Natural Product Drug Discovery Research Articles

Natural Products as Modulators of Sirtuins.

Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds, as well as the potential application of naturally occurring sirtuin inhibitors in human health and those in clinical trials.

Anti-Cancer Constituents from Plants: Mini Review

Now-a-days, cancer is a major concern globally, for which a large number of deaths occur annually, instead of the accessibility to various treatment options. Nevertheless, the latest treatment options are principally conglomerate with many side effects. Consequently, the development of an effective and competent anticancer therapy with the lower or minimum adverse or unwanted minor effect is the prime direction of research in the fields of natural product chemistry, drug design, and drug discovery. Phytochemicals available in plants have already been proven as prospective candidates in this regard. In general, phytochemicals are non-selective in their functions and restricted due to their differential activity on cancer cells along with the normal cells. As a consequence, researchers show their interest in isolating bioactive phytochemicals from nature with potent anticancer properties and generate lead compounds based on the natural skeleton of a molecule as a synthetic approach. Several phytomolecules have already been in existence for their in-vitro and in-vivo anticancer activities. This article deals with these lead phytomolecules from fifty-two species belong to thirty-five families with their reported mechanisms of action on nuclear and cellular factors involved in the treatment of carcinogenesis.
 Dhaka Univ. J. Pharm. Sci. 19(1): 83-96, 2020 (June)

The Social and Material Life of Antimicrobial Clay: Exploring Antimicrobial Resistance, Medicines' Materiality, and Medicines Optimization.

While sociologists have made significant theoretical contributions to the antimicrobial resistance (AMR) debate, little attention has been given to the antimicrobial products themselves. Here we advocate a significant new direction which centers on the social and material life of antimicrobials, specifically on what they are made from and how this affects their use. This focus is timely because, in the context of declining efficacy of biomedical antibiotics, diverse materials are increasingly taking center stage in research and drug discovery as potential agents for new antimicrobial treatments. Of particular significance are natural antimicrobials, such as plants, honey and clay, whose antimicrobial potential is well-documented and which are increasingly moving into mainstream antimicrobial research. Alongside this biomedical focus, we suggest that the social and material lives of these antimicrobial materials require attention to (i) highlight the ways they have been, and continue to be, used in diverse cultures globally, (ii) explore ways we might theorize these materials within wider AMR debates, and (iii) examine the impact of antimicrobials' materiality on their use by patients. This article takes the example of clay, whose antimicrobial properties are well-established and which has been used to treat wounds and gastrointestinal problems for millennia. We first locate clay as an exemplar of a wider shift toward natural products drug discovery in pharmaceutical science and antimicrobial research. We then offer a number of theoretical “ways in” for sociologists to begin making sense of clay as it comes under the western biomedical gaze. We map these conceptual lenses on to clay's physical and symbolic mobility from its use in the global south into western biomedical research and commercialization. We particularly concentrate on post-colonial theory as a means to understand clay's movement from global south to north; laboratory studies to examine its symbolic transformation to a black-boxed antimicrobial artifact; and valuation practices as a lens to capture its movement from the margins to the mainstream. We finish by reflecting on the importance of materiality in addressing optimal use of medicines and by advocating an interdisciplinary approach to AMR which positions sociology as a key contributor to AMR solutions.

Microbial Natural Products in Drug Discovery

Over a long period of time, humans have explored many natural resources looking for remedies of various ailments. Traditional medicines have played an intrinsic role in human life for thousands of years, with people depending on medicinal plants and their products as dietary supplements as well as using them therapeutically for treatment of chronic disorders, such as cancer, malaria, diabetes, arthritis, inflammation, and liver and cardiac disorders. However, plant resources are not sufficient for treatment of recently emerging diseases. In addition, the seasonal availability and other political factors put constrains on some rare plant species. The actual breakthrough in drug discovery came concurrently with the discovery of penicillin from Penicillium notatum in 1929. This discovery dramatically changed the research of natural products and positioned microbial natural products as one of the most important clues in drug discovery due to availability, variability, great biodiversity, unique structures, and the bioactivities produced. The number of commercially available therapeutically active compounds from microbial sources to date exceeds those discovered from other sources. In this review, we introduce a short history of microbial drug discovery as well as certain features and recent research approaches, specifying the microbial origin, their featured molecules, and the diversity of the producing species. Moreover, we discuss some bioactivities as well as new approaches and trends in research in this field.

