SOX9 promotes hypoxic pulmonary hypertension through stabilization of DPP4 in pulmonary artery smooth muscle cells.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling (PVR), primarily due to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aimed to investigate the role and molecular mechanism of SOX9 in hypoxic PH in rats. The findings revealed that SOX9 was upregulated in the pulmonary arteries and PASMCs of hypoxia-exposed rats. SOX9 knockdown inhibited hypoxia-induced proliferation and migration of PASMCs, reduced PVR, and subsequently alleviated hypoxia-induced PH in rats, suggesting that SOX9 plays a critical role in PH. Further investigation demonstrated that SOX9 interacted with DPP4, preventing its ubiquitin degradation in hypoxia-exposed PASMCs. DPP4 knockdown inhibited hypoxia-induced PASMC proliferation and migration, and administration of the DPP4 inhibitor sitagliptin (5 mg/kg) significantly reduced PVR and alleviated hypoxia-induced PH in rats, indicating that SOX9 contributes to PH by stabilizing DPP4. The results also showed that hypoxia induced YAP1 expression and dephosphorylation, leading to YAP1 nuclear localization. YAP1 knockdown promoted the degradation of HIF-1α in hypoxia-exposed PASMCs and inhibited hypoxia-induced proliferation and migration of PASMCs. Additionally, HIF-1α, as a transcription factor, promoted SOX9 expression by binding to the SOX9 promoter in hypoxia-exposed PASMCs. In conclusion, hypoxia promotes the proliferation and migration of PASMCs through the regulation of the YAP1/HIF-1α/SOX9/DPP4 signaling pathway, leading to PH in rats. These findings suggest that SOX9 may serve as a potential prognostic marker and therapeutic target for PH.

Eu(OTf)3 -Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo-[1.1.0]butanes with Nitrones: Access to Polysubstituted 2-Oxa-3-azabicyclo[3.1.1]heptanes.

Herein, we have synthesized multifunctionalized 2-oxa-3-azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta-substituted arenes, through Eu(OTf)3 -catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine.

Linkage Chemistry of S(VI) Fluorides.

Sulfur(VI)-fluoride exchange linkage as a next generation of click chemistry was introduced by Sharpless and coworkers in 2014. Distinguished from CuAAC, the SuFEx reaction proceeds under metal-free conditions, and the reactive linkers are variable, enabling access to a diverse class of linkage compounds. Therein, a series of SuFEx linkers emerged has been widely prevalent in diverse fields. The SVI -F bond in comparison to SVI -Cl bond features excellent stability and chemoselectivity. The linkage chemistry primarily involves the formation of S-O and S-N bonds via commercially available phenols and amines, yet less study on C-SuFEx linkage. This review will focus on three types of linkage for SuFEx linkers comprising S-O, S-N, and S-C bonds, and we hope to provide a practical guidance for SuFEx linkage chemistry.

Enantioselective Synthesis of Spiroketals and Spiroaminals via Gold and Iridium Sequential Catalysis.

The enantioselective cascade reaction between racemic 2-(1-hydroxyallyl)phenols and alkynols/alkynamides was realized by using a gold and iridium sequential catalytic system. In this procedure, the in situ generated exocyclic vinyl ethers or enamides undergo the asymmetric allylation/spiroketalization with π-ally-Ir amphiphilic species, which provides an efficient and straightforward access to spiroketals and spiroaminals with excellent enantioselectivities. Moreover, racemic 2-(1-hydroxyallyl)anilines were also suitable in this reaction along with a kinetic resolution process, affording enantioenriched spiroaminals and 2-(1-hydroxyallyl)anilines in good yields. The synthetic utility of this method has been demonstrated by efficient enantioselective synthesis of the analogue of Paecilospirone.

The Linkage of Sulfonimidoyl Fluorides and Unactivated Alkenes via Hydrosulfonimidoylation.

Sulfur(VI) fluoride cleavage and exchanging linkage, a new generation of linkage chemistry, exhibits enormous potential for combining a range of functional molecules in an increasing number of fields. Herein, we established a metal-free linkage of unactivated alkenes and sulfonimidoyl fluorides via hydrosulfonimidoylation to construct sulfoximines within minutes. An intermolecular hydride transfer process is the key step, and it occurs via overlap of the LUMO in the sulfonimidoyl cation and HOMO in the unactivated alkene, which was confirmed via control experiments with deuterated compounds. DFT calculations further demonstrated the concerted process involving formation of the S-C(sp3 ) bond and hydride transfer. Remarkably, abundant natural products and pharmaceuticals with multiple heteroatoms and sensitive functional groups have been subjected to the current linkage reaction to achieve various sulfoximine linkages, furnishing the basis for drug discovery and drug conjugation.

Regio- and Enantioselective γ-Allylic Alkylation of In Situ-Generated Free Dienolates via Scandium/Iridium Dual Catalysis.

