natural product literature review

• Open access
• Published: 03 April 2020

Review on natural products databases: where to find data in 2020

• Maria Sorokina   ORCID: orcid.org/0000-0001-9359-7149 1 &
• Christoph Steinbeck   ORCID: orcid.org/0000-0001-6966-0814 1  

Journal of Cheminformatics volume  12 , Article number:  20 ( 2020 ) Cite this article

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Natural products (NPs) have been the centre of attention of the scientific community in the last decencies and the interest around them continues to grow incessantly. As a consequence, in the last 20 years, there was a rapid multiplication of various databases and collections as generalistic or thematic resources for NP information. In this review, we establish a complete overview of these resources, and the numbers are overwhelming: over 120 different NP databases and collections were published and re-used since 2000. 98 of them are still somehow accessible and only 50 are open access. The latter include not only databases but also big collections of NPs published as supplementary material in scientific publications and collections that were backed up in the ZINC database for commercially-available compounds. Some databases, even published relatively recently are already not accessible anymore, which leads to a dramatic loss of data on NPs. The data sources are presented in this manuscript, together with the comparison of the content of open ones. With this review, we also compiled the open-access natural compounds in one single dataset a COlleCtion of Open NatUral producTs (COCONUT), which is available on Zenodo and contains structures and sparse annotations for over 400,000 non-redundant NPs, which makes it the biggest open collection of NPs available to this date.

Introduction

Natural products (NPs), are broadly defined as chemicals produced by living organisms. More precise definitions of NPs exist, but they do not always meet a consensus: some of the NPs include all small molecules that result from metabolic reactions, others classify as “NP” only products of secondary, or non-essential, metabolism. In this review, we made the choice to exclude molecules that participate in the primary, or essential, metabolism, such as energy or anabolic pathways, and consider only molecules that are produced by living organisms in order to accomplish a “higher” function, such as signalling or defence and still smaller than 1500 Da. However, as for most of the definitions in life sciences, the line between primary and secondary metabolites is very thin and depends on the potential application of the molecule to categorise This categorisation justifies the necessity of dedicated NP databases or a proper annotation in generalistic databases of molecules.

NPs have evolved over millions of years and acquired a unique chemical diversity, which consequently results in the diversity of their biological activities and drug-like properties. Therefore, even before the rise of the modern chemical pharmacology, NPs have been used for centuries as components of traditional medicines, in particular as active components of herbal remedies. Nowadays, some of the traditional healing practices, such as Indian Ayurveda, traditional Chinese medicine or African herbal medicines, remain the primary treatment option for many people across the world, due to economic reasons, to personal beliefs or to the difficulty in accessing pharmaceutical products. In modern pharmacology too, NPs have become one of the most important resources for developing new lead compounds and scaffolds [ 1 , 2 , 3 ]. Every week, scientific articles in peer-reviewed journals are published describing the positive effects of NPs on the healing process of various human and animal diseases. Major classes of antibiotics and antifungals are based on NPs isolated from microorganisms. Drugs used in the treatment of various cancers, cardiovascular diseases, diabetes, and more are often NPs or their derivatives. For instance, between 1981 and 2014 over 50% of newly developed drugs were developed from NPs [ 1 ]. NPs and their derivatives are also actively studied in food [ 4 , 5 , 6 , 7 , 8 ], cosmetic industries [ 9 , 10 ] and in agriculture, with natural pesticides development [ 11 ]. This growing interest over NPs and their application resolved in uncontrollable growth of the number of published open and commercial databases, industrial catalogues, books of NPs and collections of structures provided in supplementary materials or research articles, compiling NPs from various organisms, geographical locations, targeted diseases and traditional uses. It became, therefore, a real challenge to find a complete and comprehensive open database for NPs. One other major problem is the publication of structures only in graphical format, such as in the annual reviews of Marine Natural Products [ 2 ]: these are not easily retrievable to be computationally analysed and they are not automatically integrated into public molecular databases. Virtual NP collections are therefore required for virtual screening, which is the first step in all exploratory molecular analyses and to some extent, in the discovery of NP-based drug or other types of active components. For example, the prior virtual screening of known NPs can prevent loss of time with extracting and purifying samples, postponing the wet lab step to the moment of theoretical identification of best candidates. In this way, the usage of modern cheminformatics technologies allows to accelerate research and save time and money for better results. The previous reviews on NPs databases are either outdated and do not reference the actual state of NP resources [ 12 , 13 ], either focus on one particular type of application for such databases [ 14 , 15 ], in particular databases that can be used for dereplication [ 16 ], a particular geographic origin of NPs [ 17 ] or simply do not refer a significant part of NP resources [ 18 ].

For this article, we reviewed a total of 123 resources listing NP structures cited in the scientific literature after 2000. Among them 92 are open and only 50 contain molecular structures that we could retrieve for analyses of their content, the overlap between them and compilation. The quality of molecular structures stored in these databases is also challenging: stereochemistry, for example, plays a major role in the function of NPs, and is the centre of a lot of research projects in the field. Despite this known importance, almost 12% of the collected molecules lack information on stereochemistry while having stereocenters. Finally, the non-redundant collection of NPs from these open resources has been assembled in a MongoDB COlleCtion of Open Natural prodUcTs (COCONUT).

Natural products online resources: availability and characteristics

For now, there is no globally accepted community resource for NPs, where their structures and annotations can be submitted, edited and queried by a large public, like there is UniProt [ 19 ] for proteins or NCBI Taxonomy [ 20 ] for the classification of living organisms. This leads to an impressive (123) amount of various, open and commercial, with different scope and differently structured resources for NP structures and their annotations. Mentions of NP databases, datasets and collections across publications from 2000 to 2019 and in omicX [ 21 ], a catalogue of scientific databases and software, were collected and are listed in Table  1 [ 22 ].

The databases are sorted by alphabetical order of their names and the table lists their various features such as: if they are open or commercial, if they are maintained and updated, what type of NPs they contain and their origin, the approximative number of molecular structures they contain, most recent publication of the collection, if a registration is required to access the data, if extensive metadata is available (taxonomy of the organism producing the NP, tissue, the geographical location where it is isolated, it’s application in (traditional) medicine, diseases it targets, etc.) and if the download of the molecular structures for local use (such as virtual screening) is easy. All these criteria are chosen to evaluate the “FAIRness” [ 23 ] (Findable, Accessible, Interoperable and Reusable) of the NP resources.

For the purpose of this review, the first classification level of the NP databases is their open or commercial access. Next, among the open-access databases, we distinguish databases of metabolites (that contain NPs but also products of primary metabolism), generalistic databases, that do not limit themselves to a particular geographic location or taxonomic classification, databases containing experimental spectra of NPs (NMR, mass spectrometry) and can be used for dereplication applications, thematic databases, that focus on traditional medicine, on drug-like NPs, on the biodiversity of a particular geographic region or on a particular taxonomic group and, finally, open-access industrial catalogues, that are virtual collections of NPs that chemical companies synthesize or isolate and sell. Of course, this segregation is not the only one possible and was made here uniquely for the readability purpose.

Commercial databases

Commercial databases sell the data, access or licence, and in general, it is quite expensive [ 24 ], even for academic use (from 6600 US$ per year for the Dictionary of Natural Products [ 25 ] to over 40,000 US$ for Reaxys [ 26 ] and SciFinder [ 27 ]).

The Chemical Abstracts Service (CAS) launched in 1995 SciFinder [ 27 ], a curated database of chemical information, compiled and maintained by the American Chemical Society. Originally available as desktop software, the web version of SciFinder is available since 2008. As it is CAS that assigns a unique registry number to every chemical substance described in the scientific literature since 1957, the SciFinder contains one, if not the biggest collection of curated chemicals, and, subsequently, of NPs. It is estimated that the number of NPs in SciFinder is over 300,000.

Reaxys [ 26 ] is a database for substances, reactions and documents compiled and maintained by the editor Elsevier. It contains over 10 7 compounds in total, over 200,000 of which are NPs.

The Dictionary of Natural products (DNP) [ 25 ] and it’s autonomous sub-sections, the Dictionary of Marine Natural Products (DNMP) [ 28 ] and the Dictionary of Food Compounds [ 29 ], are the considered as the most complete and best-curated resources for NP.

NaprAlert [ 30 ] was created by researchers at the University of Chicago and contains manually curated information on NPs from literature with rich metadata. Nowadays offers limited free searchers under conditions for academic researchers.

National Institute of Standards and Technology-NIST (version 17) [ 31 ] is one of the standard reference databases for mass spectra (MS) data and is developed and maintained at the National Institute of Health (NIH) in the USA. The main library contains over 250,000 molecules of natural origin (the separation between primary metabolites and NPs is not clearly marked) and is only purchasable on a compact disk.

MarinLit [ 32 , 33 ] is a database of marine NPs based on literature reviews and contain highly curated data that has been collected since the 1970s at the University of Canterbury, New Zealand, and since several years is maintained by the Royal Society of Chemistry (RSC). AntiMarin [ 34 , 35 ] is a historic database of marine NPs that have a described antibiotic activity. While it is still widely cited in thematic studies, the database itself is not accessible anymore, as was apparently merged with MarinLit.

AntiBase [ 36 ] is a comprehensive database of more than 40,000 NPs from microorganisms and higher fungi with very rich metadata collected from literature and manually validated. It is not updated since 2014 and is only available for purchase on Wiley’s website [ 37 ].

eBasis (Bioactive Substances in Food Information Systems) is an online, manually curated collection of 267 foods and 794 active compounds that they contain. The database offers rich and high-quality metadata on food NP activities and structures and limited free access to scientists to try the resource.

The Natural Product Discovery System (NADI) [ 38 ] contains over 3000 natural compounds from more than 15,000 Malaysian plant species. Despite being developed and maintained by the University Sains Malaysia, it is not open for academic use.

ChemTCM [ 39 ] is a database of NPs from plants used in traditional Chinese herbal medicine. The original part of this dataset resides not only in the very rich metadata but also in the predicted activity of NPs against common Western therapeutic targets and their estimated molecular activity according to traditional Chinese herbal medicine categories. The database was developed at King’s College London, in the UK, in part with the support of Innovation China-UK.

The Natural Products Library (NPL) [ 40 ] was described in a paper by AstraZeneca, a famous pharmaceutical company, but the data, containing at the moment of publication over 800 well-curated and annotated NPs, only remained as an in-house collection.

The Ayurveda dataset [ 41 ] was initially a published database of NPs extracted from the Indian traditional medicine plants. The link in the mentioned publication is still working but redirects to a website that provides software solutions for NP and chemistry research in general. Maybe the database is still available together with the software, but the access to it is for subscriptions only.

The Berdy’s Bioactive Natural Products Database [ 42 ] database is mentioned in publications from the 2000s and early beginning of 2010s but is not accessible anymore not even for the purchase of an older version. Originally, Birdy’s company was sending the database as a paper version and with the rise of accessible digital storage, on a digital medium upon order. The company does not seem to exist anymore.

