Cu2O-catalyzed cascade phosphinylation/cyclization of 2'-aminochalcones for the synthesis of hemi-indigo derivatives.

A Cu2O-catalyzed cascade phosphinylation/cyclization reaction of 2'-aminochalcones and diphenylphosphine oxides to produce hemi-indigo derivatives has been developed. This strategy facilitates the sequential formation of a C-P bonds and a C-N bond in a single reaction step. Notably, the approach features one-pot operation, an earth-abundant copper catalyst, readily available starting materials, a broad substrate scope and high compatibility with functional groups, providing 33 compounds in acceptable yields.

Palladium-Catalyzed (3 + 2) Annulation of Aromatic Acids by C(sp3)-H Olefination and Decarboxylative Cross-Coupling Reaction.

A palladium-catalyzed (3 + 2) annulation of 2-methylbenzoic acid with maleimide using Ac-Leu-OH as a powerful ligand has been reported. Through a site-selective γ-C(sp3)-H olefination reaction and a sequential decarboxylative cross-coupling reaction, a five-membered cyclic ring was obtained as the final product. This novel reaction features great site selectivity and reactivity to generate various cyclic products in moderate to good yields.

Synthesis of ß-Hydroxysulfides via Multi-Component Cascade Hydroxysulfenylation of Styrenes with NH4 SCN and Water under Transition-metal-free Conditions.

Transition-mental-free multi-component hydroxysulfenylation of styrenes with NH4 SCN and water to from ß-hydroxysulfides is established. The reaction mechanism proceeded via a domino reaction after a radical addition to 2-phenylimidazo[1,2-a]pyridines. This approach features a wide substrate scope and functional group compatibility, providing 34 compounds in acceptable yields.

The [3 + 2] Cycloaddition Reaction of N-Substituted Pyrrole-2-carboxaldehydes with Arylalkenes under Copper Catalysis: Access to Dihydropyrrolizine Skeletons.

Herein, we found that treating N-substituted pyrrole-2-carboxaldehydes with arylalkenes in DMF in N2 at 120 °C could afford pyrrolidine scaffolds with an up to 85% yield. This approach has several remarkable features, such as atom and step economy, readily accessible raw materials, and easy-to-operate manner, providing a simple and efficient method for constructing complicated bicyclic pyrroles. Additionally, we have successfully synthesized 28 target compounds, which further demonstrates its practicality and wide applicability.

Synthesis of pyrazoles from sulfonyl hydrazone and benzyl acrylate under transition-metal-free conditions.

Pyrazoles as an important class of heterocyclic compounds, are widely found in pharmaceuticals and bioactive natural products. Herein we report a [3 + 2] cycloaddition reaction for the synthesis of a series of pyrazoles, with the yield up to 77%. This approach exhibits many notable features, such as convenient operating conditions, excellent functional group compatibility and readily accessible raw materials, providing an alternative route for the construction of pyrazole derivatives.

C-H Borylation of Benzophenones Using Hydrazone as the Traceless Directing Group.

C-H borylation is one of the powerful C-H bond functionalization reactions. In this context, a metal-free C-H borylation of benzophenones using hydrazone as the traceless directing group has been reported. The dibromoboron intermediates can be obtained in excellent yields, and the corresponding arylboronic esters are generated in moderate to excellent yields. Furthermore, the borylated compounds can be transformed in a one-pot method, avoiding the loss of overall yield caused by the separation of the arylboronic esters.

Palladium-Catalyzed Tandem Diolefination Reaction of Benzaldehyde Enabled by a Remote Directing Group.

A tandem diolefination reaction of benzaldehyde has been developed via Pd-catalyzed ß-C(sp2)-H olefination of the benzene ring and tandem C(sp2)-H olefination of acrylate. 2-((Aminooxy)methyl)benzonitrile was involved with the benzaldehyde substrate as a remote directing group to realize the C-H bond activation. The control experiments proved that the presence of a remote cyano group is essential for this novel diolefination reaction.

Tandem C-C/C-N Bond Formation via Rh(III)-Catalyzed α-Fluoroalkenylation and Sequential Annulation of 2-Arylquinazolinones and gem-Difluorostyrenes.

