Natural Molecules Research Articles

Tailor-made Biochar enhances the anti-tumour effects of butyrate-glycerides in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer death in the world. Emerging evidence suggests that the short-chain-fatty-acid butyrate diet-assumed or produced by gut microbiota may interfere with CRC. Novel, more focused and effective anti-cancer natural molecules selectively acting on tumour cells are required to improve patients' compliance compared to more aggressive drug-based schemes. This study explored the in vitro anti-cancer effects of a novel green compound consisting of butyrate-glycerides (BMDG) alone or absorbed on tailor-made Biochar (BMDG-Biochar) or on activated-carbon Norit-B (BMDG-Norit), by using two CRC cell lines, HCT116 and HT29. Tailor-made Biochar characterised by a larger share of meso and macroporosity compared to commercially available activated-carbon Norit-B, with micro-pored ultrastructure, displayed superior performances as a BMDG carrier, with higher absorption/release properties. BMDG, in particular when absorbed on Biochar, interfered significantly with CRC cell proliferation compared to BMDG-Norit that showed no effect. Analysis of cell metabolism revealed a superior sensitivity of HCT116 to the inhibitory effect of BMDG-Biochar. This compound specifically induced a shift from a glycolytic metabolism in particular in HCT116 cells where glycolysis supports the aggressive phenotype, towards the mitochondrial respiration that characterises the more differentiated and less aggressive HT29 cells. Biochar's ability to deliver the butyrate-glyceride bioactive mixture and to exert in vitro combined anti-cancer activity in colorectal cancer, interfering with the Warburg effect that characterises the aggressive CRC forms, opens future translational opportunities to develop new orally assumed green molecules as promising anti-cancer strategies for CRC.

A viscoelastic supramolecular hydrogel co-assembled from gatifloxacin and deoxyguanosine for the treatment of bacterial keratitis.

Bacterial keratitis is the most prevalent ocular surface infection, causing significant inconvenience to patients' lives and posing a risk of blindness if mismanaged. The application of antibiotic gels has been a principal clinic therapeutic intervention due to the retarded ocular surface medication retention. However, current clinical gel formulations rely on high viscosity polymer matrices to improve retention, which often results in uneven gel layers, causing sticky sensation and prone to adhesion to periocular tissues during blinking, leading to clearance. In this study, we propose a supramolecular hydrogel assembled from antibiotic and natural nucleotide molecules with viscoelastic rheology and low cohesion texture. These features enabled it spread uniformly on the ocular surface, recover deformation after blinking, and are less likely to adhere to periocular tissues, significantly improving drug retention on the ocular surface and achieving better therapeutic effects in the treatment of bacterial keratitis. Additionally, the hydrogel is easy to prepare, has good visibility and safety, offering a new strategy for the development of ophthalmic gels.

A Bio-Redox Dynamic Pickering Emulsion from Nature to Nature.

The biosafety issue of Pickering emulsions has gradually become public. It is shown that the particles that make up Pickering emulsions, previously thought to be non-physiologically toxic, may also pose a potential threat to human life and health, as well as to ecosystems, due to their inherent emulsifying capacity. Hence, the principle of "from nature to nature" is proposed, which refers to emulsifiers that are of natural origin and can be metabolized by natural biological processes to eliminate their emulsifying ability. A feasible pathway by which the natural small molecule, thioctic acid, is exploited for the preparation of Pickering emulsions is also presented. The strategy of calcium ion-induced aggregation and ring-opening polymerization of sodium thioctate is utilized for the preparation of particulate emulsifiers, thus forming stable O/W-type Pickering emulsions. Benefiting from the antioxidant property of the thioctic acid moiety and the transdermal capacity of the emulsion itself, it combines protection of the bioactive substance with transdermal delivery. Furthermore, the particulate emulsifiers that are prepared, abundantly enriched with dynamic disulfide bonds, can be integrated into the natural metabolic pathway, specifically by being reduced through the involved glutathione, thereby facilitating their natural degradation and effectively mitigating any potential biological hazards.