Open-access databases

We could identify a total of 92 open-access NP resources across the literature in the last 20 years. The concept of “Open-access” encourages and prioritizes free and open online access to academic information, such as data and scientific publications. For a dataset, whether in a database or attached as additional information to an article, it means that anyone can read, download, copy, distribute, print, search for and within and re-use all or parts of data that are contained in it. For this review, we have endeavoured to compile an exhaustive list of open-access NP resources that have been cited at least ones in a peer-reviewed scientific publication after the year 2000. As the number of such sources is quite substantial (87), a thematic classification for them has been established. First, we present larger databases of organic molecules that also contain metabolites and NPs. These are followed by the presentation of databases containing molecular spectra (mass spectrometry or NMR) that can be used for the dereplication process for the identification of organic molecules and, in particular, of NPs in experimental data. Next, the scope will be narrowed with databases containing only NPs but without any taxonomic, usage or geographic selection on them. The most diverse data source category is the so-called “thematic” one: it contains databases of NPs that focus on a particular taxonomy (e.g. plants, bacteria, fungi), on a particular usage (e.g. Chinese, Indian or African traditional medicine, NPs found in food or toxic NPs) or on a particular geographic location (e.g. marine NPs, Brazilian and Mexican biodiversity NPs). Finally, are introduced industrial catalogues of NPs. These are made available by chemical companies that synthesize or purify NPs on command.

Databases of metabolites and chemicals

The first starting points in the search for structures for organic molecules are these big chemical libraries. They contain a wide range of organic compounds, and metabolites and NPs are well identifiable in them. The reference libraries, widely accepted by the scientific community as sources of reliable molecular information are: ChEBI [ 43 ], ChEMBL [ 44 ], ChemSpider [ 45 ], PubChem [ 46 ] and ChemBank [ 47 ]. ChEBI is developed and maintained at the European Bioinformatics Institute (EBI) and its main focus is chemical ontologies, i.e. structural relationships between molecules; it contains over 15,000 clearly identified NPs. ChEMBL is also the product of EBI but it has a wider focus and is considered as a repository for experimentally elucidated molecular structures and, in particular, drugs and drug-like chemical; it contains over 1800 NPs, but this number is very probably underestimated because of the unclear labelling of molecules as NP in this database. PubChem is an integrated platform of small molecules and biological activities is an initiative of the US (NIH) and is one of the major sources for biomolecules discovery and submission. It contains over 3500 NPs, although, similarly to ChEMBL, this number is very underestimated due to the unclear labelling of compounds as NPs. ChemSpider is a chemical database offering very rich metadata, cross-references to a lot of other chemical sources and advanced search. It is maintained by the Royal Society of Chemistry and contains over 9700 easily findable NPs. ChemBank was developed by the Broad Institute of Harvard and MIT and was dedicated to the storage of raw screening data of small organic molecules. This resource is unfortunately not available anymore due to maintenance difficulties, although all data remains available for a bulk download, but is not as handy to search.

There are also databases that focus only on metabolites, chemicals that are produced by living organisms (generally, but not only through enzyme-catalyzed reactions) and that are involved in primary and secondary metabolisms. The two major and most comprehensive databases for metabolites covering most of the domains of life are KEGG [ 48 ] and MetaCyc [ 49 ]. They contain an equivalent amount of chemicals, also involved in secondary metabolism, i.e. NPs, but present a different point of view on data organization and have been widely compared in the literature [ 50 ]. The BRENDA database [ 51 ] focuses on enzyme activities, but also contains the compounds involved in enzyme-catalyzed reactions, and this, covering most of all known domains of life. The particularity of this database is the manually validated compounds, reactions and enzyme activities in its main part, and exhaustive taxonomic origins for enzymes and compounds; however, NPs and primary metabolites are not clearly separated in this resource, so it is difficult to estimate their respective numbers. The Chemical Structure Lookup Service (CSLS) [ 52 ] was developed for a very rapid metabolite structure lookup in an aggregated collection of more than 80 databases comprising more than 27 million unique structures in 2007. Not updated anymore, it is still possible to download the datasets, but the lookup service is not available so the extraction of NPs only requires an extensive data curation. The last database presented in this section is BiGG [ 53 ]: a platform for highly-curated genome-scale metabolic models. It contains, as parts of the metabolic models metabolites, but the distinction of primary and secondary metabolism is not clear, so it requires a lot of efforts to extract information on NPs only.

Databases for dereplication

Dereplication is one important step in experimental NP discovery as it prevents re-isolation and re-characterization of already known molecules. It consists of a lookup in databases with annotated experimental data (mainly mass spectrometry (MS) and Nuclear Magnetic Resonance (NMR) spectra) for comparison to newly obtained experimental data, and its annotation in case of found spectral identity. There are two big categories of databases used for dereplication based on the type of spectra they contain, MS and NMR.

Databases for dereplication for MS data

There are three distinct databases called “MassBank”: the MassBank of North America (MoNa) [ 54 ], the European MassBank [ 55 ] and the Japanese MSSJ MassBank [ 56 ]. The three contain reference MS spectra for metabolites and extensive metadata. MoNa tends to be favoured by the scientific community as it integrates data from more sources than the two others, contains rich and community-curated metadata and facilitates the submission of new datasets.

METLIN [ 57 ] is a database that allows the characterization of known metabolites and a technology platform for the identification of known and unknown metabolites and other chemical entities. It is a comprehensive resource containing over 1 million molecules including primary metabolites, toxins, small peptides, and NPs. METLIN’s high-resolution tandem mass spectrometry (MS/MS) database, which plays a key role in the identification process, has data generated from both reference standards and their labelled stable isotope analogues, facilitated by METLIN-guided analysis of isotope-labelled microorganisms. However, it does not allow an easy download of the data, but the access to the platform is free for academic use.

The Human Metabolome Database (HMDB) [ 58 ] is a metabolomic database containing comprehensive information on human metabolites with very extensive metadata and reference spectra. It contains human-produced NPs together with NPs that are essential for the function of the human organism. However, as it is the case in a lot of previously described databases, the separation between NPs and primary metabolites is tricky.

From the same institution, the Yeast Metabolome Database (YMDB) [ 59 ], was created with the same pattern as the HMDB, and therefore also contains very extensive metadata for baker’s yeast metabolites, enzymes that are involved in the molecular metabolism and reference spectra. Again, the separation between NPs and primary metabolites is difficult, do this dataset was not included in further analysis either.

The RIKEN MSn spectral database for phytochemicals (ReSpect) is a collection of in-house and literature MS plant NP spectra. The website is still maintained and is usable but the last dataset has been added in 2013.

The Global Natural Products Social Molecular Networking (GNPS) [ 60 ] is a web-based knowledge base containing MS spectra for NPs only and is intended to be the base for the community-wide organization and sharing of raw, processed or identified data. In addition to providing access to spectra, it is also possible to download solely the structures of the NPs from this database.

Databases for dereplication for NMR data

NMRshiftDB [ 61 ] an open and peer-reviewed database for organic molecules structures and their NMR spectra. It contains a big number of easily identifiable NP spectra that makes it the reference tool for NP dereplication applications.

NMRdata [ 62 ] is a Chinese initiative for the storage and elucidation of NP structures from NMR data. Unfortunately, the main website is in Chinese and the English version is limited. To access the data one needs an account in a university that participates in the NMRdata project. At the moment of the writing of this manuscript, NMRdata contains 1,167,468 spectra, which theoretically makes it the biggest resource for NMR data in the world but it is under-used due to the language barrier.

NAPROC-13 [ 63 ] is a database containing 13C spectral information of over 6000 natural compounds. All data is accessible and searchable online, however, it is not possible to download the subsequent structures.

Spektraris NMR database [ 64 ] is a collection of NMR spectra that are focusing on plant NPs. The more than 400 spectra from more than 200 compounds in this database were manually transcribed from the literature. Spectra from this database are also submitted to NMRshiftDB to profit of the advanced technological aspects of the latter.

Generalistic databases of natural products

Generalistic public databases for NPs are not specialized in any particular type of NP nor on NP origins or usages. They are generally intended as catalogues for various purposes, such as in silico screening for activity prediction, molecular docking and so on. Seven generalistic public NP databases that have been active in the last 20 years have been identified from the literature.

SuperNatural II [ 65 ] is a database that contains over 300,000 NPs together with their 2D structures, computed physicochemical properties and predicted toxicity. It also provides references to the chemical suppliers for the actual purchase of the molecules, but not to other chemical databases. The database is maintained but is probably not updated anymore as some of the companies selling molecules are not active anymore (such as MDPI [ 66 ]). Unfortunately, SuperNatural does not provide a bulk download, even if the download of separate MOL files for molecules is possible and erroneously does not contain only NPs (e.g. it contains dodecahedrane, identified in this database under SN00136231 and it is not a NP), so this resource needs to be used with caution despite its wide fame in the scientific community.

The Universal Natural Products Database (UNPD) [ 67 ] was an effort to compile all know NPs in one collection for in silico drug screening. The last accessible version of the UNPD contains over 200,000 NP structures. The database is not accessible anymore through the link provided in the original publication, but a copy of the molecular structures contained in it is still maintained on the ISDB [ 68 ] website (a database for in silico predicted MS/MS spectra for NPs).

ZINC [ 69 ] is a public access database and toolset that was initially developed to enable easy access to chemical compounds for virtual screening purposes and that became ever widely used for a big range of cheminformatic applications. It has a very clear separation of molecules in catalogues, in particular on their origin, and contains an easily searchable and retrievable collection of over 85,000 NPs.

The Natural Product Activity and Species Source Database (NPASS) [ 70 ] contains over 30,000 NPs from plants, bacteria, fungi and animals and is developed and maintained at the National University of Singapore. This database was created to provide a reliable source for highly curated NPs with structures, experimental activity values and the organisms that synthesize them.

RIKEN Natural Products Encyclopedia (NPEdia) [ 71 ] contains over 25,000 secondary metabolites isolated from various species and annotated with rich metadata, such as molecule origin and physicochemical and biological properties. The database is still available online but is not updated since 2014.

3DMET [ 72 ] is a database that was created in 2005 in the National Institute of Agrobiological Sciences in Japan and is still maintained and updated until now. The idea of such a database came during the conversion from 2D to 3D NP structures and the errors that were occurring during it that needed manual curation. Currently, the database contains over 18,000 entries, cross-referenced to the KEGG database [ 48 ], but unfortunately, the download of the structures is not possible.

The Chinese Natural Products Database (CNPD ) [ 73 ] is a generalistic database created by Chinese researchers in order to facilitate the virtual screening of NPs for drug discovery purposes. This database is mentioned in over 120 papers until 2010 but is impossible to localize, as there is no URL provided in the original publication of the database and the dataset is not added as supplementary information to it. It is therefore probably incorrect to cite this database as a data source for NP, as the only possible sources found (from NeoTrident Technology Ltd) are in Chinese only.

One big negative point is that in ZINC, SuperNatural II and UNPD databases, the three biggest ones in terms of the number of NPs, the taxonomic nor geographic origins of the organism that produced the compound cannot be identified and in general they lack metadata and literature references.

For the completeness of this list, it is also necessary to site two major tools for the discovery and prediction of NPs from protein sequence data: antiSMASH [ 74 ] and PRISM [ 75 ]. Both are trained on, among others, NP data, but the latter is not provided directly to the public.