Nanoemulsion preconcentrate of a pentacyclic triterpene for improved oral efficacy: Formulation design and in-vivo antimalarial activity

In order to develop new lead from plant, natural product drug discovery is one of the popular choices which deal numerous unprecedented challenges. Lupeol, a monohydroxylated pentacyclic triterpenoid is abundantly distributed in the plants across genus in varying amount and posses antimalarial potential. However, the therapeutic potential of pentacyclic triterpenes is still under-exploited due to their low intestinal absorption. In the present study, a nanoemulsion preconcentrate (NPs) of lupeol with oil phase and ion surfactants was prepared and evaluated for antimalarial action. Lupeol was isolated and characterized from aerial parts of Stereospermum suaveolens DC. Oil phase comprising caprylic acid: oleic acid (2:1) and Smix (surfactant and co-surfactant) was used to develop a colloidal drug carrier following low energy nanoemulsion formation method. The Smix was optimized using tween 20 and transcutol HP (Km 2:1). Optimization of nanoemulsion was achieved in terms of thermodynamic stability, phase behaviour, globule size, polydispersity, rate of drug release, and high solubility without variable absorption for stable nanoemulsion. Developed NPs was investigated for in-vivo antimalarial efficacy. Improved efficacy was observed with a half dose of lupeol in nanoemulsion which attributed to a significant increase in blood glucose and haemoglobin level as compared with vehicle-treated infected mice. The present study is demonstrating that optimized nanoemulsion preconcentrate could be applied as a drug carrier for effective pentacyclic triterpene delivery and improved therapeutic action.

Regulation of Antimycin Biosynthesis Is Controlled by the ClpXP Protease.

The survival of any microbe relies on its ability to respond to environmental change. Use of extracytoplasmic function (ECF) RNA polymerase sigma (σ) factors is a major strategy enabling dynamic responses to extracellular signals. Streptomyces species harbor a large number of ECF σ factors, nearly all of which are uncharacterized, but those that have been characterized generally regulate genes required for morphological differentiation and/or response to environmental stress, except for σAntA, which regulates starter-unit biosynthesis in the production of antimycin, an anticancer compound. Unlike a canonical ECF σ factor, whose activity is regulated by a cognate anti-σ factor, σAntA is an orphan, raising intriguing questions about how its activity may be controlled. Here, we reconstituted in vitro ClpXP proteolysis of σAntA but not of a variant lacking a C-terminal di-alanine motif. Furthermore, we show that the abundance of σAntAin vivo was enhanced by removal of the ClpXP recognition sequence and that levels of the protein rose when cellular ClpXP protease activity was abolished. These data establish direct proteolysis as an alternative and, thus far, unique control strategy for an ECF RNA polymerase σ factor and expands the paradigmatic understanding of microbial signal transduction regulation.IMPORTANCE Natural products produced by Streptomyces species underpin many industrially and medically important compounds. However, the majority of the ∼30 biosynthetic pathways harbored by an average species are not expressed in the laboratory. This unrevealed biochemical diversity is believed to comprise an untapped resource for natural product drug discovery. Major roadblocks preventing the exploitation of unexpressed biosynthetic pathways are a lack of insight into their regulation and limited technology for activating their expression. Our findings reveal that the abundance of σAntA, which is the cluster-situated regulator of antimycin biosynthesis, is controlled by the ClpXP protease. These data link proteolysis to the regulation of natural product biosynthesis for the first time to our knowledge, and we anticipate that this will emerge as a major strategy by which actinobacteria regulate production of their natural products. Further study of this process will advance understanding of how expression of secondary metabolism is controlled and will aid pursuit of activating unexpressed biosynthetic pathways.

Jatrophane and rearranged jatrophane-type diterpenes: biogenesis, structure, isolation, biological activity and SARs (1984-2019).

Diterpene compounds specially macrocyclic ones comprising jatrophane, lathyrane, terracinolide, ingenane, pepluane, paraliane, and segetane skeletons occurring in plants of the Euphorbiaceae family are of considerable interest in the context of natural product drug discovery programs. They possess diverse complex skeletons and a broad spectrum of therapeutically relevant biological activities including anti-inflammatory, anti-chikungunya virus, anti-HIV, cytotoxic, and multidrug resistance-reversing activities as well as curative effects on thrombotic diseases. Among macrocyclic diterpenes of Euphorbia, the discovery of jatrophane and modified jatrophane diterpenes with a wide range of structurally unique polyoxygenated polycyclic derivatives and as a new class of powerful inhibitors of P-glycoprotein has opened new frontiers for research studies on this genus. In this review, an attempt has been made to give in-depth coverage of the articles on the naturally occurring jatrophanes and rearranged jatrophane-type diterpenes isolated from species belonging to the Euphorbiaceae family published from 1984 to March 2019, with emphasis on the biogenesis, isolation methods, structure, biological activity, and structure–activity relationship. Electronic supplementary materialThe online version of this article (10.1007/s11101-020-09667-8) contains supplementary material, which is available to authorized users.

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.