Reactivity in cell culture medium and in vitro anticancer activity of 3,5-di-tert-butylcatechol: link to metal-catechol interactions

IntroductionCatechol moieties are common in natural bioactive molecules, and their ability to bind metal ions is widely explored both naturally with siderophores and in the development of metal-based drugs. The reactivities and biology activities of a sterically hindered model catechol compound, 3,5-di-tert-butylcatechol (dtbH2) and its oxidation product 3,5-di-tert-butyl-o-quinone (dtbQ), were studied in cell culture medium to understand better the medicinal roles of this class of molecules.MethodsAnti-proliferative activities of dtbH2 and dtbQ in fresh and aged solutions of the molecules were studied in two common human cancer cell lines, T98G (glioblastoma) and A549 (lung carcinoma). Electrospray mass spectrometry and UV/Vis spectroscopy were used to study the reactivities of the molecules in buffer solutions and cell culture medium, in the presence and absence of glutathione and imidazole.Results and DiscussionThe dtbH2 and dtbQ molecules showed high anti-proliferative activity (IC50 < 10 μM in 72 h assays) in T98G and A549 cell lines in the absence of added metal ions. The activity was observed when dtbH2 and dtbQ were freshly added to cell culture medium, while pre-incubation with the medium for 24 h reduced their activity 5-10-fold. This deactivation was avoided when the biological reductant, glutathione (GSH), was added to the medium at a physiologically relevant intracellular concentration (5.0 mM). These results were explained by speciation studies (UV/Vis spectroscopy and mass spectrometry) of dtbH2 and dtbQ in cell culture medium, aqueous buffers, or organic solvents in the presence or absence of GSH. These studies showed that a redox equilibrium was established between dtbH2 and dtbQ, with the latter rapidly coupling the GSH in an oxidative manner. The resultant adduct is likely to be responsible for the high toxicity of dtbH2 and dtbQ in GSH-rich cancer cells via oxygen-dependent radical chain reactions. Deactivation of dtbH2 and dtbQ in cell culture medium in the absence of GSH was due to the reactions of dtbQ with nucleophiles, such as amino acids, followed by the formation of polymeric species. The reported high anti-proliferative activity of V(V)-catecholato complexes can be explained by a combination of their efficient cellular uptake and rapid decomposition in thiol-rich intracellular environment with the formation of active V(V) and dtbH2/dtbQ adducts with thiols (mainly GSH). Slower decomposition and deactivation of the complexes was observed in thiol-poor extracellular environments. These data show that speciation in cell culture medium is crucial for the biological activity not only of metal complexes but also of their ligands when the complexes dissociates.

Enantioselective Synthesis of Indole-Fused Polycycles Bearing Four Consecutive Stereocenters via Rhodium Catalysis.

Indole-fused polycycles are common in natural products and bioactive molecules, yet their concise and efficient synthesis remains challenging, especially for compounds with multiple stereocenters. Herein, we report the application of a chiral CpxRhIII catalyst in the enantioselective C-H activation/[4+2] annulation of indoles with bicyclic alkenes. This chiral catalytic system exhibits high enantioselectivity and broad functional group tolerance and operates under benign conditions. The scope of this methodology encompasses a variety of substrates, delivering novel polycyclic compounds with four consecutive stereocenters and a bridged ring in good to excellent yields and remarkable enantioselectivities (≤1:99 er). This approach facilitates the synthesis of structurally diverse molecules that retain their bicyclic integrity while introducing chirality. More importantly, chiral 3ab significantly inhibited the proliferation of CESS and Kasumin-1 cells with IC50 values of 0.76 and 0.28 μM, respectively. In addition, 3ab has been demonstrated as an effective agent for promoting apoptosis in CESS cells.