Thematic databases

Thematic databases for NPs focus on one particular origin or application of these secondary metabolites. Here we list databases that contain NPs produced by a particular domain of life (e.g. plants, fungi, bacteria), produced by organisms living in a particular geographical location (e.g. marine organisms, South American organisms) or by its application (traditional medicines, food or drugs). Apart from some rare exceptions, thematic databases tend to be small (less than 3000 entries) and very specialized.

In order to avoid biological provenance confusion, it needs to be noted that in some cases, NPs isolated from plants and animals can actually be synthesized by microorganisms that live on or in the host [ 76 ]. This is particularly the case of endophytes, bacteria living inside plant cells and very difficult to differentiate from the latter during preparation for metabolomics experiments [ 77 ]. Although the confusion is rare due to the improvement of identification methods and genetic approaches, it can create a bias in reproducibility of the NP isolation and needs, therefore, to be taken into account.

Natural products by the taxonomy of the synthesizing organism

KNApSaCK [ 78 ] is a comprehensive database for plant NPs that contains over 10,000 retrievable 2D and 3D structures, information on the relationships between the NPs and their expressing organism(s). It is pretty difficult to navigate despite the original design choices, and it does not offer a bulk download of the dataset.

Collective Molecular Activities of Useful Plants (CMAUP) [ 79 ], a relatively new database, contains very extensive information on plants that are linked to human activities together with their chemical constituents, i.e. NPs. The database offers very rich metadata for NPs, such as the plants that produce them and their geographical distributions.

TriForC [ 80 ] is a European Union-funded project that aims for the “discovery and production of known and novel bioactive triterpenes for pharmaceutical and agrochemical development”. The database contains a pipeline for triterpenes discovery and 266 NPs together with the enzymes and pathways leading to their production. It contains metadata for the compounds, but no structures in computer-readable format nor the possibility of downloading them.

Alkamid database [ 81 ] references over 300  N -alkylamides from plants, a promising group of bioactive compounds in drug and crops research. The database is fully open and offers rich metadata, in particular, the taxonomical classification of plants that produces the NPs, but does not allow a bulk download of any information from it.

The Tea Metabolome Database (TMDB) [ 5 ] is a curated and literature-based database for tea components. Not accessible anymore, it contained over 1300 constituents found in tea.

Microorganisms

StreptomeDB [ 82 ] is a collection of NPs from bacteria from the Streptomyces genus, which is very important for the production of natural bioactive compounds such as antibiotics, antitumour and immunosuppressant drugs. These bacteria are of particular importance in pharmacological research as around two-thirds of all known natural antibiotics are produced by them. While collecting data for this review, we encountered some difficulties to access the website, but the data was downloadable. In addition, an old dataset is available on ZINC.

The Natural Products Atlas (NP Atlas) [ 83 ] is maintained at the Simon Fraser University in Canada and is curated by a consortium of data curators around the world. It is designed to cover NPs from microbes (bacteria, fungi, lichens and cyanobacteria) published in the peer-reviewed literature. The resource is actively updated, allows a bulk download of all data and metadata and since September 2019 is completely open.

ProCarDB [ 84 ] is a database for carotenoids produced by bacteria. It contains over 300 compounds with rich metadata and structures but does not offer any download option.

PAMDB [ 85 ] is a comprehensive Pseudomonas aeruginosa metabolome database, well-curated, with rich metadata and offering bulk download. However, it does not contain only NPs but also results of the primary metabolism, so it was not included in the COCONUT collection.

The Lichen Database [ 86 ] is a collection of over 200 metabolites that have been isolated and identified experimentally in lichens. The database is not available yet, but the data has been already published in the MetaboLights [ 87 ] repository for metabolomics experimental data.

Natural products by use

• Traditional medicines

The World Health Organization listed between 1999 and 2009 a list of over 21 000 plants used for medicinal purposes all over the world [ 88 , 89 ]. This effort was made for proper identification of safe plants, as it is estimated that plant-based traditional medicines are used by 60% of the world’s population [ 90 ]. In addition to efforts to establish formal, DNA-based identification of such plants for wider use [ 91 ], collections of medicinal plant species, and in particular of phytochemicals, NPs produced by plants, associated to their therapeutic activities and physicochemical properties are being established around the world. This is particularly the case in Asia and Africa, where traditional medicines remain an important part of everyday life for cultural, traditional and economic reasons.

Traditional Chinese Medicine (TCM) is naturally part of the Chinese public health system [ 92 , 93 ]. It is therefore coherent that in this country the scientific study of natural compounds from plants used in TCM is very advanced and is receiving strong governmental support, and they have developed a plethora of databases containing NPs, their sources and effects.

The biggest database containing NPs used in TCM is TCM@Taiwan [ 94 ]. It contains over 58,000 entries and is directly feeding iSMART [ 95 ], an integrated cloud computing web server for online virtual screening, evolution studies and drug design. In addition to this, there are several other, smaller, databases for NPs TCM that can be cited, such as the Chinese Ethnic Minority Traditional Drug Database (CEMTDD) [ 96 ], that is maintained, but not updated and contains 4000 NPs, the Chinese Traditional Medicinal Herbs Database (CHDD) [ 97 ], not maintained anymore, but according to the publication contained over 30,000 entries, now not accessible and probably lost for the scientific community. Some other databases containing phytochemicals and other active compounds used in TCM can be cited, such as the Comprehensive Herbal Medicine Information System for Cancer (CHMIS-C) [ 98 ] that is not maintained anymore, the Encyclopaedia of Traditional Chinese Medicine (ETCM) [ 99 ], that is maintained but the chemical structures it contains are not easily retrievable, the database of medicinal materials and chemical compounds in Northeast Asian TM (TM-MC) [ 100 ], which is maintained, updated, but no structures but contains precise plant species for all compounds, the Traditional Chinese Medicine Integrative Database (TCMID) [ 101 ], maintained, but not updated anymore, The Traditional Chinese Medicine Systems Pharmacology database and analysis platform (TCMSP) [ 102 ], that is also not maintained anymore but used to contain over 29,000 NPs. One can quickly realize that there is a lot of databases that focus on chemical compounds used in TCM, and creators of the latter recognize it: there is even a database called “Yet Another Traditional Chinese Medicine Database” (YaTCM) [ 103 ] that was published in 2018. Mainly, all these databases differ in the number of compounds they cover, in the richness of their metadata and on the availability of the datasets they contain.

Another extremely important traditional medicine in Asia is the Indian Ayurveda, that also got a wide popularization worldwide over the past decade. There are, however, very few databases listing natural compounds from plants, insects and animals used in Ayurveda, and they do not contain as many entries as the Chinese ones. Only two are currently online and open. The first one, IMPPAT [ 104 ] is the manually curated database of over 10,000 phytochemicals extracted from 1700 Indian medicinal plants, their phytochemistry and their therapeutic effects. The other, MedPServer [ 105 ] contains NPs from plants from North-East India used in traditional medicine. It aims towards the understanding of the therapeutic mechanisms of action of the 1124 NPs from these plants by integrating ligand-based and structure-based approaches. NeMedPlant [ 106 ] is a small (over 100 NPs) database of active compounds from plants used in North-East Indian traditional medicine, with rich metadata focused on the plants that produce the compound but without possibilities of downloading any information and is not updated anymore. Because it was cited in several peer-reviewed papers, we also need to mention TIM [ 90 ], the database created in 2011 for the Prediction of Biologically Active Natural Products from Ayurveda Traditional Medicine but never linked to an actual database not listing the NPs in the supplementary material of the publication.

Phytochemica [ 107 ] is a small database of plant-derived chemicals that contains plants from Himalaya used in both Chinese and Indian traditional medicines. There are also some databases of NPs that specialize in traditional medicines of other parts of Asia, such as the Database of Indonesian Medicinal Plants [ 108 ] and TIPdb [ 109 ] for plants from Taiwan, but most of them are relatively small and contain in general only few hundreds of compounds.

African Traditional Medicine (ATM) is the other extremely rich and developed traditional medicine with a lot of modern efforts to study, rationalize and put its teachings to the benefit of modern medicine. As for the CTM and the Ayurveda, it requires inventorying plants used by African traditional doctors, identifying the parts that are used to efficiently cure and then identify the active components that they contain. It exists also a certain number of databases focusing on NPs from plants used in traditional medicines on the African continent. Among those, the most famous and the most generalistic is AfroDB [ 110 ], although it is only accessible through the ZINC catalogues. The pan-African natural products library (p-ANAPL) also needs to be cited here, as it focuses on plants used in ATM and is available as the supplementary information if its publication [ 111 ]. Three datasets, AfroCancer [ 112 ], AfroMalariaDB [ 113 ] and Afrotryp [ 114 ], available as supplementary information of their respective publications link NPs from plants used in traditional medicines to their potential targets involved in the treatment of cancer, malaria and Trypanosoma. There are then country-specific and relatively small databases for NPs extracted from ATM plants, such as the Cameroon Medicinal Natural Products database (CamMedNP) [ 115 ], Central African Medicinal Plants database (ConMedNP) [ 116 ] and the Ethiopian Traditional Medicine Database (ETM-DB) [ 117 ].

Databases of drug-like natural compounds

Not linked, at least directly, to the traditional medicines, there is a lot of pharmacological research around the therapeutic properties of NPs, and these are compiled in the databases for drugs and drug candidates. In these databases, natural compounds are generally associated with a type of disease or molecular targets or receptors they interact with, and a rich description of their molecular and overall effects on the state of a patient or of a healthy person. The reference database in this category is DrugBank [ 118 ]. It latest version, which was greatly modified and curated compared to previous ones, contains over 10,000 drugs, among which 3732 are approved drugs and 200 approved drugs that have been produced by a living organism. In order to select only the latter, one needs to search for “nutraceuticals” in the search bar of the DrugBank website [ 119 ]. The previous version of Drugbank, 4.0 [ 120 ], contained over 8000 nutraceuticals, and they were added to COCONUT.

BindingBD [ 121 ] is an interesting database for pharmaceutical research as it contains measured binding affinities of proteins that are supposedly targets of drugs, with small drug-like molecules. Although it does contain NPs and their protein targets, they are not clearly distinguishable from synthetic drugs in this database.

The Novel Antibiotics Database [ 122 ], that is still surprisingly online, is not updated since 2003 and contains 5430 compounds of natural origin with an antibiotic activity that have been published in the Journal of Antibiotics between 1947 and 2003. However, no structure is available for download, only compound names, their activity and the organisms they were isolated from.

ChemIDplus [ 123 ] is a database part of the TOXicology DataNETwork and chemicals that have a relationship with diseases, environment, environmental health and poisoning. It contains rich metadata for each chemical, including its physicochemical properties but also its impact on health and environment. A simple search for “natural product” returns more than 9000 entries, it is however not possible to bulk download the results of the query.