An efficient method of Rh(III)-catalyzed coupling reaction between 2-arylquinazolinones and gem-difluorostyrenes has been developed. In this work, two diverse structures of monofluoroalkenes and isoindolo[1,2-b]quinazolin-10(12H)-one derivatives were respectively synthesized by controlling the amount of additives (Ca(OH)2 and AgNTf2) to achieve controlled stepwise breaking of the C-F bonds of gem-difluorostyrenes. This reaction has the characteristics of a wide range of substrates and good functional group tolerance. Meanwhile, several control experiments were conducted and a plausible mechanism was proposed.

Corrigendum: Preclinical profiles of SKB264, a novel anti-TROP2 antibody conjugated to topoisomerase inhibitor, demonstrated promising antitumor efficacy compared to IMMU-132.

[This corrects the article DOI: 10.3389/fonc.2022.951589.].

Adamantane-1-Carbonyl-Directed C-H Borylation and Hydroxylation of Benzenethiols.

A novel route has been described for C-H borylation and hydroxylation of benzenethiols directed by adamantane-1-carbonyl using BBr3. The protocol generates corresponding arylboronic esters and phenols in moderate to excellent yields under metal-free conditions. In addition, the borylated product can be transformed and the directing group can be removed in good yields, which will facilitate the synthesis of structurally diverse benzenethiols.

Ligand-Enabled Sequential C(sp3)-H and C(sp2)-H Diolefination Reaction via Palladium Catalyst.

Palladium-catalyzed sequential C(sp3)-H and C(sp2)-H bond diolefination reaction of o-toluidine has been realized for the first time using acetyl-protected aminoethyl phenyl thioether ligands. This novel reaction allows for preparation of the conjugated diene structure via an immediate second olefination on the basis of the first C(sp3)-H olefination in one pot. Various triflyl-protected anilines and acrylates were used as coupling partners elegantly. Furthermore, the unpurified diolefination products can be easily converted to tetrahydroquinoline derivatives.

Metal-Free Boron-Mediated ortho-C-H Hydroxylation of N-Benzyl-3,4,5-tribromopyrazoles.

A novel route has been reported for C-H hydroxylation of benzyl compounds directed by a 3,4,5-tribromopyrazole auxiliary via boronation/oxidation using BBr3 and NaBO3·4H2O. The strategy exhibits outstanding site selectivity and affords the corresponding phenols in moderate to excellent yields under metal-free conditions. Besides, this protocol can be achieved in one pot, which is highly promising as a practical method for use in a multistep organic synthetic process.

Rhodium(III)-catalyzed cascade C-H functionalization/annulation of sulfoximines with iodonium ylides for the synthesis of cyclohexanone-1,2-benzothiazines.

A highly efficient Rh(III)-catalyzed cascade C-H activation/annulation of sulfoximines with iodonium ylides under metal-oxidant-free conditions has been reported. The fused cyclohexanone-1,2-benzothiazine scaffold is readily achieved with a one-pot process in this reaction. This protocol exhibits good functional group tolerance and moderate to excellent yields. Additionally, the olefination of the target product illustrates the promising usefulness of this strategy.

Ligand-Enabled C-H Olefination and Lactonization of Benzoic Acids and Phenylacetic Acids via Palladium Catalyst.

A novel ligand propan-2-one O-(p-tolylcarbamoyl) oxime (L7) has been developed to promote C(sp2)-H olefination of benzoic acids and phenylacetic acids via a palladium catalyst. With the subsequent lactonization of the olefinated products through 1,4-addition, highly monoselective cyclic lactone products of benzofuranones and benzopyrones were obtained in moderate to excellent yields. The DFT calculation demonstrated that the novel ligand propan-2-one O-(p-tolylcarbamoyl) oxime (L7) could improve the C-H activation reaction to give cyclic lactone products elegantly.