Supramolecular Chiral Amplification Mediated by Tiny Structural Changes in Natural Binary Carrier‐Free Hydrogels with Promotion Methicillin‐Resistant Staphylococcus aureus‐Infected wound Healing by Inhibiting the Complement System

Natural small molecules self‐assembled to carrier‐free hydrogels have attracted widespread attention due to their simple preparation process, high drug loading capacity, good biodegradability, and biocompatibility. A group of structurally similar chiral phytochemical baicalin (BA), scutellarin (SCU), and achiral isoquinoline alkaloids chelerythrine (CHE) can self‐assemble to form binary hydrogels with helical nanofibers or twisted nanofibers. Interestingly, there is only one OH difference between SCU and BA, but the hydrogel formed by self‐assembly with CHE has huge differences in material properties, which is related to the chiral helicity of the formed supramolecules. Compared with BA‐CHE, the binary hydrogel formed by SCU‐CHE shows chiral amplification with greater helicity, is more stable, and exhibits excellent material properties, which is due to the magical noncovalent bond balance controlled by OH. This self‐assembled chiral hydrogel based on the inherent anti‐inflammatory and antibacterial activities of phytochemicals (BA, SCU, and CHE) can promote wound healing in bacterial infections by inhibiting the complement system. The phenomenon of supramolecular chirality amplification caused by tiny structural changes discovered in this study provides a horizon for the self‐assembly of natural small molecule drugs to form two‐component chiral supramolecular hydrogels and expands its application in the field of biomaterials.

Exploring Advances in Natural Plant Molecules for Allergic Rhinitis Immunomodulation in Vivo and in Vitro.

Allergic rhinitis (AR) is a prevalent allergic disease that imposes significant economic burdens and life pressures on individuals, families, and society, particularly in the context of accelerating globalization and increasing pathogenic factors. Current clinical therapies for AR include antihistamines, glucocorticoids administered via various routes, leukotriene receptor antagonists, immunotherapy, and several decongestants. These treatments have demonstrated efficacy in alleviating clinical symptoms and pathological states. However, with the growing awareness of AR and rising expectations for improvements in quality of life, these treatments have become associated with a higher incidence of side effects and an elevated risk of drug resistance. Furthermore, the development of AR is intricately associated with dysregulation of the immune system, yet the underlying pathogenetic mechanisms remain incompletely understood. In contrast, widely available natural plant molecules offer multiple targeting pathways that uniquely modify the typical pathophysiology of AR through immunomodulatory processes. This review presents a comprehensive analysis of both in vivo and in vitro studies on natural plant molecules that modulate immunity for treating AR. Additionally, we examine their specific mechanisms of action in animal models to provide new insights for developing safe and effective targeted therapies while guiding experimental and clinical applications against AR.

Lipoic acid scaffold applications in the design of multitarget-directed ligands against Alzheimer's disease.

Alzheimer's disease (AD) is becoming a fast-growing public health problem which can result in psychological problems as well as loss of speech, language, short-term memory, and motor coordination. Many medications were developed and produced to treat AD, however due to the complexity of the pathology involved in the illness, many of these medications often failed in clinical or preclinical studies. The main issue with the current anti-AD medications is their low efficacy since they use a single target. Multi-target-directed ligands (MTDLs) based on "one molecule; multiple targets" have been introduced to address these two fundamental issues. MTDLs have demonstrated improved efficacy and safety since they regulate many biological targets simultaneously. Alpha-lipoic acid (LA), a natural molecule with distinct properties, is a viable scaffold for developing new MTDLs in treating many neurodegenerative diseases, particularly AD. It is a key mitochondrial enzymes' cofactor and an organic molecule with disulfide functionality. It also has potent antioxidant characteristics that enhance mitochondrial activity. Considering the neuroprotective and anti-inflammatory effects of LA, various hybrids of LA with tacrine, rivastigmine, coumarin and chromone, ibuprofen, melatonin, niacin have been synthesized and biologically evaluated as the MTDLs. In this article, we review the design of LA-based hybrids or conjugates, their biological activities, and structure-activity relationship studies, to develop new MTDLs in the field of AD pharmacotherapy.

Elicitor-mediated simultaneous accumulation of phloridzin and ursolic acid in Annurca apple peel-derived calli.