The Herbal Ingredient Targets (HIT) [ 124 ] and the Herbal Ingredients in vivo Metabolism (HIM) [ 125 ] databases are two inter-connected collections of NPs from mainly (but not only) Chinese plants. Both are not accessible online anymore, but the structures of the NPs they contained are available on ZINC. They contained very extensive metadata on the molecular targets of the herbal active ingredients, their toxicity, a wide range of pharmacologically relevant molecular descriptors and their therapeutic effects. Unfortunately, this metadata is not available on ZINC and is probably lost.

There are several databases that focus on collecting information on NPs with anticancer properties and their mechanisms of action. The first one, NPCARE [ 126 ] contains over 6000 NPs from plants, marine organisms, fungi and bacteria with validated anticancer activities and contains extensive metadata. The website is available and seems updated but cannot be accessed sometimes, probably due to server failures on the maintenance side. The Indian Plant Anticancer Compounds Database (InPACdb) [ 127 ] is not available anymore but used to contain very broad information covering pharmaceutical and physicochemical properties of 144 NPs, cancer types and molecular targets. Fortunately, the data is still available on GitHub [ 128 ]. Another database, containing phytochemicals with anti-cancer properties is the Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) database [ 129 ] is still maintained and accessible It contains 1574 manually curated entries with rich metadata on NPs and their therapeutical mechanisms on different types of cancer. The US National Cancer Institute also maintains and makes freely available a number of small (390 on average) natural compound datasets [ 130 ] that are selected as of interest in anticancer research and are currently undergoing tests in various research groups from the US NIH.

InflamNat [ 131 ] is a small (200 NPs) but well-curated dataset of NPs with anti-inflammatory activity. The dataset consists of NP structures, their type and origin and literature references, and is available as supplementary information for its publication.

BioPhytMol [ 132 ] is a manually curated database of natural compounds from plants that have an antibacterial effect. The database has over 2500 entries with very rich metadata, in particular regarding the plant species from which the compounds were extracted. The database is open and maintained but does not offer a bulk download option to be used to further analyses.

The last database in this section is the Open Source Malaria [ 133 ], which is a very nice project as it is a totally open-source collaborative project for anti-malarial drugs discovery that already encountered certain success [ 134 ]. Drug candidates tested in this project are often of natural origin, but as the focus of this database is to collect their effects, it is not always specified, so the content of OSM was not integrated into COCONUT.

FooDB [ 8 ] is the reference database on chemical food constituents associated with extremely rich and diverse metadata. It is developed by the Wishart research group and supported by the Canadian Institutes of Health Research. In total it contains over 22,000 NPs and offers a convenient bulk download their structures.

BitterDB [ 6 ] collects bitter-tasting natural compounds associated with rich metadata on their receptors. However, it also contains synthetic molecules with a bitter taste, and in this database, it is difficult to separate them from the natural ones.

Phenol-Explorer [ 135 ] is a comprehensive database on polyphenol content in food. It currently contains over 800 phenol structures from over 400 foods. Data is derived from the scientific literature, and all data is associated with rich metadata and is available for download.

PhytoHub [ 136 ] is a database of dietary phytochemicals and the human and animal metabolites that derive from them. Over 1200 NPs from more than 350 foods are available in this resource, together with rich metadata and references to other chemical and spectral databases it, unfortunately, does not offer a bulk download for the moment.

The SuperSweet database [ 4 ] is a collection of various molecules, mainly from plant origin, but also synthetics that have a sweet taste. Their structures together with information on their number of calories, therapeutic uses and sweetness index are available. The database is still maintained but is not updated since 2011 and does not provide a bulk download of its content.

A toxin is a substance that is toxic for one or more living organisms and that has a plant or animal origin. Despite this original definition, more and more resources on toxins also integrate molecules from non-organic origin massively present in the environment as they also have a harmful effect on the living organisms. For instance, Exposome-explorer [ 137 ] is a manually curated database of biomarkers of exposure to environmental and dietary factors, and it also contains these factors and their structures. A lot of the toxic environmental and dietary factors in it are from natural origin, but also, approximately half of the compounds in this database are not NPs, which is reasonable, as, for example, environmental pollution is anthropogenic. In the same way can be mentioned the T3DB [ 138 ], the toxin and toxin-target database, as it contains a number of toxins produced by the living organism but its focus is on synthetic toxins and how human metabolism reacts to them.

The biggest (over a 1000) database of animal toxins was the Animal Toxin Database (ATDB) [ 139 ], designed originally to collect toxin structures, origins and effects, but it is not available anymore at the URL provided in the publication. More specialized databases were also published, such as the International Venom and Toxin Database [ 140 ], the Snake Neurotoxin Database [ 141 ], the Mollusk Toxin Database [ 142 ] or the Scorpion Toxin Database [ 143 ]. Unfortunately, most of these databases were based on unformatted text and were lacking effective systems for data query, and none of them is not accessible anymore. It is also unknown if the data contained in these databases is lost or is still available in some generalistic resources.

The last in this section, the Toxic Plants—Phytotoxins Database (TPPT) [ 144 ], is accessible and is maintained and updated by the Agroscope in Switzerland. It contains over 1500 phytotoxins from Central Europe and offers high-quality metadata and a convenient bulk download.

The two databases described next could not be fitted in any of the previous categories. The Carotenoids database [ 145 ] is a collection of NPs produced by a wide range of organisms and that share common substructures (polyene with possibly terminating rings) and properties as they are all yellow, orange or red pigments. Carotenoids produced by plants have particular importance for the nutritional value of the consumed food [ 146 ], but plants are not the only producers of this molecular type which is demonstrated in the Carotenoids database. This database is developed and maintained at the RIKEN institute. SuperScent [ 10 ] is a database of volatile compounds essential from an organic origin that can be scented by humans and animals. It contains over 2000 compounds with their structures and properties but does not offer any download and most of the compound pages are now working. This database is maintained at Charité Belin but is not updated since 2010.

Natural products by the geographic origin of producing organisms

There is a number of country-level efforts to catalogue the biodiversity of NPs in particular geographical zones, generally defined by country political borders. These databases are mainly plant-focused, but can also integrate NP produced by insects, by microorganisms and animal toxins. In this part, the databases are cited in the geographical order from West to East. The last part is describing collections of NPs from organisms in marine and ocean environments.

BIOFAQUIM [ 147 ] is a database published in 2019 and offers for full download over 400 unique NPs from plants, fungi and propolis from Mexican flora and fauna, the species from which the compounds were extracted and their geographical location. The Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products Database (NUBBEDB) [ 148 ] is the first NP library from Brazilian biodiversity. It currently contains over 2000 NPs, highly curated and good quality metadata and easy download of all or partial data. The UEFS dataset [ 149 ] is a collection of NPs isolated from Brazilian plants and maintained by the State University of Ferriera de Santana in Bahia, Brazil. The NPs in this collection have been published separately but there is no common publication nor public database for it, it is however accessible via ZINC.

Three databases contain NPs from the African flora and fauna. The Northern African Natural Products Database (NANPDB) [ 150 ] contains over 4500 NPs from plants, endophytes, fungi and bacteria. The database provides rich metadata, literature references, cross-references to major chemical databases and an easy bulk download. The South African natural compound database (SANCDB) [ 151 ] is very similar to NANPDB in its quality and contains over 600 NPs isolated from South African biodiversity. It is also possible to submit new molecules and to participate in the curation of the database. The Mitishamba database [ 152 ] contains 1100 NPs isolated from Kenyan plants. The database is still maintained but does not seem to be updated and it is possible to download data from it only by requesting an account.

ChemDB [ 3 ] and MAPS database [ 153 ] are two databases for natural compounds from Pakistani plants. Unfortunately, none of them is accessible anymore. VIETHERB [ 154 ] is a database published in 2018 with the aim of providing high-quality and literature-based data on herbs and active compounds from them. Despite the novelty of the database, it is not accessible anymore.

The oceans cover 71% of the surface of the Earth, therefore databases that collect NPs from marine organisms are expected to be broad, complex and cover a wide range of organisms. Unfortunately, the biggest repositories for marine NP structures are commercial (e.g. MarineLit [ 33 ] and DMNP [ 28 ] presented above). In the marine NP community, the major trend is to publish newly discovered molecules in specialised journals (such as the Journal of Natural Products [ 155 ] or Marine Drugs [ 156 ]) as images and rich textual description that are not, for now, easily machine-retrievable.

In the last 20 years, four databases containing structures of marine NPs and their metadata were published. Two of them are not accessible anymore: the Marine Compound Database (MCDB) [ 157 ] and the Marine Natural Product Database (MNPD) [ 158 ]. Both contained only a few hundreds of entries according to their respective publications but these were comprising rich metadata which is now lost. The Dragon Exploration System on Marine Sponge Compounds Interactions (DESMCI) [ 159 ] is still accessible but seems not to be maintained as the actual data, such as molecular structures and the corresponding metadata is not visible when one tries to access it. The Seaweed Metabolite Database (SWMD) [ 160 ] is the only one really maintained and it contains 1110 entries, with only 423 unique structures. Molecular structures in this database are annotated with the species of the algae that produce them, together with the geographical origin of the latter, biological activity of the compound and its physicochemical properties.

Industrial catalogues

A lot of companies that are synthesizing and isolating chemical compounds offer a catalogue of their products, and in some cases, these catalogues also contain the structures and annotations. These catalogues are often cited in the scientific literature as sources of NP structures, therefore it was important to mention the most used catalogues in this review. Surprisingly, a non-negligible number of cited catalogues of NP structures are accessible only to clients, on-demand or to registered users. This is the case of the NP catalogues from Ambinter-Greenpharma natural compound library [ 161 ], ChemBridge diversity datasets [ 162 ] (their NP catalogue seems to be not available anymore), LOPAC1280 by Merk [ 163 ], Prestwick [ 164 ] and TargetMol [ 165 ]. Open NP catalogues are provided by the following: AnalytiCon Discovery [ 166 ], InterBioScreen [ 167 ], Indofine Chemical Company [ 168 ], Pi Chemicals Systems [ 169 ] and Specs [ 170 ]. The website of the latter is not offering the download of their NPs catalogue anymore, but a dataset is available on ZINC [ 171 ]. Note that only the most famous and cited in academic research are listed and more industrial catalogues for NPs exist.

The biggest problem nowadays is that there are too many sources for NPs. A non-experienced researcher in NPs (and even a more experienced one) will just get lost in this variety and diversity of possible data sources. The next major problem is access to data and its maintenance. Indeed, a lot of publications point to a website that is not maintained anymore. This is the case of the majority of animal toxins databases, but also of a number of small regional or traditional medicine databases. In the list of NP sources presented in Table  1 , over 20% are not maintained anymore or the access is intermittent. In some rare cases, the information on the NP structures is still recoverable via the ZINC database, but it is not the case of more modern databases and ZINC does not store any metadata from these collections, only the molecular structures encoded in SMILES. Also, the description and origins of the NPs (i.e. metadata), in addition to their structure are generally lacking, and it is especially the case in data aggregators that are nevertheless the most commonly used. This leads to cases where in silico screening reveals potentially interesting compounds but requires way more efforts and investigations to identify its origins and the way of obtaining it experimentally. Only 40% of NP databases offer an easy bulk download of molecular structures that they contain for further analyses with local tools. The quality of the molecular structures might also require additional attention and curation efforts. Indeed there are no standards for NP databases for a definition of stereochemistry, aromaticity or isotopes, which leads to a variety of possible versions of the same molecule.

