Synthesis of Sulfoxides by Palladium-Catalyzed Arylation of Sulfenate Anions with Aryl Thianthrenium Salts.

A novel and highly efficient Pd-catalyzed arylation of sulfenate anions with aryl thianthrenium salts is demonstrated. This procedure provides a practical protocol to synthesize various diaryl and alkyl aryl sulfoxides in moderate-to-good yields. The new approach shows mild reaction conditions, broad substrate scope, and good functional group tolerance.

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction.

An efficient protocol for the synthesis of polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates was developed by a three-component reaction. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile afforded polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates in high yields and with high diastereoselectivity. The reaction was finished by in situ generation of activated 5-(alkylimino)cyclopenta-1,3-dienes from addition of alkyl isocyanide to two molecules of but-2-ynedioates and sequential formal [3 + 2] cycloaddition reaction with 5,6-unsubstituted 1,4-dihydropyridine.

Construction of Diverse Fused Chromene Frameworks via Isocyanide-Based Three-Component Reaction.

A convenient synthetic protocol for diverse fused chromenes was successfully developed by a three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates, and various cyclic 1,3-dipolarophiles containing o-hydroxyphenyl group. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates, and 3-(o-hydroxyarylidene)indolin-2-ones in tetrahydrofuran at 60 °C resulted in unique functionalized spiro[cyclobuta[c]chromene-1,3'-indolines] in good yields and with high diastereoselectivity. However, the similar three-component reaction with 2-(5-halo-2-hydroxyarylidene)indolin-2-ones afforded unexpected chain products in satisfactory yields. In addition, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates, and 2-(o-hydroxyarylidene)-1,3-indanediones in tetrahydrofuran at 60 °C resulted in complex indeno[2',1':5,6]pyrano[3,4-c]chromene derivatives in high yields and with high diastereoselectivity.

Synthesis of Spiro[indoline-pyridine]-dicarboxylates and Substituted Alkylidene Oxindoles by Azomethine Ylides and MBH Carbonates of Isatins.

We have developed an efficient protocol for the synthesis of spiro[indoline-pyridine]dicarboxylates and substituted alkylidene oxindoles through [3 + 3] cycloaddition and Michael addition individually by azomethine ylides and various MBH carbonates of isatins. The selective generation of cyclic products and chain products was achieved by changing the substituents at the 3-position of the oxindoles. The features of this method include convenient catalysts, mild reaction conditions, and broad substrate scopes.

Enantioselective Synthesis of Isoindolinone by Palladium-Catalyzed Aminoalkynylation of O-Phenyl Hydroxamic Ethers with Alkynes.

A highly efficient palladium-catalyzed asymmetric tandem aza-Heck/Sonogashira coupling reaction of O-phenyl hydroxamic ethers with terminal alkynes is described. This protocol enables versatile access to challenging chiral isoindolinone derivatives bearing a quaternary stereogenic center. The palladium-catalyzed aminoalkynylation reaction shows broad functional group tolerance and allows the straightforward preparation of isoindolinones with high efficiency and excellent enantioselectivity under mild conditions. DFT calculations were performed to disclose the reaction mechanism and the origins of the enantioselectivity.

Synthesis of Bis-Heterocycles Bearing Methyleneindole Motifs by Pd-Catalyzed Domino Reaction.

A highly robust, general, and practically simple palladium-catalyzed domino bicyclization strategy is presented to synthesize nitrogen-containing bis-heterocycles bearing methylene indole motifs from alkyne-tethered carbamoyl chlorides and ß,γ- or γ,δ-unsaturated hydrazones. The salient features of this transformation include broad substrate scope, good functional group tolerance, ease for scale-up, and convenient conversion.

Sequential mediating role of digital participation and health lifestyle in the relation-ship between socioeconomic status and depression of older adults / 北京大学学报(医学版)