An unprecedented asymmetric γ-allylic alkylation of free dienolates via Sc/Ir dual catalysis is reported, which affords a range of synthetically versatile γ-allylic crotonaldehydes in high efficiency with excellent chemo-, regio-, and enantioselectivities. The dienolates bearing no essential auxiliary groups were generated in situ by scandium triflate-mediated Meinwald rearrangement of vinyloxiranes atom-economically. With the assistance of computational density functional theory calculations, a Sc/Ir bimetallic catalytic cycle was proposed to illustrate the reaction mechanism.

Diastereo- and Enantioselective Synthesis of Bisbenzannulated Spiroketals and Spiroaminals by Ir/Ag/Acid Ternary Catalysis.

We reported herein an iridium/silver/acid ternary catalytic system to access bisbenzannulated [6,6]-spiroketals in high efficiency with generally high diastereo- and enantioselectivities (up to >20 : 1 dr, >99 % ee). In this procedure, readily available o-alkynylacetophenones undergo cycloisomerization to generate isochromenes in situ that participate in stereoselective allylation/spiroketalization sequence with 2-(1-hydroxyallyl)phenols. Meanwhile, 2-(1-hydroxyallyl)anilines were also compatible in this cascade reaction, furnishing structurally novel bisbenzannulated [6,6]-spiroaminals with good diastereoselectivities (8 : 1-12 : 1 dr) and excellent enantioselectivities (98 %->99 % ee). Moreover, experimental studies and theoretical calculations were performed to illustrate the reaction mechanism and stereochemistry.

Recent advances in the treatment of systemic lupus erythematosus with belimumab in children. / è´åˆ©å°¤å•æŠ—ç”¨äºŽå„¿ç«¥ç³»ç»Ÿæ€§çº¢æ–‘ç‹¼ç–®çš„ç ”ç©¶è¿›å±•.

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs, and lupus nephritis (LN) is the most common renal complication of SLE. Belimumab is a fully humanized monoclonal antibody that can reduce the number of B cells, thereby reducing the formation of autoantibodies. Belimumab can improve SLE response index and SLE disease activity score and delay the progression of LN in both adults and children and thus plays an important role in the treatment of SLE and LN. This article reviews related research reports of belimumab used in the treatment of children and adults with SLE in China and overseas and analyzes the efficacy and safety of belimumab in pediatric patients, in order to provide a reference for the clinical application of belimumab in children with SLE.

Palladium-Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio-, Diastereo-, and Enantioselective Construction of Benzofuro[3,2-b]azepine Skeletons.

The palladium-catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran-derived azadienes furnishes chiral benzofuro[3,2-b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 d.r., >99 % ee). This catalytic asymmetric [4+3] cyclization of Pd-trimethylenemethane can enrich the arsenal of Pd-TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition-metal-catalyzed asymmetric [4+3] cyclization.

Synergistic Catalysis for Asymmetric [3 + 2] Cycloadditions of 2-Indolylmethanols with α,ß-Unsaturated Aldehydes.

A catalytic asymmetric [3 + 2] cycloaddition of 2-indolylmethanols with α,ß-unsaturated aldehydes was developed for the first time. This transformation was achieved by a synergistic catalytic system consisting of a palladium complex, a Brønsted acid, and a chiral secondary amine to synthesize biologically active cyclopenta[b]indole derivatives with excellent diastereo- and enantioselectivities (up to >20:1 dr, up to 99% ee).

Enantioselective Rhodium-Catalyzed Addition of Arylboroxines to N-Unprotected Ketimines: Efficient Synthesis of Cipargamin.

Highly enantioselective rhodium-catalyzed addition of arylboroxines to N-unprotected ketimines is realized for the first time by employing chiral BIBOP-type ligands with a Rh loading as low as 1 mol %. A range of chiral α-trifluoromethyl-α,α-diaryl α-tertiary amines or 3-amino-3-aryloxindoles were formed with excellent ee values and yields by employing either WingPhos or PFBO-BIBOP as the ligand. The method has enabled an efficient enantioselective synthesis of cipargamin.

Synthesis of Polysubstituted 3-Aminothiophenes from Thioamides and Allenes via Tandem Thio-Michael Addition/Oxidative Annulation and 1,2-Sulfur Migration.

A facile synthetic method for the construction of 3-aminothiophenes from readily available thioamides and alllenes in the presence of a TBAI/TBHP catalyst system was developed. This protocol represents an efficient and straightforward way to access highly functionalized thiophenes in moderate to excellent yields under mild conditions, via a tandem thio-Michael addition, oxidative annulation, and 1,2-sulfur migration pathway.

Asymmetric Synthesis of cis-3,4-Dihydrocoumarins via [4 + 2] Cycloadditions Catalyzed by Amidine Derivatives.

A highly efficient chiral amidine derivative-catalyzed tandem Michael addition/lactonization of carboxylic acids and o-quinone methides (o-QMs) has been developed that enables the asymmetric synthesis of cis-3,4-dihydrocoumarins bearing contiguous tertiary stereogenic centers in high yields with excellent stereoselectivities.