Apple peel is rich in natural molecules, many exhibiting a significant bioactivity. In this study, our objective was to establish a novel callus line derived from the apple peel of the Italian local variety Annurca, known to accumulate high levels of dihydrochalcones and terpenes. In this regard, we tested the impact of one elicitor, yeast extract, on the expression of genes encoding key enzymes involved in phloridzin and ursolic acid biosynthesis, leading to the accumulation of these antioxidant compounds. We also assessed the bioactivity of callus extracts enriched in these phytochemicals. After the elicitation, data showed increased expression of genes directly related to the synthesis of phloridzin and ursolic acid that were found to accumulate within the cultures. This presumably could explain the remarkable activity of extracts from the elicited-calli in inhibiting the growth of Staphylococcus aureus and Bacillus cereus. Also, the extracts enriched in antioxidant compounds inhibited reactive oxygen species (ROS) production in human cells exposed to ultraviolet-A (UV-A) radiation. Our results underscore the vast potential of the Annurca apple peel cell line in producing natural compounds that can be employed as food components to promote human health. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Protective effect of Ocimum basilicum L. essential oil on Lactuca sativa L. treated with cadmium.

In recent years, essential oils (EO) are a sustainable and effective alternative to conventional chemical treatments in response to heavy metals in plants. These natural molecules can increase the resilience of plants under stress conditions. In the present work, the ability of EOs from the aerial parts of Ocimum basilicum L. cv 'Prospera' to improve plant response to heavy metals in Lactuca sativa L. grown hydroponically and subjected to Cd stress was investigated. The chemical profile of the essential oil (EO) was analyzed by GC-MS. Essential oil-induced tolerance to different Cd concentrations (36μM and 72μM) was studied by analyzing ultrastructural damage by TEM observations, antioxidant response by spectrophotometric analysis, and changes in gene expression by qRT-PCR involved in abiotic stress response. Our results indicated that exogenous EO application of basil helps preserve plastid ultrastructure and ameliorates Cd-induced damage. In addition, there was a reduction in ROS production and beneficial regulation of the activities and molecular expression of antioxidant enzymes. In conclusion, these results clearly indicate the protective ability of basil EO on cytological organization and in modulating the redox state through the antioxidant pathway, reducing Cd-induced oxidative stress.

The sphingosine-1-phosphate signaling pathway (sphingosine-1-phosphate and its receptor, sphingosine kinase) and epilepsy.

Epilepsy is one of the common chronic neurological diseases, affecting more than 70 million people worldwide. The brains of people with epilepsy exhibit a pathological and persistent propensity for recurrent seizures. Epilepsy often coexists with cardiovascular disease, cognitive dysfunction, depression, etc., which seriously affects the patient's quality of life. Although our understanding of epilepsy has advanced, the pathophysiological mechanisms leading to epileptogenesis, drug resistance, and associated comorbidities remain largely unknown. The use of newer antiepileptic drugs has increased, but this has not improved overall outcomes. We need to deeply study the pathogenesis of epilepsy and find drugs that can not only prevent the epileptogenesis and interfere with the process of epileptogenesis but also treat epilepsy comorbidities. Sphingosine-1-phosphate (S1P) is an important lipid molecule. It not only forms the basis of cell membranes but is also an important bioactive mediator. It can not only act as a second messenger in cells to activate downstream signaling pathways but can also exert biological effects by being secreted outside cells and binding to S1P receptors on the cell membrane. Fingolimod (FTY720) is the first S1P receptor modulator developed and approved for the treatment of multiple sclerosis. More and more studies have proven that the S1P signaling pathway is closely related to epilepsy, drug-resistant epilepsy, epilepsy comorbidities, or other epilepsy-causing diseases. However, there is much controversy over the role of certain natural molecules in the pathway and receptor modulators (such as FTY720) in epilepsy. Here, we summarize and analyze the role of the S1P signaling pathway in epilepsy, provide a basis for finding potential therapeutic targets and/or epileptogenic biomarkers, analyze the reasons for these controversies, and put forward our opinions. PLAIN LANGUAGE SUMMARY: This article combines the latest research literature at home and abroad to review the sphingosine 1-phosphate signaling pathway and epileptogenesis, drug-resistant epilepsy, epilepsy comorbidities, other diseases that can cause epilepsy, as well as the sphingosine-1-phosphate signaling pathway regulators and epilepsy, with the expectation of providing a certain theoretical basis for finding potential epilepsy treatment targets and/or epileptogenic biomarkers in the sphingosine-1-phosphate signaling pathway.

