Pd-Catalyzed Hydroboration of Vinylarenes with B2pin2.

A palladium(II)-catalyzed Markovnikov hydroboration of aryl alkenes with readily available bis(pinacolato)diboron (B2pin2) is reported. The reaction proceeded with low catalyst loading (0.5 mol %) in the absence of N- or P-containing ligands, affording the products in up to 90% yield. Trifluoracetic acid serves as the hydrogen source, enabling the synthesis of benzylic boronic esters under mild ambient conditions.

Asymmetric aza-Henry reaction toward trifluoromethyl ß-nitroamines and biological investigation of their adamantane-type derivatives.

Amino acid-derived quaternary ammonium salts were successfully applied in the asymmetric aza-Henry reaction of nitromethane to N-Boc trifluoromethyl ketimines. α-Trifluoromethyl ß-nitroamines were synthesized in good to excellent yields with moderate to good enantioselectivities. This reaction is distinguished by its mild conditions, low catalyst loading (1 mol%), and catalytic base. It also proceeded on a gram scale without loss of enantioselectivity. The products were transformed to a series of adamantane-type compounds containing chiral trifluoromethylamine fragments. The potent anticancer activities of these compounds against liver cancer HepG2 and melanoma B16F10 were evaluated. Six promising compounds with notable efficacy have potential for further development.

Caged xanthone derivatives to promote mitochondria-mediated apoptosis in breast cancer cells.

Caged xanthones represent a class of natural secondary metabolites exhibiting significant potential as antitumor agents. These compounds are characterized by their distinct cage-like structures, which offer novel and compelling frameworks for drug design. Nonetheless, there exists a dearth of research focused on the structural modification of these compounds, particularly in relation to their cage-like architectures. This study aims to address this gap by introducing an innovative synthetic method for constructing a novel caged structure that incorporates a widely employed maleimide group. Drawing upon the well-established synthetic approach for dihydroxanthones previously developed within our research group, we successfully synthesized 13 new caged xanthones using the Diels-Alder reaction. Subsequently, we evaluated their anti-proliferative activity against HepG2, A549, and MDA-MB-231 cell lines. The results revealed that compound 10i exhibited IC50 values of 15.86 µM ± 1.29, 19.27 µM ± 1.58, and 12.96 µM ± 0.09 against these cell lines, respectively. Further investigations into the mechanism of action of 10i demonstrated its ability to induce G2/M cell cycle arrest and initiate mitochondria-mediated apoptosis in breast cancer cells.

Copper-Catalyzed Direct Asymmetric Vinylogous Mannich Reaction between ß,γ-Alkynyl-α-ketimino Esters and ß,γ-Unsaturated N-Acylpyrazoles.

We report a Cu(I)-Ph-BPE-catalyzed asymmetric vinylogous Mannich reaction of ß,γ-alkynyl-α-ketimino esters with ß,γ-unsaturated N-acylpyrazoles. In this process, the Cu(I)-Ph-BPE catalyst activates the ß,γ-alkynyl-α-ketimino ester through N,O-coordination, enabling the subsequent nucleophilic addition of a dienolate generated from the ß,γ-unsaturated N-acylpyrazole via α-position deprotonation with a catalytic amount of tertiary amine. The reactions gave useful products with very high enantioselectivities. A broad range of substrates with various substituents are tolerated in this reaction. The versatility of this method was demonstrated by a gram-scale reaction, and subsequent elaboration of the Mannich adducts was also provided.

Potential pathological mechanisms and pharmacological interventions for cadmium-induced miscarriage.

The prevalence of cadmium (Cd) contamination has emerged as a significant global concern. Exposure to Cd during pregnancy is associated with adverse pregnancy outcomes, including miscarriage. However, there is currently a lack of comprehensive summaries on Cd-induced miscarriage. Therefore, it is imperative to further strengthen research into in vivo studies, clinical status, pathological mechanisms, and pharmacological interventions for Cd-induced miscarriage. This study systematically presents the current knowledge on animal models and clinical trials investigating Cd exposure-induced miscarriage. The underlying mechanisms involving oxidative stress, inflammation, endocrine disruption, and placental dysfunction caused by Cd-induced miscarriage are also extensively discussed. Additionally, potential drug interventions such as melatonin, vitamin C, and vitamin E are highlighted for their pharmacological role in mitigating adverse pregnancy outcomes induced by Cd.

