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.

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.

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.

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.

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.

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.

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.

Safranal Alleviated OVA-Induced Asthma Model and Inhibits Mast Cell Activation.

Introduction: Asthma is a chronic and recurring airway disease, which related to mast cell activation. Many compounds derived from Chinese herbal medicine has promising effects on stabilizing mast cells and decreasing inflammatory mediator production. Safranal, one of the active compounds from Crocus sativus, shows many anti-inflammatory properties. In this study, we evaluated the effect of safranal in ovalbumin (OVA)-induced asthma model. Furthermore, we investigate the effectiveness of safranal on stabilizing mast cell and inhibiting the production of inflammatory mediators in passive systemic anaphylaxis (PSA) model. Methods: OVA-induced asthma and PSA model were used to evaluate the effect of safranal in vivo. Lung tissues were collected for H&E, TB, IHC, and PAS staining. ELISA were used to determine level of IgE and chemokines (IL-4, IL-5, TNF-α, and IFN-γ). RNA sequencing was used to uncovers genes that safranal regulate. Bone marrow-derived mast cells (BMMCs) were used to investigate the inhibitory effect and mechanism of safranal. Cytokine production (IL-6, TNF-α, and LTC4) and NF-κB and MAPKs signaling pathway were assessed. Results: Safranal reduced the level of serum IgE, the number of mast cells in lung tissue were decreased and Th1/Th2 cytokine levels were normalized in OVA-induced asthma model. Furthermore, safranal inhibited BMMCs degranulation and inhibited the production of LTC4, IL-6, and TNF-α. Safranal inhibits NF-κB and MAPKs pathway protein phosphorylation and decreases NF-κB p65, AP-1 nuclear translocation. In the PSA model, safranal reduced the levels of histamine and LTC4 in serum. Conclusions: Safranal alleviates OVA-induced asthma, inhibits mast cell activation and PSA reaction. The possible mechanism occurs through the inhibition of the MAPKs and NF-κB pathways.

Polycyclic polyprenylated acylphloroglucinol congeners from Garcinia yunnanensis Hu with inhibitory effect on α-hemolysin production in Staphylococcus aureus.

α-Hemolysin (Hla) is an extracellular protein secreted by methicillin-resistant Staphylococcus aureus (MRSA) strains that plays a critical role in the pathogenesis of pulmonary, intraperitoneal, intramammary, and corneal infections, rendering Hla a potential therapeutic target. In this study, 10 unreported polycyclic polyprenylated acylphloroglucinol (PPAP) derivatives, garciyunnanins C-L (1-10), with diverse skeletons, were isolated from Garcinia yunnanensis Hu. The structures of these new compounds were determined by HRMS, NMR, electronic circular dichroism (ECD) calculations, single-crystal X-ray diffraction, and biomimetic transformation. Garciyunnanins C and D (1 and 2) were found to be potent Hla inhibitors in the anti-virulence efficacy evaluation against MRSA strain.

Stereodivergent Strategy in Structural Determination: Asymmetric Total Synthesis of Garcinol, Cambogin, and Related Analogues.

The asymmetric total synthesis of five biologically significant polycyclic polyprenylated acylphloroglucinols (PPAPs), including garcinol and cambogin, was achieved through a highly diastereoselective and stereodivergent strategy. Along the way, an efficient cascade Dieckmann cyclization was employed to construct the bicyclo[3.3.1]nonane core in one step. The synthesis provided a general approach toward the chiral endo-type B PPAPs and their C-30 diastereomers in a single sequence, which resolved the challenges of the absolute configuration determination/structural revision of PPAPs bearing exocyclic stereocenters.

The Protective Effects and Potential Mechanisms of Ligusticum chuanxiong: Focus on Anti-Inflammatory, Antioxidant, and Antiapoptotic Activities.

Ligusticum chuanxiong (LC) is a Chinese materia medica which is widely used in clinical settings to treat headaches, blood extravasation, and arthritis. Recent studies demonstrate that LC possesses versatile pharmacological functions, including antiatherosclerosis, antimigraine, antiaging, and anticancer properties. Moreover, LC also shows protective effects in the progression of different diseases that damage somatic cells. Oxidative stress and inflammation, which can induce somatic cell apoptosis, are the main factors associated with an abundance of diseases, whose progresses can be reversed by LC. In order to comprehensively review the molecular mechanisms associated with the protective effects of LC, we collected and integrated all its related studies on the anti-inflammatory, antioxidant, and antiapoptotic effects. The results show that LC could exhibit the mentioned biological activities by modulating several signaling pathways, specifically the NF-κB, Nrf2, protein kinase, and caspase-3 pathways. In future investigations, the pharmacokinetic properties of bioactive compounds in LC and the signaling pathway modulation of LC could be focused.