Xiaoyaosan ethyl acetate fraction alleviates depression-like behaviors in CUMS mice by promoting hippocampal neurogenesis via modulating the IGF-1Rß/PI3K/Akt signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyaosan (XYS), a representative and classic traditional Chinese medicine (TCM) prescription with function of dispersing stagnated liver and strengthening spleen, has been used for thousands of years to treat depression. XYS' anti-depression effect has been demonstrated both clinically and experimentally; however, the material basis for this effect has yet to be elucidated. AIM OF THE STUDY: This study aimed to evaluate the impact and underlying action mechanism of XYS' antidepressant active component (Xiaoyaosan ethyl acetate fraction, XYSEF) against chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice. MATERIALS AND METHODS: First, we established a behavioral despair depression mouse model to preliminarily determine the effective antidepressant dose of XYSEF. Then, we created a CUMS mouse model and used various classic behavioral tests, including SPT, ST, NFST, and TST, to assess XYSEF's antidepressant properties. IGF-1 levels in mouse serum and hippocampus were quantified using ELISA. The average optical density of Nissl bodies in the mouse hippocampal CA3 region was determined utilizing toluidine blue staining. Brdu and DCX expression in the hippocampal dentate gyrus (DG) was assayed using the immunofluorescence method. IGF-1Rß, PI3K, p-PI3K, Akt, p-Akt, Caspase-3, and cleaved Caspase-3 protein levels in the hippocampus were determined with Western blot. RESULTS: The behavioral despair mouse model findings showed that 9.1 and 40 g/kg of XYSEF both significantly shortened the immobility time of mice, suggesting that the effective dose range was 9.1-40 g/kg. Compared to the CUMS mouse model, XYSEF at 20 and 40 g/kg markedly increased the sucrose preference percentage in the SPT and grooming time in the ST, shortened the immobility time in the TST and the feeding latency in the NSFT, and reversed the downregulated IGF-1 content in mouse serum and hippocampus. In addition, XYSEF amplified the average optical density of Nissl bodies in the hippocampal CA3 region, promoted Brdu and DCX expression in DG, and diminished IGF-1Rß, p-PI3K/PI3K, p-Akt/Akt, and cleaved Caspase-3/Caspase-3 protein levels in the hippocampi of CUMS mice. CONCLUSION: XYSEF acted as an antidepressant in mice exhibiting CUMS-induced depression-like behaviors, possibly by promoting hippocampal neurogenesis, reducing neuronal apoptosis, and inhibiting the over-activation of the IGF-1Rß/PI3K/Akt pathway.

Preclinical profiles of SKB264, a novel anti-TROP2 antibody conjugated to topoisomerase inhibitor, demonstrated promising antitumor efficacy compared to IMMU-132.

Purpose: The aim of this study was to improve the intratumoral accumulation of an antibody-drug conjugate (ADC) and minimize its off-target toxicity, SKB264, a novel anti-trophoblast antigen 2 (TROP2) ADC that was developed using 2-methylsulfonyl pyrimidine as the linker to conjugate its payload (KL610023), a belotecan-derivative topoisomerase I inhibitor. The preclinical pharmacologic profiles of SKB264 were assessed in this study. Methods: The in vitro and in vivo pharmacologic profiles of SKB264, including efficacy, pharmacokinetics-pharmacodynamics (PK-PD), safety, and tissue distribution, were investigated using TROP2-positive cell lines, cell-derived xenograft (CDX), patient-derived xenograft (PDX) models, and cynomolgus monkeys. Moreover, some profiles were compared with IMMU-132. Results: In vitro, SKB264 and SKB264 monoclonal antibody (mAb) had similar internalization abilities and binding affinities to TROP2. After cellular internalization, KL610023 was released and inhibited tumor cell survival. In vivo, SKB264 significantly inhibited tumor growth in a dose-dependent manner in both CDX and PDX models. After SKB264 administration, the serum or plasma concentration/exposure of SKB264 (conjugated ADC, number of payload units ≥1), total antibody (Tab, unconjugated and conjugated mAb regardless of the number of the payload units), and KL610023 in cynomolgus monkeys increased proportionally with increasing dosage from 1 to 10 mg/kg. The linker stability of SKB264 was significantly enhanced as shown by prolonged payload half-life in vivo (SKB264 vs. IMMU-132, 56.3 h vs. 15.5 h). At the same dose, SKB264's exposure in tumor tissue was 4.6-fold higher than that of IMMU-132. Conclusions: Compared with IMMU-132, the longer half-life of SKB264 had a stronger targeting effect and better antitumor activity, suggesting the better therapeutic potential of SKB264 for treating TROP2-positive tumors.

Xiaoyao Pills Ameliorate Depression-like Behaviors and Oxidative Stress Induced by Olfactory Bulbectomy in Rats via the Activation of the PIK3CA-AKT1-NFE2L2/BDNF Signaling Pathway.

