Natural Product Drug Discovery Research Articles

Catalytic radical generation of π-allylpalladium complexes

Transition metal catalysed allylic substitution is one of the most powerful and frequently used methods in organic synthesis. In particular, palladium-catalysed allylic functionalization has become a well-established strategy for constructing carbon–carbon or carbon–heteroatom bonds, and its utility has been demonstrated in natural product synthesis, drug discovery and materials science. Several methods have been developed to generate π-allylpalladium complexes through ionic mechanisms; however, these methods typically require either prefunctionalized starting materials or stoichiometric oxidants, which naturally limits their scope. Here, we show a radical approach for the generation of π-allylpalladium complexes by employing N-hydroxyphthalimide esters as bifunctional reagents in combination with 1,3-dienes. Using this strategy, we report the 1,4-aminoalkylation of dienes. The remarkable scope and functional group tolerance of this redox-neutral and mild protocol was demonstrated across >60 examples. The utility of this strategy was further demonstrated in radical cascade reactions and in the late-stage modification of drugs and natural products. Palladium-catalysed allylic substitution is a widely used method in organic synthesis, although it requires prefunctionalized starting materials or stoichiometric oxidants. Here the authors report a radical route to form π-allylpalladium complexes, and develop a 1,4-aminoalkylation of dienes under redox-neutral conditions.

Machine learning for natural extracts

Cheminformatics Natural products and their derivatives continue to be an important source of drug candidates because of their structural diversity and wide-ranging biological activities, which are unmatched by synthetic compounds. Natural products are generally complex mixtures with chemical constituents that are not well characterized. Reher et al. report a nuclear magnetic resonance–based machine-learning tool, SMART, for rapid structural analysis of major constituents from crude natural extracts and for the discovery of new natural products. For example, SMART automatically characterized a cyanobacterial extract mixture and isolated a new chimeric macrolide, symplocolide A; it also dereplicated several known natural products. The proposed cheminformatic tool paves the way for new computer-aided approaches to natural product drug discovery. J. Am. Chem. Soc. 142 , 4114 (2020).

Repositioning Natural Products in Drug Discovery

Drug repositioning (o repurposing) has become one of the most popular and successful strategies to reduce failures typically associated with drug discovery [...].

Local Phenomena Shape Backyard Soil Metabolite Composition.

Soil covers most of Earth’s continental surface and is fundamental to life-sustaining processes such as agriculture. Given its rich biodiversity, soil is also a major source for natural product drug discovery from soil microorganisms. However, the study of the soil small molecule profile has been challenging due to the complexity and heterogeneity of this matrix. In this study, we implemented high-resolution liquid chromatography–tandem mass spectrometry and large-scale data analysis tools such as molecular networking to characterize the relative contributions of city, state and regional processes on backyard soil metabolite composition, in 188 soil samples collected from 14 USA States, representing five USA climate regions. We observed that region, state and city of collection all influence the overall soil metabolite profile. However, many metabolites were only detected in unique sites, indicating that uniquely local phenomena also influence the backyard soil environment, with both human-derived and naturally-produced (plant-derived, microbially-derived) metabolites identified. Overall, these findings are helping to define the processes that shape the backyard soil metabolite composition, while also highlighting the need for expanded metabolomic studies of this complex environment.

Using the Cancer Dependency Map to Identify the Mechanism of Action of a Cytotoxic Alkenyl Derivative from the Fruit of Choerospondias axillaris.

An extract prepared from the fruit of Choerospondias axillaris exhibited differential cytotoxic effects when tested in a panel of pediatric cancer cell lines [Ewing sarcoma (A-673), rhabdomyosarcoma (SJCRH30), medulloblastoma (D283), and hepatoblastoma (Hep293TT)]. Bioassay-guided fractionation led to the purification of five new hydroquinone-based metabolites, choerosponols A-E (1-5), bearing unsaturated hydrocarbon chains. The structures of the natural products were determined using a combination of 1D and 2D NMR, HRESIMS, ECD spectroscopy, and Mosher ester analyses. The purified compounds were evaluated for their antiproliferative and cytotoxic activities, revealing that 1, which contains a benzofuran moiety, exhibited over 50-fold selective antiproliferative activity against Ewing sarcoma and medulloblastoma cells with growth inhibitory (GI50) values of 0.19 and 0.07 μM, respectively. The effects of 1 were evaluated in a larger panel of cancer cell lines, and these data were used in turn to interrogate the Project Achilles cancer dependency database, leading to the identification of the MCT1 transporter as a functional target of 1. These data highlight the utility of publicly available cancer dependency databases such as Project Achilles to facilitate the identification of the mechanisms of action of compounds with selective activities among cancer cell lines, which can be a major challenge in natural products drug discovery.