Bicyclic polyprenylated acylphloroglucinols and their derivatives: structural modification, structure-activity relationship, biological activity and mechanism of action.

Bicyclic polyprenylated acylphloroglucinols (BPAPs), the principal bioactive benzophenone products isolated from plants of genera Garcinia and Hypericum, have attracted noticeable attention from the synthetic and biological communities due to their fascinating chemical structures and promising biological activities. However, the potential drug interaction, undesired physiochemical properties and toxicity have limited their potential use and development. In the last decade, pharmaceutical research on the structural modifications, structure-activity relationships (SARs) and mechanisms of action of BPAPs has been greatly developed to overcome the challenges. A comprehensive review of these scientific literature is extremely needed to give an overview of the rapidly emerging area and facilitate research related to BPAPs. This review, containing over 226 references, covers the progress made in the chemical synthesis-based structure modifications, SARs and the mechanism of action of BPAPs in vivo and vitro. The most relevant articles will focus on the discovery of lead compounds via synthetic modifications and the important BPAPs for which the direct targets have been deciphered. From this review, several key points of the SARs and mode of actions of this novel class of compounds have been summarized. The perspective and future direction of the research on BPAPs are concluded. This review would be helpful to get a better grasp of medicinal research of BPAPs and become a compelling guide for chemists dedicated to the synthesis of these compounds.

Cytotoxic xanthone derivatives from the twigs of Garcinia oligantha.

Ten undescribed xanthone derivatives, garoliganthins A-I and oliganthaxanthone C, along with eight known compounds, were isolated from the twigs of Garcinia oligantha Merr. Their structures and absolute configurations were determined by extensive spectroscopic methods, single-crystal X-ray diffraction analysis, electronic circular dichroism analysis, and chiral HPLC/HPLC-CD analysis combined with density functional theory calculations. Garoliganthin A is an unprecedented tetrahydro-xanthone derivative possessing a bicycle [3.2.2] nonane skeleton, and garoliganthins B-E are the first examples of a new class of rearranged xanthone derivatives with six-membered lactone core scaffold. The cytotoxic effects of the isolates on four human cancer cell lines (HeLa, PC-3, A549, and K562) were measured using an MTT assay. Seven compounds showed good inhibitory activities against four cancer cell lines with IC50 values ranging from 2.1 to 16.8 µM.

Safranal Alleviates Dextran Sulfate Sodium-Induced Colitis and Suppresses Macrophage-Mediated Inflammation.

Introduction: Crocus sativus (saffron) is widely used in China, Iran, and India for dyeing and as a food additive and medicinal plant. Safranal, as one of the main constituents of saffron, is responsible for its aroma and has been reported to have anticancer, antioxidant, and anti-inflammation properties. Objective: In this study, we investigated the anti-inflammatory effects of Safranal in RAW264.7 cells, bone marrow-derived macrophages (BMDMs), and dextran sulfate sodium (DSS)-induced colitis mice. Methods: Safranal toxicity was determined using an MTT assay. We evaluated the inhibitory effect of nitric oxide (NO) and levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells and BMDMs. We assessed the inhibitory effect of pro-inflammatory cytokines, and the mRNA expressions of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), classical inflammatory pathways (MAPK and NF-κB), and the nuclear translocation factors AP-1 and NF-κB p65 were investigated. The in vivo anti-inflammatory effects of Safranal were assessed in a DSS-induced colitis model. DSS3.5% was used to induce colitis in mice with or without Safranal for 7 days; weight and disease activity index (DAI) were recorded daily. At the end of the experiment, the colon, mesenteric lymph nodes (MLNs), and spleen were collected for flow cytometry, ELISA, and Western blot analysis. Results: Safranal suppressed NO production, iNOS, and COX-2 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and BMDMs. Safranal decreased the production and mRNA expression of IL-6 and TNF-α in the RAW264.7 cell line and inhibited the phosphorylation and nuclear translocation of components of the MAPK and NF-κB pathways. Safranal alleviated clinical symptoms in the DSS-induced colitis model, and colon histology showed decreased severity of inflammation, depth of inflammatory involvement, and crypt damage. Immunohistochemical staining and flow cytometry showed reduced macrophage infiltration in colonic tissues and macrophage numbers in MLNs and the spleen. The levels of colonic IL-6 and TNF-α also decreased in Safranal-treated colitis mice. This study elucidates the anti-inflammation activity of Safranal, which may be a candidate for inflammatory bowel syndrome (IBD) therapy.

