Natural Products Research Articles

Clickable tryptophan modification for late-stage diversification of native peptides.

As the least abundant residue in proteins, tryptophan widely exists in peptide drugs and bioactive natural products and contributes to drug-target interactions in multiple ways. We report here a clickable tryptophan modification for late-stage diversification of native peptides, via catalyst-free C2-sulfenylation with 8-quinoline thiosulfonate reagents in trifluoroacetic acid (TFA). A wide range of groups including trifluoromethylthio (SCF3), difluoromethylthio (SCF2H), (ethoxycarbonyl)difluoromethylthio (SCF2CO2Et), alkylthio, and arylthio were readily incorporated. The rapid reaction kinetics of Trp modification and full tolerance with other 19 proteinogenic amino acids, as well as the super dissolving capability of TFA, render this method suitable for all kinds of Trp-containing peptides without limitations from sequences, hydrophobicity, and aggregation propensity. The late-stage modification of 15 therapeutic peptides (1.0 to 7.6 kilodaltons) and the improved bioactivity and serum stability of SCF3- and SCF2H-modified melittin analogs illustrated the effectiveness of this method and its potential in pharmacokinetic property improvement.

Study on the inhibitory activity and mechanism of Mentha haplocalyx essential oil nanoemulsion against Fusarium oxysporum growth

Mentha haplocalyx essential oil (MEO) has demonstrated inhibitory effects on Fusarium oxysporum. Despite its environmentally friendly properties as a natural product, the limited water solubility of MEO restricts its practical application in the field. The use of nanoemulsion can improve bioavailability and provide an eco-friendly approach to prevent and control Panax notoginseng root rot. In this study, Tween 80 and anhydrous ethanol (at a mass ratio of 3) were selected as carriers, and the ultrasonic method was utilized to produce a nanoemulsion of MEO (MNEO) with an average particle size of 26.07 nm. Compared to MTEO (MEO dissolved in an aqueous solution of 2% DMSO and 0.1% Tween 80), MNEO exhibited superior inhibition against F. oxysporum in terms of spore germination and hyphal growth. Transcriptomics and metabolomics results revealed that after MNEO treatment, the expression levels of certain genes related to glycolysis/gluconeogenesis, starch and sucrose metabolism were significantly suppressed along with the accumulation of metabolites, leading to energy metabolism disorder and growth stagnation in F. oxysporum. In contrast, the inhibitory effect from MTEO treatment was less pronounced. Furthermore, MNEO also demonstrated inhibition on meiosis, ribosome function, and ribosome biogenesis in F. oxysporum growth process. These findings suggest that MNEO possesses enhanced stability and antifungal activity, which effectively hinders F. oxysporum through inducing energy metabolism disorder, meiotic stagnation, as well as ribosome dysfunction, thus indicating its potential for development as a green pesticide for prevention and control P. notoginseng root rot caused by F.oxyosporum.

Natural hypoglycaemic bioactives: Newer avenues and newer possibilities.

The incidences of endocrine and metabolic disorders like diabetes have increased worldwide. Several proposed molecular pathways mechanisms for the management of diabetes have been identified, but glycaemic control is still a challenging task in the drug discovery process. Most of the drug discovery processes lead to numerous scaffolds that are prominent in natural products. The review deals with the natural bioactives as an α-amylase inhibitors, α-glucosidase inhibitors, protein tyrosine phosphatase-1B inhibitors, dipeptidyl peptidase-IV inhibitors, G-protein coupled receptors-40 agonists, PPAR-γ agonists and the activators of 5'-adenosine monophosphate-activated protein kinase and glucokinase. So, in this review, we focused on the hypoglycaemic bioactives, which will assist scientific developers, traditional medicinal practitioners, and readers to discover some potent antidiabetic molecules. Strategies like chemometric approaches, scaffold hopping, and total synthesis of natural products by group modification or ring opening/closing mechanism could be useful for the development of novel hit/lead antidiabetic molecules. The study concludes that each phyto molecule inherits a potential to get explored by repurposing techniques for various antidiabetic targets and offer an alternative antidiabetic therapeutic medicinal potential.

Photoinduced Metal-Free Radical Addition/Cyclization of 2-Cyanoaryl Acrylamides to Prepare gem-Difluorinated Naphthyridinone Scaffolds.

Direct construction of gem-difluorinated heterocycles represents a long-standing challenge in organic chemistry. Herein, we developed a transition-metal-free photocatalytic radical addition/cyclization of BrCF2COR with 2-cyanoaryl acrylamides to give gem-difluorinated naphthyridinone scaffolds in moderate to good yields. Furthermore, some natural products were found to be suitable in the reaction system. The easily available substrates, mild reaction conditions, simple operation, and wide functionality tolerance show practical and environmental advantages in this method.