A Convolutional Neural Network-Based Approach for the Rapid Annotation of Molecularly Diverse Natural Products.

This report describes the first application of the novel NMR-based machine learning tool "Small Molecule Accurate Recognition Technology" (SMART 2.0) for mixture analysis and subsequent accelerated discovery and characterization of new natural products. The concept was applied to the extract of a filamentous marine cyanobacterium known to be a prolific producer of cytotoxic natural products. This environmental Symploca extract was roughly fractionated, and then prioritized and guided by cancer cell cytotoxicity, NMR-based SMART 2.0, and MS2-based molecular networking. This led to the isolation and rapid identification of a new chimeric swinholide-like macrolide, symplocolide A, as well as the annotation of swinholide A, samholides A-I, and several new derivatives. The planar structure of symplocolide A was confirmed to be a structural hybrid between swinholide A and luminaolide B by 1D/2D NMR and LC-MS2 analysis. A second example applies SMART 2.0 to the characterization of structurally novel cyclic peptides, and compares this approach to the recently appearing "atomic sort" method. This study exemplifies the revolutionary potential of combined traditional and deep learning-assisted analytical approaches to overcome longstanding challenges in natural products drug discovery.

Metabolomics in the Context of Plant Natural Products Research: From Sample Preparation to Metabolite Analysis.

Plant-derived natural products have long been considered a valuable source of lead compounds for drug development. Natural extracts are usually composed of hundreds to thousands of metabolites, whereby the bioactivity of natural extracts can be represented by synergism between several metabolites. However, isolating every single compound from a natural extract is not always possible due to the complex chemistry and presence of most secondary metabolites at very low levels. Metabolomics has emerged in recent years as an indispensable tool for the analysis of thousands of metabolites from crude natural extracts, leading to a paradigm shift in natural products drug research. Analytical methods such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) are used to comprehensively annotate the constituents of plant natural products for screening, drug discovery as well as for quality control purposes such as those required for phytomedicine. In this review, the current advancements in plant sample preparation, sample measurements, and data analysis are presented alongside a few case studies of the successful applications of these processes in plant natural product drug discovery.

Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity.

We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2 + 2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular architecture with at least three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C-C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. Density functional theory calculations were used to compute the T1-S0 free energy gap of the olefin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasibility.

Natural product drug discovery using zebrafish screening: Anti-obese constituents hunting by combination with culture cells and mice experiments.

Natural product drug discovery using zebrafish screening: Anti-obese constituents hunting by combination with culture cells and mice experiments.

Bridging the gap between natural product synthesis and drug discovery.

Covering: 1986 to 2020Natural products are an enduring source of chemical information useful for probing biologically relevant chemical space. Toward gathering further structure-activity relationship (SAR) information for a particular natural product, synthetic chemists traditionally proceeded first by a total synthesis effort followed by the synthesis of simplified derivatives. While this approach has proven fruitful, it often does not incorporate hypotheses regarding structural features necessary for bioactivity at the synthetic planning stage, but rather focuses on the rapid assembly of the targeted natural product; a goal that often supersedes the opportunity to gather SAR information en route to the natural product. Furthermore, access to simplified variants of a natural product possessing only the proposed essential structural features necessary for bioactivity, typically at lower oxidation states overall, is sometimes non-trivial from the original established synthetic route. In recent years, several synthetic design strategies were described to streamline the process of finding bioactive molecules in concert with fathering further SAR studies for targeted natural products. This review article will briefly discuss traditional retrosynthetic strategies and contrast them to selected examples of recent synthetic strategies for the investigation of biologically relevant chemical space revealed by natural products. These strategies include: diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS), diverted-total synthesis (DTS), analogue-oriented synthesis (AOS), two-phase synthesis, function-oriented synthesis (FOS), and computed affinity/dynamically ordered retrosynthesis (CANDOR). Finally, a description of pharmacophore-directed retrosynthesis (PDR) developed in our laboratory and initial applications will be presented that was initially inspired by a retrospective analysis of our synthetic route to pateamine A completed in 1998.