Objective:To explore the potential mechanisms of the relationship between socioeconomic status(SES)and depression of Chinese older adults through the mediating role of digital participation and health lifestyle.Methods:Using the nationally representative data from the China Family Panel Studies in 2020,4 846 participants aged 60 years and older were analyzed in our study.We explored the potential mechanisms of the relationship between SES and depression of Chinese older adults in the digital era through a chain multiple mediating effects model.The KHB(The Karlson,Holm,and Breen)method was used to analyze the mediating role of digital participation and health lifestyle and the propor-tion of mediating effect between the two was also calculated.A series of robustness tests were further con-ducted and the fit of the model was checked by structural equation modeling.Results:The mean age of the 4 846 older adults included in this study was(68.20±5.07)years,48.06％of whom were female and 51.94％were male.The KHB results showed that both digital participation and health lifestyle could mediate the relationship between SES and depression of older adults(P＜0.000 1)and the mediating role of health lifestyle accounted for a greater proportion than digital participation.And our study mainly found three potential pathways of SES and depression of older adults,including:(1)SES → digital par-ticipation → health lifestyle → depression,(2)SES → health lifestyle → depression,and(3)SES →depression.Structural equation modeling tests proved the overall fit of the model in this study.Conclu-sion:Our findings showed that in the digital age,in addition to the direct relationship between SES and depression of older adults,and the health lifestyle as a mediator between the relationship,there is also a sequential mediating role of digital participation and health lifestyle to reduce the risk of depression.The findings suggest that we should pay more attention to the probability of the digital divide exacerbating health inequalities and socioeconomic inequalities accumulation in the digital age and promote the co-progress of digital literacy and health literacy among older adults.

Mechanism of Rhei Radix et Rhizoma-Coptidis Rhizoma Improving Liver Insulin Resistance in db/db Mice by Regulating AMPK/ULK1/Beclin1 Pathway / 中国实验方剂学杂志

ObjectiveThis study aims to examine the effect of Rhei Radix et Rhizoma-Coptidis Rhizoma on reducing insulin resistance in db/db mice by regulating the adenylate activated protein kinase （AMPK）/UNC-51-like kinase 1 （ULK1）/key molecule of autophagy， benzyl chloride 1 （Beclin1） pathway and elucidate the underlying mechanism. MethodSixty 6-week-old male db/db mice were studied. They were randomly divided into the model group， metformin group （0.26 g·kg-1）， and low-， middle-， and high-dose groups （2.25， 4.5， 9 g·kg-1） of Rhei Radix et Rhizoma-Coptidis Rhizoma. A blank group of db/m mice of the same age was set， with 12 mice in each group. After eight weeks of continuous intragastric administration， the blank group and model group received distilled water intragastrically once a day. The survival status of the mice was observed， and fasting blood glucose （FBG） was measured using a Roche blood glucose device. Fasting serum insulin （FINS） was measured using an enzyme-linked immunosorbent assay， and the insulin resistance index （HOMA-IR） was calculated. Hematoxylin-eosin （HE） staining was performed to observe the pathological changes in the liver of the mice. The protein expression levels of AMPK， Beclin1， autophagy associated protein 5 （Atg5）， and p62 in liver tissue were determined by using Western blot. The protein expression levels of autophagy associated protein 1 light chain 3B （LC3B） and ULK1 in liver tissue were determined using immunofluorescence. Real-time fluorescence quantitative PCR （Real-time PCR） was used to measure mRNA expression levels of AMPK， Beclin1， Atg5， ULK1， and p62. ResultCompared with the blank group， the model group exhibited a significant increase in body mass （P<0.01）. Additionally， the levels of FBG， FINS， and HOMA-IR significantly changed （P<0.01）. The structure of liver cells was disordered. The protein expression levels of AMPK， Beclin1， and Atg5 in liver tissue were significantly decreased （P<0.01）， while the expression level of p62 protein was significantly increased （P<0.01）. The expression levels of mRNA and proteins were consistent. Compared with the model group， the body mass of the metformin group and high and medium-dose groups of Rhei Radix et Rhizoma-Coptidis Rhizoma was significantly decreased （P<0.05）. FBG， FINS， and HOMA-IR were significantly decreased （P<0.05，P<0.01）. After treatment， the liver structure damage in each group was alleviated to varying degrees. The protein expressions of AMPK， Beclin1， Atg5， LC3B， and ULK1 were increased （P<0.05，P<0.01）， while the protein expression of p62 was decreased （P<0.01）. The expression levels of mRNA and proteins were generally consistent. ConclusionThe combination of Rhei Radix et Rhizoma-Coptidis Rhizoma can effectively improve liver insulin resistance， regulate the AMPK autophagy signaling pathway， alleviate insulin resistance in db/db mice， and effectively prevent the occurrence and development of type 2 diabetes.

Direct Regioselective Reductive Allylation of Imines: Application to Synthesis of Oxazines with Halogenated Reagent.

Oxazines are an important class of compounds in oxazine ligands and medical chemistry. Here, we describe a linear-selective allylation of imines with allyl electrophiles via cross-electrophile coupling reactions, followed by cyclization with halogenated reagents, providing a new strategy to afford oxazine compounds with a tetrasubstituted carbon center. Mechanistic studies indicate that α-amino carbanion, generated by successive single-electron transfer processes, is a key intermediate for nucleophile attack on π-allylpalladium in photoredox/palladium catalysis.