A classic antibiotic reimagined: Rationally designed bacitracin variants exhibit potent activity against vancomycin-resistant pathogens

Bacitracin is a macrocyclic peptide antibiotic that is widely used as a topical treatment for infections caused by gram-positive bacteria. Mechanistically, bacitracin targets bacteria by specifically binding to the phospholipid undecaprenyl pyrophosphate (C55PP), which plays a key role in the bacterial lipid II cycle. Recent crystallographic studies have shown that when bound to C55PP, bacitracin adopts a highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of the bacitracin-C55PP complex, presumably interacting with the bacterial cell membrane. These insights led us to undertake structure-activity investigations into the individual contribution of the nonpolar amino acids found in bacitracin. To achieve this we designed, synthesized, and evaluated a series of bacitracin analogues, a number of which were found to exhibit significantly enhanced antibacterial activity against clinically relevant, drug-resistant pathogens. As for the natural product, these next-generation bacitracins were found to form stable complexes with C55PP. The structure-activity insights thus obtained serve to inform the design of C55PP-targeting antibiotics, a key and underexploited antibacterial strategy.

Discovery of Uncommon Tryptophan-Containing Diketopiperazines from Aspergillus homomorphus CBS 101889 Using an Aspergillus nidulans Heterologous Expression System.

Fungal secondary metabolite (SM) biosynthetic gene clusters (BGCs) containing dimethylallyltryptophan synthases (DMATSs) produce structurally diverse prenylated indole alkaloids with wide-ranging activities that have vast potential as human therapeutics. To discover new natural products produced by DMATSs, we mined the Department of Energy Joint Genome Institute's MycoCosm database for DMATS-containing BGCs. We found a DMATS BGC in Aspergillus homomorphus CBS 101889, which also contains a nonribosomal peptide synthetase (NRPS). This BGC appeared to have a previously unreported combination of genes, which suggested the cluster might make novel SMs. We refactored this BGC with highly inducible promoters into the model fungus Aspergillus nidulans. The expression of this refactored BGC in A. nidulans resulted in the production of eight tryptophan-containing diketopiperazines, six of which are new to science. We have named them homomorphins A-F (2, 4-8). Perhaps even more intriguingly, to our knowledge, this is the first discovery of C4-prenylated tryptophan-containing diketopiperazines and their derivatives. In addition, the NRPS from this BGC is the first described that has the ability to promiscuously combine tryptophan with either of two different amino acids, in this case, l-valine or l-allo-isoleucine.

Targeting ferroptosis by natural products in pathophysiological conditions.

Ferroptosis is a form of cell death that is induced by iron-mediated accumulation of lipid peroxidation. The involvement of ferroptosis in different pathophysiological conditions has offered new perspectives on potential therapeutic interventions. Natural products, which are widely recognized for their significance in drug discovery and repurposing, have shown great promise in regulating ferroptosis by targeting various ferroptosis players. In this review, we discuss the regulatory mechanisms of ferroptosis and its implications in different pathological conditions. We dissect the interactions between natural products and ferroptosis in cancer, ischemia/reperfusion, neurodegenerative diseases, acute kidney injury, liver injury, and cardiomyopathy, with an emphasis on the relevance of ferroptosis players to disease targetability.

Natural products as promising modulators of breast cancer immunotherapy

Breast cancer (BC) is the most common malignancy among women and is considered a major global health challenge worldwide due to its high incidence and mortality rates. Treatment strategies for BC is wide-ranging and include surgery, radiotherapy, chemotherapy, targeted hormonal therapy and immunotherapy. Immunotherapy has gained popularity recently and is often integrated as a component of personalized cancer care because it aims to strengthen the immune system and enable it to recognize and eradicate transformed cells. It has fewer side-effects and lower toxicity than other treatment strategies, such as chemotherapy. Many natural products are being investigated for a wide range of therapeutic pharmacological properties, such as immune system modulation and activity against infection, auto-immune disease, and cancer. This review presents an overview of the major immune response-related pathways in BC, followed by detailed explanation of how natural compounds can act as immunomodulatory agents against biomolecular targets. Research has been carried out on many forms of natural products, including extracts, isolated entities, synthetic derivatives, nanoparticles, and combinations of natural compounds. Findings have shown significant regulatory effects on immune cells and immune cytokines that lead to immunogenic cancer cell death, as well as upregulation of macrophages and CD+8 T cells, and increased natural killer cell and dendritic cell activity. Natural products have also been found to inhibit some immuno-suppressive cells such as Treg and myeloid-derived suppressor cells, and to decrease immunosuppressive factors such as TGF-β and IL-10. Also, some natural compounds have been found to target and hinder immune checkpoints such as PD-L1.