This multiplicity of databases comes also from the publishing pressure on scientists, the infamous “publish or perish”. Nowadays, publishing a dataset or a database is a relatively easy publication and have the potential to generate a high number of citations. However, this trend generates a plethora of databases that are unmaintained beyond the publication time (like it is the case of VIETHERB [ 154 ] for example, published only 1 year prior to the writing of the present review and already not accessible anymore), despite the journals requirements to provide accessibility to the published datasets and databases for a number of years ahead.

Comparison and analysis of the content of open NP databases

The 50 NP collections from which NP structures could be downloaded were analysed in order to evaluate their overlap in terms of molecular structures and coherence of their content. 19 physicochemical properties, such as molecular weight, NP-likeness [ 172 , 173 ], logP, TPSA Efficiency, and Zagreb Index, were computed and their distributions are shown in an interactive graphic at https://npreview.naturalproducts.net . Due to the high number of databases to compare, a non-interactive would not be visible. Globally, the physicochemical properties of all datasets are comparable. The NP subset of Drugbank contains molecules that are less likely to be NPs, which can be explained by its high content in NP-derived drugs and the difficulty in dissociating the latter from synthetic ones. The average mass of all NPs in the assembled collection is of 454 Da, and the Spektraris and TCM@Taiwan databases contain the heaviest molecules: both contain molecules with an average of 612 Da. The logP is a lipophilicity measure commonly used in analytical chemistry; the more it is positive, the more lipophilic is the compound and the more negative, the more hydrophilic. Here, the logP was computed with two algorithms, AlogP and XlogP available in the CDK [ 174 ]. In general, NPs tend to be lipophilic, which allows them to have higher membrane penetration, but all datasets also contain in lesser amounts, hydrophilic molecules. CarotenoidsDB and the SeaWeed Metabolites Database outstand from others with their very lipophilic content. On the other side, ReSpect contains more hydrophilic molecules than other datasets.

The overlap in terms of molecular structures between the databases was also calculated and is presented in Fig.  1 and in Additional file 1 : Table S1. In Fig.  1 , which represents a network of overlap between databases, there is a directed edge between database A and database B if more than 50% of the unique molecules from database A are present in database B. An interactive version of this network, where the user can change the percentage of similarity between databases to display is available at https://npreview.naturalproducts.net . It should be noted that 40 of the 50 open NP databases have an overlap of at least 50% with at least one other open database. Except for the Lichen Database, all datasets share at least 10% of their compounds with at least one other open dataset.

Network of content similarity between the 50 open natural products databases. The network is directed, and there is an arrow from database A to database B if more than 50% of molecules in database A are also present in database B. The interactive version of this network is available at https://npreview.naturalproducts.net

In the majority of the databases, stereochemistry is defined for at least some of their content. Only three databases, TCMid, ReSpect, and NPCARE don’t have any stereochemistry defined for any of the molecules in them. The fraction of NPs with stereochemistry in each database is accessible in Table  1 . On average in the open NP databases, more than 50% of the molecules have a defined stereochemistry. When a 2D molecular structure is present in two databases and stereo information was elucidated, in general, open databases tend to agree on the latter. Doing a pairwise comparison between databases on their overlapping content, pairs of databases tend to agree on the stereochemistry, in on average 70% of NP than they share. The whole list of pairwise agreement between databases on the stereochemistry of their overlapping molecules can be found on FigShare ( https://doi.org/10.6084/m9.figshare.11926047.v2 ).

Five NPs are found in 34 of these 50 databases: apigenin, quercetin, kaemferol, catechin and naringenin. Interestingly, belong all to the flavanol group, part of the flavonoids family and share a common skeleton (Fig.  2 a) with only differences in hydroxy groups. In the top ten most frequent molecules in open databases, in addition to more flavonoids, there is also coumaric acid (Fig.  2 b), gallic acid (Fig.  2 c), scopoletin (Fig.  2 d) and ellagic acid (Fig.  2 e). According to the literature, all these compounds are well-known plant products, however, most of the flavanols, coumaric acid and scopoletin are also present in the bacterial NP database, StreptomeDB.

Most frequent molecules in open databases. a Common biggest substructure in the top 5 most frequent molecules, found in 34 out of 50 open databases. b Coumaric acid; c gallic acid; d scopoletin; e ellagic acid

COlleCtion of Open NatUral producTs (COCONUT)

In its current version, COCONUT contains 411,621 unique molecules, unified on the stereochemistry-free InChi keys, that were collected from 50 open and accessible NP databases, listed in Table  1 . This number is big, as this dataset still needs to undergo a curation process, as, despite their claims, some of the NP collections do not contain only natural compounds. 27.9% of molecules in COCONUT do not have stereo centres defined in any of the databases where they have been collected from. Among the latter, 57.7% (66,374 unique molecules) have truly no stereocenters, and the remaining 48,611 NPs have at least one stereocenter, but this information is not provided.

50% of the unique molecules have only one stereochemical version of their 3D structure, and 22.1% have more than one. The latter could be different valid stereoisomers of the same base constitution or errors in the databases. Addressing those errors will be subject of future curation of COCONUT. When a 2D molecule has several possible 3D structures, these can originate from the same public database, where stereochemistry is precisely defined, but also from different databases. Note that unknown NP structures or mixtures are not included in COCONUT. The collection is available as a MongoDB dump and a CSV file on Zenodo ( https://doi.org/10.5281/zenodo.3547718 ) and a user-friendly web interface to browse it is under development. The aim of COCONUT is to make the NP-related data as FAIR as possible.

There are currently 123 data collections of natural products (NPs) that have been published and cited in the scientific literature between 2000 and 2019. Only 50 of them are open access or have their content accessible (in ZINC for example) and among them, the overlap of their content is significant, as 40 of these datasets share at least 50% of the compounds they contain with at least one other dataset.

There are several aggregators, such as the ZINC catalogue for NPs, SuperNatural II and UNPD (not maintained anymore), but they do not cover the entire space of known NPs and do not allow submissions of newly discovered compounds.

There is a need for an aggregator database for NPs, that will be commonly recognized, well organized and allowing an easy submission of newly found molecules, like it is the case for UniProt for proteins.

Conclusions

Natural products are important molecules for medical, chemical and social research. There is no, for now, any universal, community-accepted database for NP discovery, screening and dereplication. Instead, there is an extremely high number of very diverse databases and datasets, not all maintained or open access in 2020, which represents a serious loss of knowledge. There is a need for a unified universal repository for NPs, to avoid the unnecessary duplication of online resources and facilitate NP research. For the purpose of this review, a COlleCtion of Open Natural prodUcTs (COCONUT) has been assembled, analyzed and made available in Zenodo ( https://doi.org/10.5281/zenodo.3547718 ). A web interface is currently under development for user-friendly querying, exploration and download of the known open NP space. In the future, the annotations of the molecules contained in COCONUT will be improved, in particular, systematically linking the compound to the first publication where it was described and to the organisms that synthesize it.

Materials and methods

All databases in Table  1 were downloaded in July and September 2019. Molecular structures were processed with CDK 2.3 and, when available, annotations were parsed with Java (code available on GitHub https://github.com/mSorok/COCONUT ). Resulting original and non-redundant collections of NPs are stored in a MongoDB database, available as a dump on Zenodo ( https://doi.org/10.5281/zenodo.3547718 ). Redundancy was eliminated based on InChi Keys, computed without stereochemistry (JNI-inchi option of the InChi generator set to “Snon”, “ChiralFlagOff” and “AuxNone”). Stereochemistry was not taken into account during this unification step as it is encoded differently between some databases and there are databases where it is not encoded at all. The overlap between databases in terms of similar stereochemistry was also performed with CDK 2.3. All network representations of overlaps between databases are made with Cytoscape [ 175 ]. Plots and comparative analyses made with Python and the Plotly and Dash libraries. The code for the interactive plots is available on GitHub at https://github.com/mSorok/NPDBReviewDash .

Availability of data and materials

Data and software are freely available under the MIT license. The source code for data processing can be freely obtained from GitHub (github.com/mSorok/COCONUT), the COCONUT data is available on Zenodo ( https://doi.org/10.5281/zenodo.3547718 ). The interactive application for natural products exploration is available at https://npreview.naturalproducts.net/ and the code is available on GitHub ( https://github.com/mSorok/NPDBReviewDash ). The table compiling all assembled natural products resources is available on FigShare ( https://doi.org/10.6084/m9.figshare.11926047.v2 ).

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This work was supported by the German Research Foundation within the framework CRC1127 ChemBioSys.

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Overlap (in percent) of compound content between open natural products databases.

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Sorokina, M., Steinbeck, C. Review on natural products databases: where to find data in 2020. J Cheminform 12 , 20 (2020). https://doi.org/10.1186/s13321-020-00424-9

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Chemical proteomics approaches for identifying the cellular targets of natural products From DOI: 10.1039/C6NP00001K

Dereplication, sequencing and identification of peptidic natural products: from genome mining to peptidogenomics to spectral networks From DOI: 10.1039/C5NP00050E

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While recent breakthroughs in the discovery of peptide antibiotics and other Peptidic Natural Products (PNPs) raise a challenge for developing new algorithms for their analyses, the computational technologies for high-throughput PNP discovery are still lacking. We discuss the computational bottlenecks in analyzing PNPs and review recent advances in genome mining, peptidogenomics, and spectral networks that are now enabling the discovery of new PNPs via mass spectrometry. We further describe the connections between these advances and the new generation of software tools for PNP dereplication, de novo sequencing, and identification. From DOI: 10.1039/C5NP00050E

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This highlight focuses on one of Nature's key strategies to doubly modify an amino acid during nonribosomal peptide biosynthesis by using a single enzyme, an interrupted adenylation domain. From DOI: 10.1039/C4NP00120F

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• Review Article
• Published: 14 January 2022

Natural product anticipation through synthesis

• Belinda E. Hetzler   ORCID: orcid.org/0000-0002-0372-9126 1 ,
• Dirk Trauner   ORCID: orcid.org/0000-0002-6782-6056 1 &
• Andrew L. Lawrence   ORCID: orcid.org/0000-0002-9573-5637 2  

Nature Reviews Chemistry volume  6 ,  pages 170–181 ( 2022 ) Cite this article

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• Biosynthesis
• Natural product synthesis

An Author Correction to this article was published on 22 February 2022

This article has been updated

Natural product synthesis remains one of the most vibrant and intellectually rewarding areas of chemistry, although the justifications for pursuing it have evolved over time. In the early years, the emphasis lay on structure elucidation and confirmation through synthesis, as exemplified by celebrated studies on cocaine, morphine, strychnine and chlorophyll. This was followed by a phase where the sheer demonstration that highly complex molecules could be recreated in the laboratory in a rational manner was enough to justify the economic expense and intellectual agonies of a synthesis. Since then, syntheses of natural products have served as platforms for the demonstration of elegant strategies, for inventing new methodology ‘on the fly’ or to demonstrate the usefulness and scope of methods established with simpler molecules. We now add another aspect that we find fascinating, viz. ‘natural product anticipation’. In this Review, we survey cases where the synthesis of a compound in the laboratory has preceded its isolation from nature. The focus of our Review lies on examples where this anticipation of a natural product has triggered a successful search or where synthesis and isolation have occurred independently. Finally, we highlight cases where a potential natural product structure has been suggested as a result of synthetic endeavours but not yet confirmed by isolation, inviting further collaborations between synthetic and natural product chemists.