Bee venom peptide Anoplin conjugates as antibacterial agents for both Gram-positive and Gram-negative bacteria.

The Bee venom peptide Anoplin (GLLKRIKTLL) was synthesized and modified by using antibiotics at its N-terminus, resulting in three peptide derivatives: Ano1, Ano2 and Ano3. The synthetic yields were 92.3%, 75.1% and 95.4%, respectively. Multi-spectroscopy methods were employed to investigate the interaction between these peptides and ct-DNA. The experimental results revealed that Anoplin, Ano1 and Ano2 interacted with ct-DNA in a groove-binding mode, whereas Ano3 exhibited a mosaic-binding mode. Moreover, circular dichroism revealed that these peptides have ability to unfold parallel G-quadruplex structures, indicating that they can interact with secondary nucleic acid structure. Notably, antimicrobial activity results indicated that all three derived peptides exhibited excellent antimicrobial activity against both gram-positive and gram-negative bacteria. The synthesized peptide conjugate Ano3 exhibited a MIC value of 1.4μM to S. flexneri. Scanning electron microscopy results distinctly showed that Ano3 could rupture the cell wall of bacteria. These results provide novel methods to create effective antibacterial agents for both Gram-positive and Gram-negative bacteria by utilizing natural toxic molecules.

Nanoparticle-based flavonoid therapeutics: Pioneering biomedical applications in antioxidants, cancer treatment, cardiovascular health, neuroprotection, and cosmeceuticals.

Flavonoids, a type of natural polyphenolic molecule, have garnered significant research interest due to their ubiquitous nature and diverse biological activities, including antioxidant, anti-inflammatory, and anticancer effects, making them appealing to various scientific disciplines. In this regard, the use of a flavonoid nanoparticle delivery system is to overcome low bioavailability, bioactivity, poor aqueous solubility, systemic absorption, and intensive metabolism. Therefore, this review summarizes the classification of nanoparticles (liposomes, polymeric, and solid lipid nanoparticles) and the advantages of using nanoparticle-flavonoid formulations to boost flavonoid bioavailability. Moreover, this review illustrated the pioneering biomedical applications of nanoparticle-based flavonoid therapeutics, as well as safety and toxicity considerations of using a flavonoid nanoparticle delivery system.

A novel supramolecular nanodrugs for improving the cognitive function of schizophrenia by protecting active lactone of arecoline.

Over 30 % of patients with schizophrenia experience treatment resistance and severe side effects. The limited efficacy of antipsychotic therapies poses a challenge, partly due to the blood-brain barrier (BBB) and the non-selective targeting of these drugs. Herein, we report on arecoline (ARE), a water soluble natural small molecule, which was successfully constructed a phospholipid complex by noncovalent interactions. Most striking, this arecoline-phospholipid complex nanoplatforms (ARE-PC NPs) could prevent the hydrolyzation of its ester group by carboxylesterases, which showed sustained release, superior physiological stability and long circulatory capability. Both in vitro cells and in vivo mice speculated that this ARE-PC NPs might has a high cellular uptake and stronger penetration ability of the BBB. Additionally, our results demonstrated that this phospholipid complex might facilitate ARE delivery to the brain tissue and obviously improve the schizophrenia-like behavior in cuprizone induced animal models. This study highlights ARE-PC NPs as a promising antipsychotic nanodrug for the therapy of schizophrenia.

Supramolecular delivery systems for polyphenols: A green approach to predict in vivo permeability through an in vitro setup.