Design, synthesis, and biological evaluation of gambogenic acid derivatives: Unraveling their anti-cancer effects by inducing pyroptosis.

Gambogenic acid (GNA), a caged xanthone derived from Garcinia hanburyi, exhibits a wide range of anti-cancer properties. The caged skeleton of GNA serves as the fundamental pharmacophore responsible for its antitumor effects. However, limited exploration has focused on the structural modifications of GNA. This study endeavors to diversify the structure of GNA and enhance its anti-cancer efficacy. Sulfoximines, recognized as pivotal motifs in medicinal chemistry due to their outstanding properties, have featured in several anti-cancer drugs undergoing clinical trials. Accordingly, a series of 33 GNA derivatives combined with sulfoximines were synthesized and evaluated for their anti-cancer effects against MIAPaCa2, MDA-MB-231, and A549 cells in vitro. The activity screening led to the identification of compound 12k, which exhibited the most potent anti-cancer effect. Mechanistic studies revealed that 12k primarily induced pyroptosis in MIAPaCa2 and MDA-MB-231 cells by activating the caspase-3/gasdermin E (GSDME) pathway. These findings suggested that 12k is a promising drug candidate in cancer therapy and highlighted the potential of sulfoximines as a valuable functional group in drug discovery.

Sequential Dieckmann cyclization enables the total synthesis of 7-epi-clusianone and 18-hydroxy-7-epi-clusianone.

A unified approach for the construction of the bicyclo[3.3.1]nonane-2,4,9-trione core of polycyclic polyprenylated acylphloroglucinols (PPAPs) was reported. This approach involves a sequential process of two distinct Dieckmann condensation reactions from the linear precursor. Using this method, the divergent total synthesis of the natural products 7-epi-clusianone and 18-hydroxy-7-epi-clusianone and the formal synthesis of sampsonione P were achieved. Additionally, other key steps to realize this strategy include RuCl3-catalyzed oxidative olefin cleavage and Pd-catalyzed Tsuji-Trost decarboxylative allylation. The synthesis indicated that bicyclo[3.3.1]nonane-2,4,9-triones could also be constructed via 6-membered intermediates.

Metabolomics approach to growth-age discrimination in mountain-cultivated ginseng (Panax ginseng C. A. Meyer) using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry.

Mountain-cultivated ginseng is typically harvested after 10 years, while ginseng aged over 15 years is considered wild ginseng. This study aims to differentiate mountain-cultivated ginseng by age, as the fraudulent practice of selling low-aged cultivated ginseng disguised as high-aged one is damaging the market. In this study, LC-MS analyzed 98 ginseng samples, and multivariate statistical analysis identified patterns between samples to select influential components. Machine learning models were developed to identify ginseng samples of different ages. The untargeted metabolomic analysis clearly divided samples aged 4-20 years into three age groups. Twenty-two potential age-dependent biomarkers were discovered to differentiate the three sample groups. Three machine learning models were used to predict new samples, and the optimal model was selected. Some biomarkers could determine age phases according to the differentiation of mountain-cultivated ginseng samples. These biomarkers were thoroughly analyzed for variation trends. The machine learning models established using the screened biomarkers successfully predicted the age group of new samples.

Multiple Hydrogen-Bonding Catalysts Enhance the Asymmetric Cyanation of Ketimines and Aldimines.