Regioselective and Diastereoselective Construction of Diverse Dispiro-Indanone-Fluorenone-Oxindole Motifs.

A convenient synthetic protocol for regioselective and diastereoselective construction of complex dispiro-indanone-fluorenone-oxindole motifs was developed by the base-promoted annulation reaction of bindone and MBH carbonates of isatins by adjusting reaction conditions. DABCO promoted the annulation reaction of bindone and MBH carbonates of isatins in DCM at room temperature, affording dispiro[indene-2,4'-fluorene-1',3″-indoline] derivatives in good yields and with high diastereoselectivity. Triethylamine promoted the annulation reaction of two molecular 1,3-indanediones and MBH esters of isatins in ethanol at elevated temperature and selectively gave dispiro[indene-2,4'-fluorene-3',3″-indolines] in moderate yields. However, triethylamine promoted the annulation reaction of excess 1,3-indanediones and MBH esters of isatins in refluxing ethanol, affording dispiro[indene-2,4'-fluorene-3',3″-indolines] with the Z-isomer as the major product and the E-isomer as the minor product.

Construction of diverse spirooxindoles via a domino reaction of arylamines, but-2-ynedioates and 3-hydroxy-3-(indol-3-yl)indolin-2-ones.

An iodine-promoted domino reaction of arylamines/benzylamines, dialkyl but-2-ynedioates and 3-hydroxy-3-(indol-3-yl)indolin-2-ones showed very interesting molecular diversity. The reaction in acetonitrile at 65 °C in the presence of 30% mmol I2 resulted in spiro[indoline-3,1'-pyrido[4,3-b]indoles] in satisfactory yields. When anilines without para-substituents were used in the reaction, a direct substitution of the hydroxyl group to 2-(phenylamino)maleate at the para-position of aniline gave chain products in good yields. Additionally, similar reactions with benzylamines not only gave spiro[indoline-3,1'-pyrido[4,3-b]indoles], but also afforded spiro[indoline-3,1'-pyrano[4,3-b]indol]-2-ones in lower yields. A plausible domino annulation mechanism was rationally proposed for the formation of different kinds of polycyclic compounds.

Construction of Unique Spiro[dibenzo[a,f]azulene-6,2'-indenes] via Unprecedented Annulation of ortho-C-H Bond of Benzylidene Group.

The domino reaction of alkyl and aryl isocyanides with two molecules of 2-arylidene-1,3-indanediones in acetonitrile at 80 °C resulted in unique functionalized spiro[dibenzo[a,f]azulene-6,2'-indenes] in good yields, in which the two 2-arylidene-1,3-indanediones acted as different building blocks to construct the polycyclic system. More importantly, the unprecedented anticipation of the ortho-position of benzylidene group to form a novel dibenzo[a,f]azulene ring through a formal [5 + 2] cycloaddition process was first observed. On the other hand, DABCO-promoted reaction of the isocyanides with two molecules of 2-arylidene-1,3-indanediones in acetonitrile at 80 °C afforded functionalized spiro[cyclopenta[a]-indene-2,2'-indene] derivatives.

Novel biotin-linked amphiphilic calix[4]arene-based supramolecular micelles as doxorubicin carriers for boosted anticancer activity.

Supramolecular carrier-mediated chemotherapy is a highly attractive strategy for targeted drug delivery. In this study, four novel biotin-linked calix[4]arenes BPCA1-BPCA4 have been rationally designed to construct nano-complex with doxorubicin. The in vitro and in vivo assessments reveal that BPCA4-DOX with excellent stability are capable of affording significantly superior anti-tumor activity and lower side effects.

Selective construction of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] via three-component reaction.

A convenient synthetic procedure for the construction of novel dispirooxindole motifs was successfully developed by base-promoted three-component reaction of ammonium acetate, isatins and in situ-generated 3-isatyl-1,4-dicarbonyl compounds. The piperidine-promoted three-component reaction of ammonium acetate, isatins and the in situ-generated dimedone adducts of 3-ethoxycarbonylmethyleneoxindoles afforded mutlifunctionalized dispiro[indoline-3,2'-quinoline-3',3''-indoline] derivatives in good yields and with high diastereoselectivity. On the other hand, a similar reaction of the dimedone adducts of 3-phenacylideneoxindoles afforded unique dispiro[indoline-3,2'-pyrrole-3',3''-indoline] derivatives with a cyclohexanedione substituent. A plausible reaction mechanism is proposed to explain the formation of the different spirooxindoles.

Emissive Nanoparticles from Co-assembly of Metallatetragon and Amphiphilic Tetraphenylethylene for Cancer Theranostics.