Prophylaxis and treatment aspect of COVID-19 with the use of Indian traditional plant-based medicine: A hypothetical review

HCoV (human coronavirus) is a retrovirus containing an enveloped virus belongs to Coronaviridae family. Coronavirus (CoV) family is composed of numerous viral strains and responsible for the cause of common cold, breathing problem, and fever. The chronic CoV infection may cause pneumonia and severe acute respiratory syndrome coronavirus (SARS-CoV) in human beings. The known strains of HCoV are HCoV-OC-43, -229E, and -HKU1. The more extensively known strain is SARS-CoV which caused a worldwide threat with the sky-scraping number of deaths with high mortality rate in 2003. In the year of 2012, the World Health Organization (WHO) nominated a sixth type of HCoV infection recognized as Middle East respiratory syndrome coronavirus (MERS-CoV) which affected Middle East region of the world and showed a high fatality rate. In a similar way, currently coronavirus disease-2019 (COVID-19) has been pandemic and fatal worldwide, which has been originated at China during December 2019. At present, there is no vaccine or treatment to cure COVID-19 infection. In such a time, the pharmaceuticals should promote and encourage natural product drug discovery programs. They should inspire the academic organizations to perform committed research activities to develop natural and alternative therapeutics. Till the date numbers of Indian traditional plants have been reported showing their antiviral potential, immunemodulating potential, and respiroprotective effects. In this review, such kinds of potent antiviral traditional plants are listed and described in very detailed manner along with their active phytoconstituents as well as mechanism of actions. In the current pandemic situation of COVID-19, these traditional plants can be a rich source to develop and design novel natural medicines, therapies, or vaccines against HCoV-2.

Dereplication of Natural Products with Antimicrobial and Anticancer Activity from Brazilian Cyanobacteria.

Cyanobacteria are photosynthetic organisms that produce a large diversity of natural products with interesting bioactivities for biotechnological and pharmaceutical applications. Cyanobacterial extracts exhibit toxicity towards other microorganisms and cancer cells and, therefore, represent a source of potentially novel natural products for drug discovery. We tested 62 cyanobacterial strains isolated from various Brazilian biomes for antileukemic and antimicrobial activities. Extracts from 39 strains induced selective apoptosis in acute myeloid leukemia (AML) cancer cell lines. Five of these extracts also exhibited antifungal and antibacterial activities. Chemical and dereplication analyses revealed the production of nine known natural products. Natural products possibly responsible for the observed bioactivities and five unknown, chemically related chlorinated compounds present only in Brazilian cyanobacteria were illustrated in a molecular network. Our results provide new information on the vast biosynthetic potential of cyanobacteria isolated from Brazilian environments.

Potential Targets of Actein Identified by Systems Chemical Biology Methods.

Actein is the main active ingredient of medicinal plant Cimicifuga racemosa (L.) Nutt, which has been reported to have various pharmacological effects, but the mechanism of actein remains undetermined. In this study, systems chemical biology methods were used to predict the targets and elucidate the pharmacological mechanisms of actein. First, 54 gene co-expression modules were obtained by biclustering. Then, the top 1 % agents with the highest regulatory similarity were screened out to be highly functionally similar to actein. Finally, the results of molecular docking and molecular dynamics simulation showed that actein has a stronger interaction with eight targets than original ligands. It suggests that the antipsychotic effect of actein probably occurs by targeting the key residues of the eight receptors, which are compatible with previously reported information. This study not only provides predicted targets of actein, but also a new method for exploring the mechanisms of other natural products in drug discovery.

Integration of micro-fractionation, high-performance liquid chromatography-ultraviolet detector-charged aerosol detector-mass spectrometry analysis and cellular dynamic mass redistribution assay to accelerate alkaloid drug discovery

Natural products, including alkaloids, are important resources for new drugs. However, in today's high throughput screening (HTS) environment, natural product drug discovery programs are challenged for their low efficiency. In order to adapt to current HTS models, we here developed a rapid, sample-saving and miniaturized paradigm that seamlessly integrated alkaloid micro-fractionation, quantitative analysis, qualitative analysis and phenotypic screening. In the work, alkaloid samples were analyzed and fractionated on an analytical charged C18 column (150 × 4.6 mm, i.d.), and fraction qualities were determined by a charged aerosol detector (CAD). Fraction activities on dopamine D2 receptor were screened by cellular dynamic mass redistribution (DMR) assay and active fractions were further characterized by high-resolution mass spectrometry (MS). The whole workflow was first validated by mixed standard for accuracy, and then by 300 μg of Corydalis yanhusuo extract for its feasibility in complex samples. Finally, the method was applied for sample prioritization in four papaveraceae family plants and 21 compounds were predicted to be active, and Corydalis yanhusuo and Corydalis decumbens were determined as promising species for activity tracking. Overall, these results highlighted the feasibility of this miniatured and integrated model in rapid alkaloid screening. Advantages of this workflow were: first, the highly efficient separation method accelerated alkaloid fractionation; second, the analytical and biological test were conducted on the same scale; third, the quantification method ensured accurate screening on microscale; last, the combination of MS analysis and data mining strategy accelerated the decision-making process in the primary screening.