A highly enantioselective cyanation of imines (up to >99 % ee) has been developed using well-designed C2 -symmetric hydrogen bonding catalysts. The catalytic strategy was characterized with low catalyst loading (0.1-1 mol %), easily accessible catalysts with diverse functional groups, and catalytic base additives. A wide range of imines, including the challenging N-Boc and N-Cbz protected ketimines and aldimines, as well as fluoroalkylated ketimines, were investigated under mild conditions to afford the products with good to excellent yields (up to 99 % yield) and high enantioselectivity (up to >99 % ee). Control experiments revealed that the multiple hydrogen bonding catalysts enhanced the reactivity and enantioselectivity of the Strecker reaction initiated by the base.

Synergistic Ni/Pd Catalysis for Asymmetric Allylic Alkylation of 2-Acyl Imidazoles.

The asymmetric α-allylation of α-aryl-substituted 2-acetyl imidazoles synergistically catalyzed by Ni/Pd catalysts has been developed. In this process, the nickel-bisoxazoline complex activates the enolate of an acetyl imidazole, which then reacts with a π-allyl palladium electrophile generated from an allyl alcohol derivative by a palladium-based catalyst. A broad scope of substrates was suitable for this reaction. The utility of this method was demonstrated by a gram-scale reaction and subsequent elaboration of the allylation products.

Finding the priority and cluster of inflammatory biomarkers for infectious preterm birth: a systematic review.

Infectious preterm birth (PTB) is one of the most important causes of perinatal death. It is difficult to find reliable biomarkers accurate to gestational weeks for infectious PTB prediction clinically. Infectious PTB is found usually accompanied with immune imbalance. Thus, the systematic study to find the priority of inflammatory biomarkers and innovative inflammatory clusters for infectious PTB prediction is urgently needed.This systematic study that focused on the inflammatory clusters and infectious PTB in the PubMed database was analyzed by using the criteria of the Population, Intervention, Comparison, Outcome, and Study design (PICOS) framework according to the recommendations of preferred reporting items for systematic reviews and meta-analysis (PRISMA).The network meta-analyzed results showed that the prioritization of the inflammatory factors for infectious PTB prediction is soluble tumor necrosis factor receptor 2 (sTNFR2) > tumor necrosis factor α (TNFα) > interleukin-10 (IL-10) > interleukin-6 (IL-6) > C-reactive protein (CRP) > interleukin-1ß (IL-1ß). Furthermore, the results also indicated that global consideration of multiple inflammatory factors, such as CRP/IL-1ß/IL-6 biomarker cluster in gestational 27-34 weeks, and the tumor necrosis factor/nerve growth factor (TNF/NGF) family during gestational 25-33 weeks, were potential biomarker clusters that specific for infectious PTB prediction.This study systematically pointed out prioritization of the inflammatory factors for infectious PTB prediction. The results also provided evidence that maternal inflammatory clusters can predict infectious PTB occurrence at accurate gestational week. The global consideration of multiple inflammatory factors at accurate gestational age is highlighted.

A novel method for age identification of mountain-cultivated ginseng.

Panax ginseng, a slow-growing perennial herb, is the most praised and popular traditional medicinal herb. Mountain-cultivated ginseng (MCG) and cultivated ginseng (CG) both belong to Panax ginseng C. A. Meyer. The market price and medical effects of this popular health product are closely related to its age. It is widely acknowledged that CG is typically harvested after 4-6 years of growth, but MCG is often collected after 10 years. Until now, the age identification of MCG or mountain wild ginseng (MWG) has remained a major challenge. In this study, we established a novel and rapid method for staining xylem vessels with phloroglucinol and identifying the "annual growth rings" of ginseng by utilizing a stereoscope, which serves as a reliable indicator of the age of MCG. Statistical analysis of the ring radius and the ring density of MCG aged from 1 to 20 years shows that the secondary xylem of MCG increases rapidly in the first 3 years but then gradually slows down from 4 to 10 years, and minor fluctuation is observed in the next 10 years. Meanwhile, the space between the growth rings (ring density) becomes increasingly small with age. This straightforward staining approach can reveal the age of MCG with remarkable clarity and can distinguish MCG from CG. RESEARCH HIGHLIGHTS: A novel rapid staining method for Panax ginseng was established. The age of mountain-cultivated ginseng (MCG) can be identified by microscopic techniques. MCG and cultivated ginseng (CG) can be discriminated by microstructure characteristics.