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Acknowledgements

B.E.H. thanks New York University for a MacCracken fellowship. The authors thank B. S. Matsuura for helpful discussions. The authors thank B. S. Matsuura, A. J. E. Novak and K.-P. Rühmann for their critical review of the manuscript.

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Hetzler, B.E., Trauner, D. & Lawrence, A.L. Natural product anticipation through synthesis. Nat Rev Chem 6 , 170–181 (2022). https://doi.org/10.1038/s41570-021-00345-7

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Recent strategies in nanodelivery systems for natural products: a review

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Natural products are major molecules for drug discovery due to their structural diversity and their interaction with various biological targets, yet their clinical application is limited by poor water solubility or low lipophilicity, inappropriate molecular size, low dissolution rate and permeation, instability, high metabolic rate and rapid clearance. These issues can be solved by nanomedicine, by improving bioavailability and therapeutic efficacy. Here we review nanocarriers made of polymer or lipid constituents. Specifically, we describe the technological characteristics of each nanosystem, with examples of application to single natural constituents or plant extracts, and possible routes of administration. We report in vitro and in vivo studies and we conclude with the potential advantages of nanodelivery systems in terms of increased stability and solubility, improved biodistribution and efficacy, reduced adverse effects and toxicity.

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Nanotechnology Applications for Natural Products Delivery

Natural Products and Nanopharmaceuticals

Polymeric Nanocarriers for the Delivery of Phytoconstituents

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Introduction

Natural products as isolated compounds or extracts of botanical, animal and mineral origin have represented for millennia the only resource to maintain health and to cure or prevent human and animal diseases (Khan et al. 2012 ; Mehta et al. 2015 ). Currently, their role in therapy is still unquestionable and supported by numerous scientific evidences. Natural products also represent the main source of bioactive molecules and play a key role in innovative drug discovery (Newman and Cragg 2020 ) thanks to their enormous structural and chemical variability, which is incomparable to that of any synthetic libraries (Cameron et al. 2011 ; Bilia et al. 2017 ). The extraordinary interest for natural products is mainly due to their capacity to modulate multiple biological targets, activating various signaling or functional pathways and producing a huge therapeutic significance especially for emerging multifactorial and complex diseases, such as cancer, cardiovascular and neurological pathologies (Rodrigues et al. 2016 ). Conversely, many natural products do not possess drug-like characteristics, and their efficacy and clinical use are limited because of physical and/or chemical instability, unsuitable partition coefficient (log P), unfavourable intrinsic dissolution rate or inappropriate molecular size. These unfavourable biopharmaceutical properties often cause low aqueous solubility, poor permeation and absorption through biological membranes and barriers, low biodistribution or rapid metabolism and clearance, resulting in drug plasma levels below the therapeutic concentration and reduced or annulled efficacy. A low bioavailability can be also related to distribution/accumulation of drugs in non-targeted tissues and organs, leading to numerous side effects (Kesarwani et al. 2013 ; Jain & Chella 2020 ) .

Diverse strategies have been used to optimise the bioavailability of natural products (Dragicevic & Maibach 2016 ; Jain & Chella 2020 ; Paroha et al. 2020 ; Saka et al. 2020 ). They are mainly chemical strategies producing semisynthetic compounds or synthetic analogues (Fang & Leu 2006 ; Ita 2016 ), but recently there is an increasing interest in developing appropriate formulations, specifically nanodelivery systems, which present numerous advantages in comparison to conventional drug formulations, such as controlled release kinetics, targeted delivery, enhanced solubility and permeation, increased chemical and physical stability, and extended shelf-life, with a consequent considerable greater clinic effectiveness and less side-effects (Bilia et al. 2017 , 2018 , 2019b ; Chamundeeswari et al. 2019 ).

Drug delivery systems, generally between 50 and 300 nm, up to 1 μm, have nanoscale dimensions ranging, in nature, from the size of a water molecule to the red blood cell diameter, as reported in Fig. 1 . Some nanosized delivery systems have already entered in the clinic because they can offer an advanced approach to optimise the therapeutic efficacy, targeting definite tissues and organs or crossing biological barriers, in addition to improve the safety profile and the compliance of drugs (Bilia et al. 2017 , 2019b ).

Nanosized drug delivery systems in the scale of nature

This review reports on recent strategies in developing nanodelivery systems for natural products, according to their classification as polymeric-based and lipid-based nanovectors (Fig. 2 ), evidencing their characteristics, advantages and limitations. Specifically, polymeric-based nanocarriers include polymeric nanoparticles, among which nanospheres and nanocapsules, polymeric micelles and dendrimers, whereas lipid nanocarriers include solid lipid nanoparticles, nanostructured lipid carriers, vesicles, nanocochleates, nanoscale emulsions, namely nanoemulsions and microemulsions, and self-microemulsifying drug delivery systems.

Lipid-based nanovectors, including solid lipid nanoparticles, nanostructured lipid carriers, vesicles, nanocochleates and micro/nanoemulsions. Polymeric-based nanovectors, including nanospheres, nanocapsules, dendrimers and polymeric micelles. W: water, O: oil

This article is an abridged version of the chapter by Anna Rita Bilia, Vieri Piazzini, Maria Camilla Bergonzi ( 2020 ) Nanotechnology Applications for Natural Products Delivery. Sustainable Agriculture Reviews 44 (pp. 1-46). Springer, Cham.

Polymeric nanocarriers

Polymeric nanocarriers include nanoparticles (nanocapsules and nanospheres), dendrimers and polymeric micelles (Fig. 2 ), made of natural, semi-synthetic or synthetic polymers, selected on the basis of their biodegradability, biocompatibility and surface characteristics, with the aim to produce novel and safe carriers having a controlled and targeted drug delivery. Natural polymers originate from bacteria, fungi, animals, plants, and are mainly represented by polysaccharides (principally chitosan, cellulose, alginic acid, carrageenan, arabic gum, pectin, starch, xanthan, gellan) (Divya et al. 2018 ; Parhi 2020 ) and proteins (albumin, casein, gelatin, soy protein hydrolysate) (Elzoghby et al. 2012 ). Synthetic polymers include poly-cyanoacrylate alkyl esters, polylactic acid, poly (N-vinyl pyrrolidone), polyvinyl alcohol, polyglycolic acid, polylactic glycolic acid (Bilia et al. 2017 , 2018 , 2019b ; Kumar et al. 2019 ), whereas semi-synthetic polymers are obtained by modification of natural polymers with synthetic polymers or synthetic chemicals by different methods, such as blending, crosslinking and grafting (Sithole et al. 2017 ).

Polymeric nanoparticles

Generally, polymeric nanoparticles consist of nanocapsules and nanospheres with dimensions ranging from 100 to 500 nm. In nanocapsules the drug is loaded in the central cavity delimited by the polymeric membrane, whereas in nanospheres the drug is distributed inside the polymeric matrix. Nanoparticles can be used for different administration routes, including the oral and parenteral ones, and they can strongly increase drug bioavailability, as well as allow sustained release of the loaded drug or selectively cross barriers, such as the blood-brain barrier (Guccione et al. 2017 ; Ahuja et al. 2020 ).

Specifically, nanoparticles for parenteral administration, formulated using a mixture of polymers, namely poly lactide-co-glycolide and monomethoxy polyethylene glycol, were loaded with ginkgolides and bilobalide, the active constituents of Ginkgo biloba L., with an encapsulation efficiency of about 79% and a drug loading of ca. 12 mg per 150 mg of polymer. The mean diameter of developed nanoparticles was ca. 123 nm, while the zeta potential was ca. -30 mV. The half-life time of the gingko compounds was moreover considerably increased by loading into the polymeric nanoparticles (Han et al. 2012 ).

Polymeric nanoparticles are also able to modify the pharmacokinetic profile of curcumin after oral administration. Nanoparticles were prepared using polylactic polyglycolic acid, enhancing the relative oral bioavailability of curcumin by 563% compared to the unformulated curcumin. The increased bioavailability was due to the inhibition of P-gp-mediated efflux, allowing to rise permeability and absorption of drug in the blood stream (Xie et al. 2011 ).

Polymeric nanoparticles have been also evaluated for their capability to cross blood-brain barrier after systemic administration in rats. Specifically, nanoparticles based on poly ethylcyanoacrylate, and coated with polysorbate 80, were loaded with salvianolic acid B and evaluated for their biodistribution (Grossi et al. 2017 ). Salvianolic acid B represents the main constituent of Salvia miltiorrhiza L. and it is able to prevent nervous degeneration in numerous animal models with different biological mechanisms (Bonaccini et al. 2015 ), however its poor chemical stability and low bioavailability severely limit its therapeutic use. The study included intracerebral injection of nanoparticles in healthy rats, in order to observe the distribution of nanoparticles within the injected hemisphere, where they mainly interacted with microglial cells, probably involved in their clearance by phagocytosis. Nanoparticles were furthermore found to be no toxic by chronical administration in C57/B6 mice. The encapsulation efficacy of salvianolic acid B was about 99%, whereas the loading capacity was about 53%. The mean diameter of nanoparticles resulted less than 300 nm and zeta potential was about -8.4 mV. The nanoparticles moreover showed a modified release of salvianolic acid B, during 8 h (Grossi et al. 2017 ).

Recently, albumin nanoparticles, prepared using two different cross-linking methods, the chemical and the thermal one, were investigated as alternative approach to cross the blood-brain barrier after intravenous and intraperitoneal administration in healthy rats. Nanoparticles were found to be safe by behavioural tests on rats, including tests on locomotor and explorative activities, as well as on the cognitive function (Bergonzi et al. 2016 ). Also, nanoparticles did not induce any inflammatory reaction. In a further investigation, developed albumin nanoparticles were thereby loaded with the characteristic terpenoid andrographolide, the main active constituent of Andrographis paniculate L., whose properties in the neurodegenerative pathologies are well known (Casamonti et al. 2019a ). The ability of albumin nanoparticles in crossing the blood-brain barrier was compared with that of poly ethylcyanoacrylate nanoparticles (Guccione et al. 2017 ). The studies were carried out using an in vitro model of blood–brain barrier based on human cerebral microvascular endothelial cell line (hCMEC/D3). The authors found that free andrographolide did not cross the endothelial cell line, giving consistent results with the in silico studies; poly ethylcyanoacrylate nanoparticles were able to cross the barrier, but they provisionally disordered the integrity of the barrier model, whereas albumin nanoparticles permeated the barrier model, preserving the integrity of the barrier (Guccione et al. 2017 ).