Unexpected O-H Insertion of Rhodium-Azavinylcarbenes with N-Acylhydrazones: Divergent Synthesis of 3,6-Disubstituted- and 3,5,6-Trisubstituted-1,2,4-Triazines.

A practical and efficient method for divergent synthesis of 3,6-disubstituted- and 3,5,6-trisubstituted-1,2,4-triazines via unexpected rhodium-catalyzed O-H insertion/rearrangement/conditions-controlled intramolecular cyclization and oxidation reaction under mild conditions has been developed. Notably, it is the first example for the synthesis of 1,2,4-triazines with different substituted-patterns via a common intermediate with excellent chemoselectivities by the reaction of N-acylhydrazones as aze-[3C] or [4C] synthons with N-sulfonyl-1,2,3-triazoles as aze-[2C] synthons. Furthermore, this method allows direct access to di(het)aryl ketone frameworks containing 1,2,4-triazine moiety for the first time, serving as a versatile building block for the synthesis of other useful heterocyclic skeletons, such as pyridine or pyridazinone-fused triazine in excellent yields.

Stereoselective Synthesis of Pyrrolidines Containing a 3-Fluoro Quaternary Stereocenter via Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition.

A highly efficient asymmetric 1,3-dipolar cycloaddition of azomethine ylides to ß,ß-disubstituted ß-fluoroacrylates catalyzed by a chiral N,O-ligand/Cu(CH3CN)4BF4 system is reported, affording chiral densely substituted pyrrolidines with four contiguous stereocenters, including one fluorinated quaternary stereocenter at the 3-position, in good to excellent yields (up to 99%), with excellent levels of diastereo- and enantioselectivities (dr >20:1; ee up to 99%).

α,ß-Double Electrophilic Addition of Allene-1,3-Dicarboxylic Esters for the Construction of Polysubstituted Furans by KI/tert-Butyl Hydroperoxide (TBHP)-Promoted Oxidative Annulation.

An unprecedented KI/tert-butyl hydroperoxide promoted tandem Michael addition/oxidative annulation of allene-1,3-dicarboxylic esters and 1,3-dicarbonyl compounds has been developed. This procedure provides a new, facile, and transition-metal-free synthetic approach to afford polysubstituted furans in moderate to excellent yields (up to 93 %). This method first establishes a α,ß-double electrophilic reaction mode of allene-1,3-dicarboxylic esters to form 1,3-dicarbonyl compounds.

Regioselective Iodine-Catalyzed Construction of Polysubstituted Pyrroles from Allenes and Enamines.

A novel I2-catalyzed tandem Michael addition/oxidative annulation of allenes and enamines for the construction of polysubstituted pyrroles has been developed. This protocol represents an efficient and highly regioselective way to access functionalized pyrroles in moderate to excellent yields under mild conditions.

Highly Enantioselective Rhodium-Catalyzed Addition of Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of Escitalopram.

Highly enantioselective additions of arylboroxines to simple aryl ketones have been achieved for the first time with a Rh/(R,R,R,R)-WingPhos catalyst, thus providing a range of chiral diaryl alkyl carbinols with excellent ee values and yields. (R,R,R,R)-WingPhos has been proven to be crucial for the high reactivity and enantioselectivity. The method has enabled a new, concise, and enantioselective synthesis of the antidepressant drug escitalopram.

Diastereodivergent Asymmetric Michael Addition of Cyclic Azomethine Ylides to Nitroalkenes: Direct Approach for the Synthesis of 1,7-Diazaspiro[4.4]nonane Diastereoisomers.

The first highly diastereoselective and enantioselective catalytic asymmetric Michael addition of cyclic azomethine ylides with nitroalkenes have been developed to diastereodivergently generate either the syn or anti adducts by employing N,O-ligand/Cu(OAc)2 and N,P-ligand/Cu(OAc)2 catalytic systems. Both catalytic systems exhibit broad substrate applicability to afford the corresponding Michael adducts in good to excellent yields, with excellent levels of diastereo- (up to 99:1 diastereomeric ratio) and enantioselectivities (up to >99% enantiomeric excess). Importantly, the chiral 1,7-diazaspiro[4.4]nonane diastereomer derivatives can be easily obtained in good yields through facile NaBH4 reduction of the Michael adducts.

Chiral N,O-Ligand/[Cu(OAc)2 ]-Catalyzed Asymmetric Construction of 4-Aminopyrrolidine Derivatives by 1,3-Dipolar Cycloaddition of Azomethine Ylides with α-Phthalimidoacrylates.

A protocol to access useful 4-aminopyrrolidine-2,4-dicarboxylate derivatives has been developed. A variety of chiral N,O-ligands derived from 2,3-dihydroimidazo[1,2-a]pyridine motifs have been evaluated in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7-Cl-DHIPOH provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction. The reaction tolerates both ß-substituted and ß-unsubstituted α-phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4-aminopyrrolidine cycloadducts with excellent diastereo- (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH4 reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.