Platinum(II)-based metallacycles/cages have obtained tremendous attention due to their fascinating topology and wide range of applications, such as fluorescent materials, cell imaging, and tumor treatment. In this work, a metallatetragon (1) was constructed from 4-(4-(1,2,2-triphenylvinyl)phenyl)pyridine (2) and 90° cis-Pt(II) (Pt) in acetone through the strategy called "coordination driven self-assembly". Interestingly, through co-assembly of 1 and poly(ethylene glycol)-modified tetraphenylethylene (TPE-PEG22), fluorescent nanotheranostics, which could generate singlet oxygen (1O2) under the NIR irradiation and release Pt drugs under a low-pH microenvironment, were prepared successfully. The obtained theranostics could realize living cell imaging and synergistic chemo-photodynamic therapy in vitro and in vivo.

Tandem ring-opening and formal [3 + 2] cycloaddition of furo[2,3-d]pyrimidine-2,4-diones.

The base promoted tandem annulation reaction of activated cyclic 1,3-dipolarophiles such as 2-arylidene-1,3-indanediones, 2-(o-hydroxybenzylidene)-1,3-indanediones and 3-methyleneoxindoles with functionalized furo[2,3-d]pyrimidine-2,4-diones was systematically investigated. This reaction provided efficient synthetic protocols for complex dispiro/dispiro fused tricyclic compounds including dispiro[indene-2,3'-cyclopentane-1',5''-pyrimidines], dispiro[indoline-3,3'-cyclopentane-1',5''-pyrimidines] and spiro[cyclopenta[c]indeno[1,2-b]chromene-3,5'-pyrimidines] in good yields and with high diastereoselectivity. The reaction was believed to proceed via sequential ring-opening of the furyl ring, formal [3 + 2] cycloaddition and annulation of the o-hydroxyphenyl group.

Convenient Synthetic Protocols for Diverse Functionalized Dihydrobenzofuran-Fused Spiro-indanedione-oxindole Scaffolds.

Diverse functionalized dihydrobenzofuran spiro-indanedione-oxindole scaffolds were conveniently synthesized by base-promoted cyclization reaction of Morita-Baylis-Hillman (MBH) carbonates of isatins and 2-(o-hydroxybenzylidene)-1,3-indanediones. The two diastereomeric dispiro[indene-2,1'-cyclopenta[b]benzofuran-2',3″'-indolines] could be selectively synthesized by using DABCO or DMAP as a base promoter. More importantly, DABCO or DMAP facilitated the annulation reaction of MBH formates of isatins and 2-(o-hydroxybenzylidene)-1,3-indanediones selectively, resulting in spiro[cyclopropa[c]chromene-1,2'-indene]-1',3'-diones or dispiro[indene-2,1'-cyclopenta[b]benzofuran-2',3″'-indolines]. Additionally, a similar reaction with MBH maleimides of isatins afforded dispiro[indene-2,5'-benzofuro[2',3':1,5]cyclopenta[1,2-c]pyrrole-4',3″'-indolines] in high yields and with high diastereoselectivity.

The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition.

The three-component reaction of isoquinolines, dialkyl acetylenedicarboxylates, and 5,6-unsubstituted 1,4-dihydropyridines in acetonitrile at room temperature afforded functionalized isoquinolino[1,2-f][1,6]naphthyridines in good yields and with high diastereoselectivity. More importantly, the formal [2 + 2] cycloaddition reaction of dialkyl acetylenedicarboxylates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile gave unique 2-azabicyclo[4.2.0]octa-3,7-dienes as major products and 1,3a,4,6a-tetrahydrocyclopenta[b]pyrroles as minor products via further rearrangement.

Pd/Cu-catalyzed cascade Heck-type reactions of alkenyl halides with terminal alkynes toward substituted pyrrolidine analogues.

Pd/Cu-catalyzed cascade Heck-type reactions of alkenyl halides with terminal alkynes have been developed. This research provides an efficient atom-economical approach to access a variety of highly substituted pyrrolidines in moderate to good yields. This protocol features readily available substrates, broad substrate scope, easy scale-up, high selectivities and versatile transformations.

Synthesis of Multisubstituted Allenes by Palladium-Catalyzed Carboetherification of ß,γ-Unsaturated Ketoximes with Propargylic Acetates.

A highly efficient Pd-catalyzed carboetherification reaction of ß,γ-unsaturated ketoximes with propargylic acetates is demonstrated. This method provides a practical protocol for accessing the incorporation of an allene moiety into 3,5-disubstituted and 3,5,5-trisubstituted isoxazolines. The salient features of this transformation include a broad substrate scope, good functional group tolerance, an easy scale-up, versatile transformations, and applications in the late-stage modification of drugs.