Ketone Scope and Their Limitations in Transition Metal Catalyzed Direct Asymmetric Hydrogenative Aminations

AbstractChiral amines are valuable building blocks in the manufacture of agrochemicals, pharmaceuticals, natural products, fine chemicals, functional materials among others. Compared to asymmetric hydrogenation of imines/enamides and biocatalytic/organocatalytic asymmetric reductive amination, transition metal catalyzed direct asymmetric hydrogenative amination reactions (DAHA) using molecular dihydrogen as the reductant are highly economical, atom and/or step‐efficient and thus attractive for researchers from both industry and academia. In previous reviews, catalysts/methods development, applications in synthesis of pharmaceuticals and [N] source were summarized and discussed. In this review, we summarize and discuss the ketone substrates scope upon utilizing the state‐of‐the‐art transition metal catalysts. The substrate limitations, potential applications and key mechanisms are also critically concluded.

Chemoenzymatic Synthesis of Fluorinated Mycocyclosin Enabled by the Engineered Cytochrome P450-Catalyzed Biaryl Coupling Reaction.

Installing fluorine atoms onto natural products holds great promise for the generation of fluorinated molecules with improved or novel pharmacological properties. The enzymatic oxidative carbon-carbon coupling reaction represents a straightforward strategy for synthesizing biaryl architectures, but the exploration of this method for producing fluorine-substituted derivatives of natural products remains elusive. Here, in this study, we report the protein engineering of cytochrome P450 from Mycobacterium tuberculosis (MtCYP121) for the construction of a series of new-to-nature fluorine-substituted Mycocyclosin derivatives. This protocol takes advantage of a "hybrid" chemoenzymatic procedure consisting of tyrosine phenol lyase-catalyzed fluorotyrosine preparation from commercially available fluorophenols, intermolecular chemical condensation to give cyclodityrosines, and an engineered MtCYP121-catalyzed intramolecular biphenol coupling reaction to complete the strained macrocyclic structure. Computational mechanistic studies reveal that MtCYP121 employs Cpd I to abstract a hydrogen atom from the proximal phenolic hydroxyl group of the substrate to trigger the reaction. Then, conformational change makes the two phenolic hydroxyl groups close enough to undergo intramolecular hydrogen atom transfer with the assistance of a pocket water molecule. The final diradical coupling process completes the intramolecular C-C bond formation. The efficiency of the biaryl coupling reaction was found to be influenced by various fluorine substitutions, primarily due to the presence of distinct binding conformations.

Natural products as promising modulators of breast cancer immunotherapy

Natural products as promising modulators of breast cancer immunotherapy

De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis.

Precisely controlling the product selectivity of a reaction is an important objective in organic synthesis. α-Ketoamides are vital intermediates in chemical transformations and privileged motifs in numerous drugs, natural products, and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing catalysis challenge. Herein, an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction for assembling ketoamides in aqueous DMSO from (hetero)aryl halides and pseudohalides under mild conditions is reported. The effectiveness and utility of this protocol are demonstrated by its diverse substrate scope (93 examples), the ability to late-stage modify pharmaceuticals, scalability to large-scale synthesis, and the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand that modulates the Pd-catalyzed double isocyanide insertion process, thereby selectively providing the desired α-ketoamides in a unique manner. In addition, the imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, confirming that they are probable intermediates in the catalytic pathway.

De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis.

Precisely controlling the product selectivity of a reaction is an important objective in organic synthesis. α-Ketoamides are vital intermediates in chemical transformations and privileged motifs in numerous drugs, natural products, and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing catalysis challenge. Herein, an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction for assembling ketoamides in aqueous DMSO from (hetero)aryl halides and pseudohalides under mild conditions is reported. The effectiveness and utility of this protocol are demonstrated by its diverse substrate scope (93 examples), the ability to late-stage modify pharmaceuticals, scalability to large-scale synthesis, and the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand that modulates the Pd-catalyzed double isocyanide insertion process, thereby selectively providing the desired α-ketoamides in a unique manner. In addition, the imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, confirming that they are probable intermediates in the catalytic pathway.