Natural Products in Drug Discovery: Antibacterial and Antifungal Activity of Essential Oil of Compound Isolated from Senecio royleanus

Chandra Mohan Singh Bisht1, S.M. Shakeel Iqubal2* , Aejaz A. Khan2,Tasneem Mohammed2 , Areej Dawoud2, Mohammed Gamal3,4 , S.K. Singh5 and Basim H. Asghar6Article: 5750 | Pages: 1611-1617Abstract | Full Text | PDF | XML https://doi.org/10.22207/JPAM.13.3.34

Two Trifunctional Leloir Glycosyltransferases as Biocatalysts for Natural Products Glycodiversification.

Two promiscuous Bacillus licheniformis glycosyltransferases, YdhE and YojK, exhibited prominent stereospecific but nonregiospecific glycosylation activity of 20 different classes of 59 structurally different natural and non-natural products. Both enzymes transferred various sugars at three nucleophilic groups (OH, NH2, SH) of diverse compounds to produce O-, N-, and S-glycosides. The enzymes also displayed a catalytic reversibility potential for a one-pot transglycosylation, thus bestowing a cost-effective application in biosynthesis of glycodiversified natural products in drug discovery.

Computational methods for NMR and MS for structure elucidation II: database resources and advanced methods

Abstract Technological advances have contributed to the evolution of the natural product chemistry and drug discovery programs. Recently, computational methods for nuclear magnetic resonance (NMR) and mass spectrometry (MS) have speeded up and facilitated the process of structural elucidation even in high complex biological samples. In this chapter, the current computational tools related to NMR and MS databases and spectral similarity networks, as well as their applications on dereplication and determination of biological biomarkers, are addressed.

The Application of Ribosome Engineering to Natural Product Discovery and Yield Improvement in Streptomyces

Microbial natural product drug discovery and development has entered a new era, driven by microbial genomics and synthetic biology. Genome sequencing has revealed the vast potential to produce valuable secondary metabolites in bacteria and fungi. However, many of the biosynthetic gene clusters are silent under standard fermentation conditions. By rational screening for mutations in bacterial ribosomal proteins or RNA polymerases, ribosome engineering is a versatile approach to obtain mutants with improved titers for microbial product formation or new natural products through activating silent biosynthetic gene clusters. In this review, we discuss the mechanism of ribosome engineering and its application to natural product discovery and yield improvement in Streptomyces. Our analysis suggests that ribosome engineering is a rapid and cost-effective approach and could be adapted to speed up the discovery and development of natural product drug leads in the post-genomic era.

Biochemometrics and Required Tools in Botanical Natural Products Research: A Review.

This review serves to highlight the role of chemometrics and biochemometrics in recent literature as well as including a perspective on the current state of the field, as well as the future needs and possible directions. Specifically examining the analytical methods and statistical tools that are available to chemists, current applications of QTOF-MS, Orbitrap-MS, LC with PDA/UV detectors, NMR, and IMS coupled MS are detailed. Of specific interest, these techniques can be applied to botanical dietary supplement quality, efficacy, and safety. Application in natural products drug discovery, industrial quality control, experimental design, and more are also discussed.

Studies on antivenom activity of Lactuca serriola methanolic extract against Buthus atlantis scorpion venom by in vivo methods

Lactuca serriola is a well-known plant in the El kalaa of Sraghna region that occupies an important place in traditional medicine for its alleged effectiveness against the venom of scorpions and snakes.This work aims to study the neutralizing capacity of Lactuca serriola extracts on scorpion Buthus atlantis venom by histological and biochemical analyses.In this study we test for the first time, the anti-venom activity of Lactuca serriola against Buthus atlantis venom by fixing the dose of venom at LD99, while the dose of the extract was variable (0.5, 2 g/kg). Histological changes in vital organs as well as biochemical changes in mice were recorded. The quantification and qualification of polyphenols were performed by High Performance Liquid phase Chromatography (HPLC).The results showed that the LD50 of Buthus atlantis venom subcutaneously is 0.4 mg/kg, and the methanolic extract of the plant Lactuca serriola at the dose of 2 g/kg administered orally had a 66.66% protective capacity. Based on the results of the histological and biochemical study, the effect of the venom revealed tissue damage and enzyme imbalance, whereas the administration of the plant extract showed restoration of lesions in the different tissues, and a counteraction of the serum enzyme imbalance. HPLC analysis of the polyphenols revealed the presence of chlorogenic acid, sorbic acid, coumaric acid and quercetin.The present study supports the traditional use of Lactuca serriola as anti-venom and the potential for natural product drug discovery.