In a very recent study, andrographolide-loaded albumin nanoparticles were evaluated after parental administration for their distribution and pharmacological effects in brain using TgCRND8 mice, a mouse model of Alzheimer's disease. The nanoparticles had mean size of about 160 nm and a zeta potential of about -25 mV. Encapsulation efficiency was greater than 99%. Nanoparticles administered to TgCRND8 mice were evaluated using the step down inhibitory avoidance test and it was observed that nanoparticles significantly enhanced ( p <0.0001) the efficacy of loaded drug in TgCRND8 mice, which reached comparable performances to those obtained in wild type mice. In the object recognition test, both animals treated and untreated with andrographolide-loaded albumin nanoparticles showed no deficiencies in locomotor activity, exploratory activity and directional movement towards objects, in addition to no cognitive impairments ( p <0.0001). Albumin nanoparticles loaded with the fluorescent probe, fluorescein sodium salt, were traced in the brain parenchyma of TgCRND8 mice, after intravenous and intraperitoneal administration. In addition, the immunofluorescent analyses revealed the distribution of NAF-loaded nanoparticles both in the pE3-Aβ plaque surroundings and inside the pE3-Aβ plaque, evidencing their ability to cross the blood-brain barrier and penetrate both undamaged and damaged brain tissues (Bilia et al. 2019a ).

Reviewed studies are some examples of the wide research on polymeric nanoparticles as future nanomedicines for the treatment of various diseases. Polymeric nanoparticles were found to be viable nano-sized delivery system in loading diverse type of natural products, such as ginkgolides, bilobalide, curcumin, salvianolic acid B and andrographolide, for oral and parenteral administration, thanks to the high biocompatibility of constituents, resulting a promising strategy for the translation in clinical therapy.

Polymeric micelles

Polymeric micelles are nanovectors, ranging from 20 to 200 nm, formed by the aggregation of amphiphilic block copolymers made of hydrophobic and hydrophilic monomer units. Micelles spontaneously form by self-association, when the concentration of the monomer unit reaches the critical micellar concentration, similarly to the formation of surfactant-based micelles (Fig. 3 ). Polymeric micelles are very versatile, stable, safe and low cost nanovectors, and they can be used for almost all the administration routes (Bilia et al. 2017 , 2019b ).

Polymeric micelles are formed by the aggregation of amphiphilic block copolymers, made of hydrophobic and hydrophilic monomer units. Micelles spontaneously form by self-association, when the concentration of the monomer unit reaches the critical micellar concentration (CMC), similarly to the formation of surfactant-based micelles

A study on polymeric micelles loaded with curcumin was carried out to evaluate the inhibition of human brain glioblastoma proliferation. These micelles (about 142 nm) were prepared with an amphiphilic block copolymer synthetized by esterification of polyethylene glycol 400 (hydrophilic portion) and oleoyl chloride (lipophilic portion). In addition, their effects on regular human fibroblastic cells (HFSF‑PI3) and adult human bone marrow stromal cells were investigated. Glioblastoma cell viability was not affected by unformulated curcumin. By contrast curcumin-loaded micelles significantly ( p < 0.001) inhibited the proliferation of glioblastoma, meanwhile the same dosages (20, 25, 30 and 35 μM) of micelles did not affect regular fibroblastic cells and stromal cells, demonstrating a very high selectivity (Tahmasebi Mirgani et al. 2014 ).

Another study focused on polymeric micelles made of soluplus (polymer of polyvinyl caprolactam, polyethylene glycol and polyvinyl acetate) and polymeric mixed micelles made of soluplus plus vitamin E polyethylene glycol 1000 succinate (TPGS) in 20:1 gravimetric ratio, for the oral administration of silymarin. Increasing amounts of the active constituent (from 0.5 to 4 mg/mL) were loaded inside micelles. Up to 3 mg/mL, silymarin-loaded micelles maintained similar sizes (about 60 nm), low polydispersity index (≤ 0.1) and high encapsulation efficiency (> 92%). Apparent solubility of silymarin in the micelles was considerably increased, up 6-fold, and the nanovectors eluded silymarin degradation in the gastrointestinal tract. The in vitro permeation assay, by parallel artificial membranes mimicking the intestinal membrane, confirmed the enhancement of passive diffusion of silymarin when loaded in micelles, whereas the transport studies with Caco 2 cell lines, besides demonstrating that both types of micelles entered into Caco-2 cells via energy-dependent mechanisms, also indicated that polymeric mixed micelles enhanced the permeability of silymarin compared to polymeric micelles and unformulated extract (Piazzini et al. 2019 ). In the last years, nano-sized micelles have obtained increasing interest for diagnosis and treatments of many diseases, culminated with the approval by the Food and Drug Administration of the first micelle formulation of paclitaxel for the treatment of breast, ovarian and lung cancer. The lipophilic core increases the solubility of poorly water-soluble molecules, such as curcumin and silymarin, as described in reported studies, and provides a controlled drug release, while the hydrophilic shell protects the encapsulated drug from the external medium, resulting in long circulation properties and increased drug bioavailability.

The name “dendrimer” comes from the Greek word “ δένδρον” (dendron), meaning “tree”. In fact, dendrimers are self-assembling globular structures with a central core surrounded by branched polymers. Their size range (from some nanometers up to 10-20 nm) is modulated by varying dendrimer generation numbers (for instance G0, G1, G2, Fig. 4 ). Different surface properties can be obtained according to the linked functional groups. Drugs can be chemically linked to the superficial moieties or encapsulated into the internal cavities. Amine derivatives (poly(amidoamine) and poly(propylene imine)) are used for the preparation of dendrimers, whereas other polymers are used to functionalise their surface, such as the poly-L-glutamic acid and the polyethylenglycol (Bilia et al. 2017 , 2019b ).

Dendrimers are self-assembling nanoparticles with a central core surrounded by branched polymers. Their size range is modulated by varying dendrimer generation numbers, for instance G0, G1, G2. Different surface properties can be obtained according to the different linked functional groups. Drugs can be chemically linked to the superficial moieties or encapsulated into the internal cavities

Recently, dendrimers with spherical shape and about 150 nm diameter were prepared using polyamidoamine and loaded with curcumin, in order to increase its solubility and bioavailability. The developed dendrimers had no cytotoxic effects in breast cancer MCF-7 cells and curcumin solubility was enormously increased; it was found to be up to ca. 415 times more soluble than unformulated curcumin (Falconieri et al. 2017 ).

Dendrimers are increasingly fascinating researchers and they hold a promising future not only in delivery of drugs and phytochemical bioactive compounds, but also in diagnosis and management of diseases. Multistep synthesis sometimes gives low yield which can be overcome by variation of the chemical method of preparation. A certain cytotoxicity, which depends on generation to which dendrimers belong and on nature of functional groups on their surface, was also observed, but can be managed by modifications of structure and constituents of dendrimers (Chis et al. 2020 ). Overall, their unique properties such as nanoscale uniform size, high degree of branching, polyvalency, water solubility, available internal cavities and convenient synthesis approaches make them promising agents for biological and drug delivery applications (Sherje et al. 2018 ).

Lipid nanocarriers

Lipid-based nanovectors are prepared using natural and synthetic fatty acids, fatty alcohols, waxes, oils and fats, steroid, amphipathic steroids (Bilia et al. 2019b ). These nanovectors include nano-scale emulsions (microemulsions and nanoemulsions), self-microemulsifying drug delivery systems, solid lipid nanoparticles, nanostructured lipid carrires and vesicles, which can be converted in nanocochleates (Fig. 2 ) (Bilia et al. 2019b ).

Microemulsions and nanoemulsions

Microemulsions and nanoemulsions are prepared using an oily phase, an aqueous phase and surfactants agents (McClements et al. 2012). The resulting system is optically transparent with droplets (oil in water or water in oil) of nano-sized dimensions (10-100 nm). However, the two systems are significantly different (Fig. 2 ). In fact, nanoemulsions have a spontaneous propensity to separate in the two initial immiscible phases and need high energy, generally by a microfluidic or ultrasonic approach, to be formed (Tayeb at al. 2018). By contrast, microemulsions can generate spontaneously when all the components are mixed together and they are optical isotropic, homogeneous and thermodynamically stable transparent systems (Tartaro et al. 2020 ). They can be described as oil in water emulsions, water in oil emulsion or biphasic bicontinuos systems (Fig. 5 ), (Bilia et al. 2017 , 2019b ). In many cases, self-microemulsifying drug delivery systems can be formulated as microemulsion precursors, since the latter can form as soon as they come in contact with the external phase (Kang et al. 2004 ). Very interesting, microemulsions and nanoemulsion can be used for loading isolated natural compounds or complex mixtures of natural products (Kumar et al. 2018 ), such as extracts and essential oils (Barradas et al. 2020 ). In addition, all the administration routes are suitable for these versatile systems (Bilia et al. 2017 , 2019b ).

Microemulsions can be water (W) in oil (O), bicontinuos systems or oil in water

An oil-in-water nanoemulsion containing capsaicin was formulated with olive oil (oily phase), Tween 80, Span 80 (surfactants), ethanol (co-surfactant) and water, in order to treat pain and inflammatory disorders. The internal phase droplets had very small sizes ( ca. 14 nm) and did not show coalescence phenomena for periods longer than 8 months, at 4°C and 45°C. The obtained nanoemulsion was formulated as gel (Carbopol®) and cream (cholesterol, liquid paraffin, soft paraffin, cetyl alcohol and beeswax) containing 0.075% capsaicin. After topical application, the capsaicin-formulation showed significant anti-inflammatory activity in rat paw oedema and high resistance to pain signals (Ghiasia et al. 2019 ).

Three microemulsions, made of Cremophor EL, lecithin, Tween 20 and Tween 80 as surfactants, and containing wheat germ oil, olive oil and vitamin E as oily phase, were tested in vitro for permeation evaluation of curcumin after oral administration, using the parallel artificial membrane permeability assay. The best performance, with a curcumin permeation of about 70%, was obtained by the formulation prepared with vitamin E (3.3 g/100 g), Tween 20 (53.8 g/100 g), ethanol (6.6 g/100 g) and water (36.3 g/100 g), (Bergonzi et al. 2014 ).

Recently, Piazzini and coworkers (Piazzini et al. 2017a , 2017b ) successfully tested innovative oil-in-water nanoemulsions, with droplet sizes ranging from 10 to 20 nm, in order to improve the oral absorption of extracts of Vitex agnus-castus L. and Silybum marianum L. Silybum marianum L. extract (4% w/w ) was formulated using Labrasol, Cremophor EL, Labrafil and water. Vitex agnus-castus L. extract (6% w/w ) was instead formulated using triacetin, Labrasol, Cremophor EL and water. The studies extensively proved that nanoemulsions improved the permeation of the characteristic constituents of the extracts, when compared with the unformulated extracts.

In a further study, a microemulsion based on Labrasol, Cremophor EL, glycerol and water was formulated and loaded with green tea catechins and caffeine. The microemulsions well-preserved the antioxidant properties of the loaded constituents and the formulation was safe for mammalian cells (Gupta et al. 2019).