Effect of Jinhuahecha—A Fermented Green Tea on DSS-Induced Ulcerative Colitis in Mice and Its Preliminary Pharmacological Mechanism

Background: Ulcerative colitis (UC) is an inflammatory bowel disease. Jinhuahecha (JHHC)-a fermented green tea is obtained by micro-fermentation of Anji white tea (AJWT) inoculated with high-purity "E. cristatum". Purpose: This study is aimed to unravel the protective effect of JHHC to UC in mice. Methods: High performance liquid chromatography (HPLC) was applied to determine the effective components and their contents in JHHC and AJWT. UC mouse model was constructed by ingestion of 2.5% dextran sulfate sodium (DSS) aqueous solution for 9 days. Disease activity index (DAI) was evaluated with the daily weight, fecal characters, and bloody stool condition, the length of colon and the spleen coefficients in mice was measured. Hematoxylin and eosin and Alcian blue-periodic acid Schiff staining was performed to observe the histopathological changes of the colon tissue. The positive expression of MyD88 and TNF-α were observed by immunofluorescence and immunohistochemistry. The possible mechanism was speculated by via transcriptomics. Results: HPLC results indicated that compared with AJWT, in JHHC, the content of gallic acid was significantly increased, the caffeine content was slightly decreased, and the polyphenolic components were notably declined. Compared to normal control group, in model control group, DAI score and spleen coefficient were elevated, the length of colon was shortened, and the colon tissue was severely damaged. In contrast to model control group, the above indexes were improved in treatment group, especially in JHHC group, which was possibly associated with regulation of inflammatory response. Conclusions: JHHC, as a natural plant product, has anti-inflammatory effects that can alleviate UC in mice.

Identification of potential natural product derivatives as CK2 inhibitors based on GA-MLR QSAR modeling, synthesis and biological evaluation

Identification of potential natural product derivatives as CK2 inhibitors based on GA-MLR QSAR modeling, synthesis and biological evaluation

Oral Nanoformulations in Cardiovascular Medicine: Advances in Atherosclerosis Treatment

Atherosclerosis (AS) is the formation of atherosclerotic plaques on the walls of the arteries, causing them to narrow. If this occurs in the coronary arteries, the blood vessels may be completely blocked, resulting in myocardial infarction; if it occurs in the blood vessels of the brain, the blood vessels may be blocked, resulting in cerebral infarction, i.e., stroke. Studies have shown that the pathogenesis of atherosclerosis involves the processes of inflammation, lipid infiltration, oxidative stress, and endothelial damage, etc. SIRT, as a key factor regulating the molecular mechanisms of oxidative stress, inflammation, and aging, has an important impact on the pathogenesis of plaque formation, progression, and vulnerability. Statistics show that AS accounts for about 50 per cent of deaths in Western countries. Currently, oral medication is the mainstay of AS treatment, but its development is limited by side effects, low bioavailability and other unfavourable factors. In recent years, with the rapid development of nano-preparations, researchers have combined statins and natural product drugs within nanopreparations to improve their bioavailability. Based on this, this paper summarises the main pathogenesis of AS and also proposes new oral nanoformulations such as liposomes, nanoparticles, nanoemulsions, and nanocapsules to improve their application in the treatment of AS.

Pressurized Hot Water Extraction as Green Technology for Natural Products as Key Technology with Regard to Hydrodistillation and Solid–Liquid Extraction

Pressurized Hot Water Extraction as Green Technology for Natural Products as Key Technology with Regard to Hydrodistillation and Solid–Liquid Extraction

Iron-sulphur protein catalysed [4+2] cycloadditions in natural product biosynthesis

To the best of our knowledge, enzymes that catalyse intramolecular Diels-Alder ([4+2] cycloaddition) reactions are frequently reported in natural product biosynthesis; however, no native enzymes utilising Lewis acid catalysis have been reported. Verticilactam is a representative member of polycyclic macrolactams, presumably produced by spontaneous cycloaddition. We report that the intramolecular [4+2] cycloadditions can be significantly accelerated by ferredoxins (Fds), a class of small iron-sulphur (Fe-S) proteins. Through iron atom substitution by Lewis acidic gallium (Ga) iron and computational calculations, we confirm that the ubiquitous Fe-S cluster efficiently functions as Lewis acid to accelerate the tandem [4+2] cycloaddition and Michael addition reactions by lowering free energy barriers. Our work highlights Nature’s ingenious strategy to generate complex molecule structures using the ubiquitous Fe-S protein. Furthermore, our study sheds light on the future design of Fd as a versatile Lewis acid catalyst for [4+2] cycloaddition reactions.

Potent and Selective Oxidatively Labile Ether-Based Prodrugs through Late-Stage Boronate Incorporation.

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin-based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non-cancerous cell lines. This late-stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.

Pressurized Hot Water Extraction as Green Technology for Natural Products as Key Technology with Regard to Hydrodistillation and Solid–Liquid Extraction

Pressurized Hot Water Extraction as Green Technology for Natural Products as Key Technology with Regard to Hydrodistillation and Solid–Liquid Extraction