for the synthesis of 2-amino-4,6-diarylpyridine derivatives 4-6 through the cascade reaction, which includes Michael addition, intramolecular cyclization, aromatization, and/or loss of HNO, of different types of α,β-unsaturated ketones 1 and 1,1-enediamines 2 and 3 in 1,4-dioxane promoted by the base CsCO or piperidine. This method is suitable for the efficient parallel synthesis of pyridines. A library of highly functional 2-amino-4,6-diarylpyridine derivatives was easily constructed using the cascade reaction described in this study.