Me2AlSEt-Promoted Domino Dieckmann Cyclization Enables the Total Synthesis of Polycyclic Polyprenylated Acylphloroglucinols.

A bioinspired, Me2AlSEt-promoted domino Dieckmann cyclization via an 8-membered ring intermediate to construct bicyclo[3.3.1]nonanes was developed, and the divergent syntheses of nine complex polycyclic polyprenylated acylphloroglucinols were achieved. This novel domino cyclization tolerates a series of congested substrates, providing a very efficient way to construct diverse polycyclic structures. The selectivity and the advantages of the domino cyclization were studied. Moreover, the structure-activity relationship study leads to the identification of three simplified potent antitumor agents.

Xanthone derivatives from the leaves of Garcinia oligantha.

Nine new and unique xanthone derivatives, including one novel hybrid monoterpene-tetrahydroxanthone (1), three dihydro-xanthone derivatives (2-4), and five skeleton-rearranged xanthone derivatives (5-9), were obtained from a 95% EtOH extract of Garcinia oligantha leaves by a LC-MS-guided fractionation procedure. The structures of the new compounds were elucidated by analysis of their 1D and 2D NMR and MS data. The relative configurations of 2 and 8 were determined via X-ray crystallographic data analysis, while the absolute configurations of 1-2, 5-9 were assigned based on a comparison of calculated and experimental ECD and/or OR data. In SRB, PI-exclusion and Hoechst staining assays, 6 showed strong cytotoxic activities which could dose-dependently induce Taxol-insensitive quiescent LNCaP cell death. Additionally, a preliminary mechanism investigation using immunoblotting and Caspase-3 activity assay, indicated that 6 induced quiescent LNCaP cell death potentially through caspase-dependent mitochondrial apoptosis pathway.

Uncariitannin, a polyphenolic polymer from Uncaria gambier, attenuates Staphylococcus aureus virulence through an MgrA-mediated regulation of α-hemolysin.

A global transcriptional regulator, MgrA, was previously identified as a key determinant of virulence in Staphylococcus aureus. An 80% EtOH extract of Uncaria gambier was found to attenuate the virulence of S. aureus via its effects on MgrA. Using bioassay-guided fractionation, a polyphenolic polymer, uncariitannin, was found to be the main bioactive constituent of the extract, and its structure was characterized using spectral and chemical analysis. The molecular weight and polydispersity of uncariitannin were determined by gel permeation chromatography-refractive index-light scattering analysis. An electrophoretic mobility shift assay showed that uncariitannin could effectively inhibit the interaction of MgrA with DNA in a dose-dependent manner. Treatment with uncariitannin could decrease the mRNA and protein levels of Hla in both the S. aureus Newman and USA300 LAC strains. Further analysis of Hla expression levels in the Newman ΔmgrA and Newman ΔmgrA/pYJ335-mgrA strains indicated that uncariitannin altered Hla expression primarily in an MgrA-dependent manner. A mouse model of infection indicated that uncariitannin could attenuate MRSA virulence. In conclusion, uncariitannin may be a potential candidate for further development as an antivirulence agent for the treatment of S. aureus infection.

Cytotoxic Prenylated Xanthones from the Leaves of Garcinia bracteata.

Six new prenylated xanthones (1: -6: ) and seventeen known xanthones were isolated from extracts of Garcinia bracteata leaves. Their structures were determined by extensive NMR and MS spectroscopic data analysis. The inhibitory activities of the isolates were assayed on HeLa, A549, PC-3, HT-29, and WPMY-1 cell lines. Compounds 1: and 15: -17: showed moderate inhibitory effects on tumor cell growth, with IC50s ranging from 3.7 to 14.7 µM.