Copper-Catalyzed Asymmetric Propargylic Substitution of 2,2,2-Trifluoroethyl-isoxazoles with Propargylic Alcohol Derivatives.

The trifluoromethyl group is one of the most functional and widely used fluoroalkyl groups in medicinal chemistry and drug discovery. However, few methodologies have been reported for the asymmetric introduction of the trifluoromethyl group into organic molecules. In this study, a diastereo- and enantioselective propargylic substitution reaction was performed between propargylic carbonates and 2,2,2-trifluoroethyl-substituted nitroisoxazoles catalyzed by a Cu-pybox complex. This method enables the preparation of a series of propargylation products with two contiguous stereogenic centers, one of which is a chiral trifluoromethyl-bearing carbon. In most cases, the desired products were produced in high yields with good to excellent diastereo- and enantioselectivities.

Garcinol and its analogues: Synthesis, cytotoxic activity and mechanistic investigation.

Garcinol is a polyisoprenylated benzophenone isolated from Garcinia. It has been reported to have a variety of intriguing biological effects, including anticancer, anti-inflammatory, and antioxidant capabilities. The purpose of this research is to thoroughly evaluate garcinol and a series of its analogues in terms of synthesis, structural diversity, biosynthesis, and potential for preventing carcinoma cell proliferation. Garcinopicrobenzophenone and eugeniaphenone, which contain a unique cyclobutyl unit at C-5, were initially synthesized using the procedures utilized in the synthesis of garcinol. All the natural analogs of garcinol were produced at completion of the synthesis, and their structures and absolute configurations were clarified. Based on the synthesis, a possible biogenetic synthesis pathway towards cambogin, 13,14-didehydroxyisogarcinol via O-cyclization, and garcinopicrobenzophenone or eugeniaphenone via C-cyclization was proposed. The cytotoxicity of polyisoprenylated benzophenones produced in our group was tested, and the structure-activity relationship was summarized. The mechanism by which garcinol, cambogin, and 21' induce apoptosis was studied. Cambogin and 21' were shown to have a greater capacity to cause apoptosis in pancreatic cancer BXPC3 cells, and the suppression of BXPC3 cells by 21' might be attributed to the target of STAT3 signaling. Garcinol could cause pyroptosis and apoptosis in pancreatic cancer cells at the same time, which was the first time that garcinol was identified as a possible chemotherapeutic agent that could significantly promote pyroptosis in cancer cells.

Effectiveness of Scutellaria baicalensis Georgi root in pregnancy-related diseases: A review.

The root of Scutellaria baicalensis Georgi, also called Huangqin, is frequently used in traditional Chinese medicine. In ancient China, S. baicalensis root was used to clear heat, protect the fetus, and avoid a miscarriage for thousands of years. In modern times, pregnancy-related diseases can seriously affect maternal and fetal health, but few systematic studies have explored the mechanisms and potential targets of S. baicalensis root in the treatment of pregnancy-related diseases. Flavonoids (baicalein, wogonin and oroxylin A) and flavonoid glycosides (baicalin and wogonoside) are the main chemical components in the root of S. baicalensis. This study presents the current understanding of the major chemical components in the root of S. baicalensis, focusing on their traditional uses, potential therapeutic effects and ethnopharmacological relevance to pregnancy-related disorders. The mechanisms, potential targets and experimental models of S. baicalensis root for ameliorating pregnancy-related diseases, such as recurrent spontaneous abortion, preeclampsia, preterm birth, fetal growth restriction and gestational diabetes mellitus, are highlighted.

Biphenyls in Clusiaceae: Isolation, structure diversity, synthesis and bioactivity.