The use of in vitro markers able to reproduce the in vivo permeability and diffusivity of orally administered drugs, could represent an innovative starting point for the formulation of delivery systems, in particular for low soluble and low permeable drugs belonging to BCS class II and IV. Considering the great interest in the green pharmaceutical approaches and the increasing use of natural molecules as novel therapeutic drugs, in this study, rutin, hesperidin and curcumin have been selected as lipophilic model drugs to investigate their possible enhancement of their permeability and bioavailability after oral administration. As the low solubility of the three drugs hinders their application, β-cyclodextrins (CD), amphiphilic natural moieties able to form stable inclusion complexes, have been considered to promote their solubilization. Notably, hydroxypropyl-β-CD (HPBCD) and methyl-β-CD (MBCD), have been selected and the formation of the inclusion complexes with a stoichiometric ratio of 1:1 has been detected through phase-solubility studies and rationalized via docking calculations, revealing a strong complexation and an increased hydrophilicity of the systems. The diffusion experiments performed through the novel UV-Vis localized spectroscopy method confirmed a the extremely high stability of the CD-drugs complexes, especially in the cease of curcumin, which makes this as the predominant chemical specie to diffuse and permeates. The PermeaPad® plate, an in vitro cell-free assay, allowed to investigate the permeability behavior of the drugs, demonstrated that the type of β-cyclodextrins can influence the permeability through the biomimetic membrane, reflecting the effect of the unstirred water layer (UWL). Moreover, in the case of curcumin, the spectroscopic-mathematical approach suggested the formation of nano-supramolecular systems, detected by DLS, supporting the precision of the fitting model.

Neurotoxins Acting on TRPV1—Building a Molecular Template for the Study of Pain and Thermal Dysfunctions

Transient Receptor Potential (TRP) channels are ubiquitous proteins involved in a wide range of physiological functions. Some of them are expressed in nociceptors and play a major role in the transduction of painful stimuli of mechanical, thermal, or chemical origin. They have been described in both human and rodent systems. Among them, TRPV1 is a polymodal channel permeable to cations, with a highly conserved sequence throughout species and a homotetrameric structure. It is sensitive to temperature above 43 °C and to pH below 6 and involved in various functions such as thermoregulation, metabolism, and inflammatory pain. Several TRPV1 mutations have been associated with human channelopathies related to pain sensitivity or thermoregulation. TRPV1 is expressed in a large part of the peripheral and central nervous system, most notably in sensory C and Aδ fibers innervating the skin and internal organs. In this review, we discuss how the transduction of nociceptive messages is activated or impaired by natural compounds and peptides targeting TRPV1. From a pharmacological point of view, capsaicin—the spicy ingredient of chilli pepper—was the first agonist described to activate TRPV1, followed by numerous other natural molecules such as neurotoxins present in plants, microorganisms, and venomous animals. Paralleling their adaptive protective benefit and allowing venomous species to cause acute pain to repel or neutralize opponents, these toxins are very useful for characterizing sensory functions. They also provide crucial tools for understanding TRPV1 functions from a structural and pharmacological point of view as this channel has emerged as a potential therapeutic target in pain management. Therefore, the pharmacological characterization of TRPV1 using natural toxins is of key importance in the field of pain physiology and thermal regulation.

Decoding the Role of Antimicrobial Peptides in the Fight against Mycobacterium tuberculosis.

Tuberculosis (TB), a leading infectious disease caused by the pathogen Mycobacterium tuberculosis, poses a significant treatment challenge due to its unique characteristics and resistance to existing drugs. The conventional treatment regimens, which are lengthy and involve multiple drugs, often result in poor patient adherence and subsequent drug resistance, particularly with multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. This highlights the urgent need for novel anti-TB therapies and new drug targets. Antimicrobial peptides (AMPs), which are natural host defense molecules present in all living organisms, offer a promising alternative to traditional small-molecule drugs. AMPs have several advantages, including their broad-spectrum activity and the potential to circumvent existing resistance mechanisms. However, their clinical application faces challenges such as stability, delivery, and potential toxicity. This review aims to provide essential information on AMPs, including their sources, classification, mode of action, induction within the host under stress, efficacy against M.tuberculosis, clinical status and hurdles to their use. It also highlights future research directions to address these challenges and advance the development of AMP-based therapies for TB.