Numerous studies have revealed that oxidative stress is closely associated with the occurrence and development of depression. Xiaoyao Pills (XYW) are included in the Chinese Pharmacopoeia and are frequently used for treating anxiety and depression by smoothing the liver, strengthening the spleen, and nourishing the blood. However, the antidepressant effects of XYW have not yet been thoroughly investigated. The objective of our study was to investigate the antidepressant-like effects of XYW and the underlying molecular mechanism in the olfactory bulbectomized (OB) rat model of depression using the open field test (OFT), sucrose preference test (SPT), splash test (ST), and novelty suppressed feeding test (NSFT). Results showed that XYW (0.93 and 1.86 g·kg-1) significantly alleviated depression-like behaviors in rats, which was indicated by increased sucrose preference in the SPT, prolonged grooming time in the ST, decreased horizontal movement in the OFT, and shorter feeding latency in the NSFT. In addition, XYW treatment dramatically reversed the reduced activity of superoxide dismutase and the decreased level of glutathione, while also lowering levels of malondialdehyde, an inflammatory mediator (nitric oxide), and pro-inflammatory cytokines (interleukin-6 and 1ß) in the serum and cortex of OB rats. Mechanistically, XYW induced marked upregulation of mRNA and protein expression levels of NFE2L2, KEAP1, GPX3, HMOX1, SOD1, NQO1, OGG1, PIK3CA, p-AKT1/AKT1, NTRK2, and BDNF, and downregulation of ROS in the cortex and hippocampus via the activation of the NFE2L2/KEAP1, PIK3CA/AKT1, and NTRK2/BDNF pathways. These findings suggest that XYW exert antidepressant-like effects in OB rats with depression-like symptoms, and these effects are mediated by the alleviation of oxidative stress and the enhancement of neuroprotective effects through the activation of the PIK3CA-AKT1-NFE2L2/BDNF signaling pathways.

Palladium-Catalyzed ß-C(sp3)-H Arylation of Aliphatic Ketones Enabled by a Transient Directing Group.

The direct arylation of aliphatic ketones has been developed via Pd-catalyzed ß-C(sp3)-H bond functionalization with 2-(aminooxy)-N,N-dimethylacetamide as a novel transient directing group (TDG), which showed remarkable directing ability to generate arylated products in moderate to good yields. Furthermore, the reaction can tolerate abundant substrate of ketones and aryl iodides. This study expands the scope of applications for TDGs.

Metal-Free ortho-Selective C-H Borylation of 2-Phenylthiopyridines Using BBr3.

A novel route for ortho-selective C-H borylation of 2-phenylthiopyridines using BBr3 as the boron source under metal-free conditions has been reported. The reaction exhibited site exclusivity, and the synthesized aryl boronates were freely converted to various useful intermediates. Thus, this facile method would be beneficial to synthesize structurally diversified phenylthioethers derivatives and other materials containing boron-nitrogen coordination.

Polysaccharides from Laminaria japonica: an insight into the current research on structural features and biological properties.

Laminaria japonica, one of the most widespread seafood consumed in China and many other nations, has been traditionally utilized as an effective therapeutically active substance for treating weight loss, phlegm elimination, and detumescence for more than 2000 years. Numerous studies have found that the polysaccharides play an indispensable role in the nutritional and medicinal value of L. japonica. Water extraction and alcohol precipitation method is the most used method. Approximately 56 LJPs were successfully isolated and purified from L. japonica, whereas only few of them were well characterized. Modern pharmacological studies have shown that L. japonica polysaccharides (LJPs) have high-order structural features and multiple biological activities, including anti-tumor, anti-thrombotic, anti-atherosclerosis, hypolipidemic, hypoglycemic, antioxidant, anti-inflammatory, renoprotective, and immunomodulatory. In addition, the structural characteristics of LJPs are closely related to their biological activity. In this review, the extraction and purification methods, structural characteristics, biological activities, clinical settings, toxicities, and structure-activity relationships of LJPs are comprehensively summarized. The structural characteristics and biological activities as well as the underlying molecular mechanisms of LJPs were also outlined. Furthermore, the clinical settings and structure-activity functions of LJPs were highlighted. Some research perspectives and challenges in the study of LJPs were also proposed.