Clusiaceae plants contain a wide range of biologically active metabolites that have gotten a lot of interest in recent decades. The chemical compositions of these plants have been demonstrated to have positive effects on a variety of ailments. The species has been studied for over 70 years, and many bioactive compounds with antioxidant, anti-proliferative, and anti-inflammatory properties have been identified, including xanthones, polycyclic polyprenylated acylphloroglucinols (PPAPs), benzophenones, and biphenyls. Prenylated side chains have been discovered in many of these bioactive substances. To date, there have been numerous studies on PPAPs and xanthones, while no comprehensive review article on biphenyls from Clusiaceae has been published. The unique chemical architectures and growing biological importance of biphenyl compounds have triggered a flurry of research and interest in their isolation, biological evaluation, and mechanistic studies. In particular, the FDA-approved drugs such as sonidegib, tazemetostat, daclatasvir, sacubitril and trifarotene are closely related to their biphenyl-containing moiety. In this review, we summarize the progress and development in the chemistry and biological activity of biphenyls in Clusiaceae, providing an in-depth discussion of their structural diversity and medicinal potential. We also present a preliminary discussion of the biological effects with or without prenyl groups on the biphenyls.

Recent advances in the synthesis of natural products containing the phloroglucinol motif.

Covering: June 2009 to 2021Natural products containing a phloroglucinol motif include simple and oligomeric phloroglucinols, polycyclic polyprenylated acylphloroglucinols, phloroglucinol-terpenes, xanthones, flavonoids, and coumarins. These compounds represent a major class of secondary metabolites which exhibit a wide range of biological activities such as antimicrobial, anti-inflammatory, antioxidant and hypoglycaemic properties. A number of these compounds have been authorized for therapeutic use or are currently being studied in clinical trials. Their structural diversity and utility in both traditional and conventional medicine have made them popular synthetic targets over the years. In this review, we compile and summarise the recent synthetic approaches to the natural products bearing a phloroglucinol motif. Focus has been given on ingenious strategies to functionalize the phloroglucinol moiety at multiple positions. The isolation and bioactivities of the compounds are also provided.

Asymmetric Synthesis of 2,2-Difluorotetrahydrofurans through Palladium-Catalyzed Formal [3+2] Cycloaddition.

The asymmetric synthesis of 2,2-difluorinated tetrahydrofurans was accomplished via enantioselective formal [3+2] cycloaddition catalyzed by palladium. The asymmetric reaction between gem-difluoroalkenes and racemic vinyl epoxides or vinylethylene carbonates resulted in the formation of enantioenriched 2,2-difluorotetrahydrofurans with an enantioselectivity up to 98 %. Notably, the reaction used the readily available (R)-BINAP as the ligand at a low loading and yielded a wide variety of difluorinated products in moderate to high yields. Both chiral diastereomers could be obtained in a single sequence.

Xanthone Glucosides: Isolation, Bioactivity and Synthesis.

Xanthones are secondary metabolites found in plants, fungi, lichens, and bacteria from a variety of families and genera, with the majority found in the Gentianaceae, Polygalaceae, and Clusiaceae. They have a diverse range of bioactivities, including anti-oxidant, anti-bacterial, anti-malarial, anti-tuberculosis, and cytotoxic properties. Xanthone glucosides are a significant branch of xanthones. After glycosylation, xanthones may have improved characteristics (such as solubility and pharmacological activity). Currently, no critical review of xanthone glucosides has been published. A literature survey including reports of naturally occurring xanthone glucosides is included in this review. The isolation, structure, bioactivity, and synthesis of these compounds were all explored in depth.

Enantioselectivity switch in asymmetric Michael addition reactions using phosphonium salts.

Efficient access to two enantiomers of one chiral compound is critical for the discovery of drugs. However, it is still a challenging problem owing to the difficulty in obtaining two enantiomers of one chiral catalyst. Here, we report a general method to obtain both enantiomeric products via fine tuning the hydrogen-bonding interactions of phosphonium salts. Amino acid derived phosphonium salts and dipeptide derived phosphonium salts exhibited different properties for controlling the transition state, which could efficiently promote the Michael addition reaction to give opposite configurations of products with high yields and enantioselectivities. Preliminary investigations on the mechanism of the reaction and applications of the products were also performed.