Transcriptome Reveals the Promoting Effect of Beta-Sitosterol on the Differentiation of Bovine Preadipocytes.

Natural small molecule compounds play crucial roles in regulating fat deposition. Beta-sitosterol exhibits multiple biological activities such as cholesterol reduction and anticancer effects. However, its regulatory mechanism in the differentiation of bovine preadipocytes remains unclear. We identified potential associations of Beta-sitosterol with biological processes such as cholesterol regulation and lipid metabolism through the prediction of its targets. We utilized techniques such as Oil Red O staining, Western blotting, RNA-seq, and others to elucidate the promoting effect of Beta-sitosterol on the differentiation of bovine preadipocytes. Furthermore, reducing the expression of the most downregulated gene among differential expressed genes (DEGs), MGP, promotes the differentiation of bovine preadipocytes. After interfering with MGP, RNA-seq analysis on the sixth day of differentiation revealed that DEGs were most significantly enriched in the PPAR signaling pathway. In this pathway, the expression levels of genes related to adipocyte differentiation, including CD36, RXRα, RXRγ, FABP4, PLIN1, ADIPO, and CAP, were significantly upregulated (P < 0.01). Western blot and ELISA analysis on genes related to the PPAR signaling pathway showed that interfering with MGP increased the expression of proteins such as RXRα, indicating the possible activation of the PPAR signaling pathway. In summary, Beta-sitosterol may promote the differentiation of bovine preadipocytes by reducing the expression of MGP, thereby activating the PPAR signaling pathway.

Enantioselective [3+2] Annulation of Aldimines with Alkynes by Scandium-Catalyzed C-H Activation.

The enantioselective [3+2] annulation of readily accessible aldimines with alkynes via C-H activation is, in principle, a straightforward and atom-efficient route for synthesizing chiral 1-aminoindenes, which are important components in a wide array of natural products, bioactive molecules, and functional materials. However, such asymmetric transformation has remained undeveloped to date due to the lack of suitable chiral catalysts. Here, we report for the first time the enantioselective [3+2] annulation of aldimines with alkynes via C-H activation using chiral half-sandwich scandium catalysts. This protocol enabled the synthesis of diverse multi-substituted chiral 1-aminoindene derivatives with 100 % atom-efficiency, broad substrate scope, and high regio- and enantioselectivity. Density functional theory (DFT) analyses have revealed that a noncovalent C-H⋅⋅⋅π interaction between a tert-Bu substituent in the chiral cyclopentadienyl (Cp) ligand and the phenyl ring of an aromatic aldimine substrate played an important role in achieving a high level of enantioselectivity. This work not only offers an efficient and selective route for synthesizing a new family of chiral 1-aminoindene derivatives but also offers unprecedented insights into enantioselectivity control in chiral Cp-ligated metal catalysts.

Phosphine‐Catalyzed Divergent γ,γ‐ and ε,γ‐Umpolung Domino Additions of Bisoxindoles with Allenoates: Construction of Vicinal All‐Carbon Quaternary Stereocenters and Formal Total Synthesis of Dimeric Cyclotryptamine Alkaloids

Comprehensive SummaryVicinal all‐carbon quaternary stereocenters are widely present in natural products and bioactive molecules. However, the construction of such motif in one step from readily available starting materials remains a significant challenge. Herein, we report a phosphine‐catalyzed divergent γ,γ‐ and ε,γ‐umpolung domino addition of bisoxindoles with allenoates. This method serves as a practical tool for the concise synthesis of a series of bisoxindole derivatives bearing sterically hindered vicinal all‐carbon quaternary stereocenters under mild reaction conditions. The applicability of this novel method was demonstrated with the gram‐scale synthesis of three known advanced intermediates for the total syntheses of calycanthine, chimonanthine and folicanthine.