Another microemulsion, composed of triacetin, Tween 20, Labrasol and water, was loaded with Salicis cortex L. extract (40 mg/mL). Droplet sizes were about 40 nm and the solubility of the characteristic constituents of Salicis cortex L. was improved with respect to the unformulated extract (between 2 and 3.6 times more). In vitro tests, by parallel artificial membranes and Caco-2 cells, evidenced an enhanced permeation of Salicis cortex L. constituents when the extract was loaded in microemulsion (Piazzini et al. 2018a ).

A self-microemulsifying drug delivery system, formulated with castor oil, Cremophor EL and 1,2-propanediol, was loaded in sustained-release pellets, for the oral administration of puerarin. The pharmacokinetic profile and the bioavailability of loaded drug was assessed in beagle dogs. The absolute bioavailability of puerarin loaded in the innovative formulation increased 2.6-fold, when compared with that obtained using a conventional formulation, while the relative bioavailability was found to be 259.7% (Zhang et al. 2012a).

Another study was focused on two microemulsions and two self-microemulsifying drug delivery systems for the oral administration of a complex commercial blend based on carbon dioxide extract of Serenoa repens L. (saw palmetto). Stability of the formulations was assessed in simulated gastric and intestinal fluids. The in vitro parallel artificial membrane permeation assay furthermore indicated a greater mucosal permeation for blend based on saw palmetto extract formulated in the nanosystems compared to the raw commercial blend or the single saw palmetto extract. Permeation values of developed nanoemulsions and self-microemulsifying drug delivery systems were between 30% and 70% (Guccione et al. 2018 ).

Recently, an olive extract from Tuscan unripe olives ( Olea europaea L.), characterized by oleuropein ( ca. 31%), ligstroside ( ca. 3%) and verbascoside ( ca. 2.5%) was loaded at the concentration of 35 mg/mL in a microemulsion, for oral administration. The developed formulation, composed of Capryol 90, Cremophor EL, Transcutol and water, was stable at +4°C for three months. The permeability of phenol constituents, evaluated using the parallel artificial membrane permeation assay, was more than 2 times higher compared to that of unformulated olive extract. The transport studies carried out with Caco-2 cells moreover confirmed the increased permeation of the formulated extract (P app of 26.99 ± 0.45 × 10 -6 cm/s versus 16.14 ± 0.05 × 10 -6 cm/s for the unformulated extract), (Cecchi et al. 2020 ).

Isolated natural products (capsaicin, curcumin, puerarin), hydroalcoholic extracts ( Vitex agnus-castus L., Silybym marianum L., Salicis cortex L., Olea europaea L.) and carbon dioxide extracts ( Serenoa repens L.) were successfully formulated in microemulsions or nanoemulsions or self-microemulsifying drug delivery systems, obtaining increased solubility or increased permeability through artificial membranes mimicking intestinal mucosa or improved bioavailability. Over the last decades, nano-sized emulsions have been areas of study for a wide range of applications, from food science to cosmetics and drug delivery. In order to facilitate the translation of nano-sized emulsion from research laboratories to the pharmaceutical market, a careful selection of constituents must be done, with regard to safety concerns including hypersensitivity. The selection of biocompatible and approved excipients is a prerequisite for any future pharmaceutical application. In addition, formulation challenges such as ease of synthesis at large scale, storage and stability must be addressed in view of the therapeutic application (Tayeb at al. 2018; Tartaro et al. 2020 ).

Solid lipid nanoparticles and nanostructured lipid carriers

Solid lipid nanoparticles and nanostructured lipid carriers (Fig. 2 ) are colloidal systems with a lipid matrix stabilized by surfactants. They have dimensions ranging from 50 to 1000 nm, and they are suitable for all the administration routes (Mehnert and Mäder 2012 ). These nanovectors are highly biocompatible, biodegradable, safe and very stable. Typically, the lipid core of solid lipid nanoparticles consists of glycerides, fatty acids, fatty alcohols and waxes, which are solid at room temperature and generally recognized as safe ingredients. Nanostructured lipid carriers represent an evolution of solid lipid nanoparticles, obtained by modification of the lipid core structure, adding a liquid lipid at room temperature (Das and Chaudhury 2010 ). Due to the generation of an imperfect matrix, nanostructured lipid carriers are characterized by higher entrapment efficiency and more stable drug loading (Poonia et al. 2016 ; Bilia et al. 2019b ). The liquid lipids are generally represented by medium chain triglycerides and edible oils, including corn oil, soybean oil, sunflower oil, vitamin E (Tamjidi et al. 2013 ).

Solid lipid nanoparticles based on stearic acid, lecithin and Myrj 52 were loaded with curcumin and investigated for their efficacy in an allergic rat model of asthma by intraperitoneal injection. The nanovectors had dimensions of ca. 190 nm, with 75% drug entrapment efficiency. Enhanced plasmatic and tissue curcumin concentrations, especially in lung and liver, were obtained with the solid lipid nanoparticles when compared with unformulated curcumin. The nanovectors inhibited airway hyper-responsiveness and cell infiltration, in addition to suppress the expression of interleukin-4 and interleukin-13 (Wang et al. 2012 ). Since curcumin has a wide spectrum of biological properties, but it is poorly soluble in water with consequent low oral bioavailability, it has been also formulated in solid lipid nanoparticles for oral administration by Righeschi and coworkers (Righeschi et al. 2016 ), with the aim to enhance its permeation through gastrointestinal mucous membranes. These solid lipid nanoparticles, prepared with Compritol and GRAS ingredients, and loaded with curcumin, had average diameter of about 300 nm, drug loading capacity of ca. 1.60% and drug entrapment efficiency of 80%. They showed high stability over one month of storage at +4°C and significantly improved the permeation of curcumin by parallel artificial membranes.

Other interesting active molecules has been delivered by solid lipid nanoparticles, in order to improve their oral bioavailability. An example is andrographolide, formulated in nanoparticles based on compritol 888 ATO, glyceryl monostearate, lecithin and Tween-80, with entrapment efficiency of about 91% and drug loading of about 3.5%. Its bioavailability and antihyperlipidemic activity were improved in comparison to the unformulated andrographolide, by increasing its solubility and stability in the intestine and by changing its transport mechanism (evaluated in Caco-2 cell line), (Yang et al. 2013 ). Andrographolide was also formulated in stealth solid lipid nanoparticles based on compritol 888 ATO and Brij 78, for parenteral administration and brain delivery. Developed nanoparticles remained unchanged in presence of human serum albumin and plasma, in addition to be chemically and physically stable over 1 month of storage. The ability of these nanovectors to cross the blood-brain barrier was assessed using parallel artificial membranes and hCMEC/D3 cells, a well-establish in vitro model of human blood-brain barrier, in order to predict andrographolide absorption by transcellular passive diffusion. The permeation of andrographolide loaded in nanoparticles was increased with respect to the unformulated andrographolide. Furthermore, after intravenous administration in healthy rats, fluorescent solid lipid nanoparticles were detected in brain parenchyma outside the vascular bed, confirming their ability in vivo to cross the blood-brain barrier (Graverini et al. 2018 ).

Silymarin, extracted from seeds of  Silybum marianum L., has been used for decades as hepatoprotectant and, recently, it has been proposed for beneficial effects in type 2 diabetes patients. However, silymarin is poorly soluble in water, with limited oral bioavailability. Thus, in order to enhance its solubility and intestinal absorption, Piazzini and coworkers (Piazzini et al. 2018b ) developed nanostructured lipid carriers using stearic acid, capryol 90 and Brij S20. Obtained nanovectors were stable after incubation in simulated gastric and intestinal fluids. Evaluation of permeability of formulated silymarin, by parallel artificial membrane permeability assay and Caco-2 cells, evidenced an increased uptake via active transport mechanisms. Other authors also investigated nanostructured lipid carriers made of glyceryl monostearate and oleic acid, for the hepatic delivery of silymarin by oral route. In vivo studies in rats highlighted that silymarin loaded in the nanovectors was absorbed through the lymphatic system after oral gavage and its relative bioavailability was 2-fold higher compared to the suspension of silymarin. In addition, a significant amount of silymarin reached the liver 2 h after the administration (Chaudhary et al. 2015 ).

However, the nanostructured lipid carriers can be formulated also for dermal application. Nanoparticles made of soy lecithin, glyceryl monostearate, stearic acid, and medium chain triglycerides, for instance, were loaded with quercetin and evaluated as topical delivery system. The average particle sizes were ca. 215 nm, the drug loading was about 3% and the encapsulation efficiency was about 90%. In vitro permeation studies, using mouse skin, evidenced the enhanced permeation of quercetin with respect to the unformulated quercetin, whereas in vivo drug distribution experiments evidenced quercetin retention in epidermis and dermis (Chen-Yu et al. 2012 ).

Solid lipid nanocarriers were developed in the early ‘90s to overcome the weaknesses of traditional colloidal carriers, like polymeric nanoparticles and liposomes. Reviewed researches deal with the formulation of natural products, such as curcumin, andrographolide, silymarin and quercetin, recognized as pharmacological active substances, but poorly soluble in water and with low bioavailability. The good biocompatibility of lipid excipients makes it possible to use solid lipid nanocarriers in several delivery routes, including parenteral, oral, and topical, as described. However, despite the increased research interests on these drug carriers, limited pharmaceutical products containing solid lipid nanoparticles are on the market. More knowledge are required concerning the interactions between excipients and biological tissues of the target sites, as well as the fate of solid lipid nanocarriers in the systemic distribution. Additionally, an easy production on large-scale may also advance the commercializing process (Mishra et al. 2018 ; Mu et al. 2018 ; Scioli Montoto et al. 2020 ).

Lipid vesicles

Vesicle preparation was firstly reported in 1965 using natural phospholipids. Vesicles can be obtained using amphiphilic molecules, represented by natural or synthetic phospholipids (liposomes) or non-ionic surfactants (niosomes), (Fig. 2 ). Vesicles are generally spherical with sizes ranging from 50 nm to several microns and having a primary role in affecting their biodistribution and pharmacokinetics. Cholesterol is commonly added as fluidizing of the bilayer, although it does not participate in the bilayer formation (Bilia et. al 2019b ; Bozzuto et al. 2015 ). They are characterized by high biocompatibility and biodegradability, high versatility because they are suitable for all the administration routes and can be loaded with both hydrophilic and hydrophobic drugs with resulting enhanced solubility, permeability, stability, improved bioavailability, controlled release and decreased toxicity of drugs. Vesicles also present ease surface modification to obtain passive or active targeting delivery or prolonged circulation and life time. Major limit is the possible drug leakage, due to the release from the vesicles, together with the low stability of the colloid (Bilia et al. 2014a , 2014b , 2017 , 2019b ).

Conventional liposomes

Conventional liposomes are first-generation drug delivery systems but still represent extremely relevant carriers. Their usefulness is also related to their versatility and wide-ranging use because of their flexibility in being formulated in a broad range of pharmaceutical dosage forms, including (colloidal) solutions, aerosol, semi-solid or solid forms. Accordingly, many approaches of formulations have been applied both to isolated natural products, extracts and essential oils (Bilia et al. 2017 , 2019b ).

An in vivo study on verbascoside-loaded liposomes demonstrated that the liposomal formulation improved the chemical stability and the therapeutic performance of the active molecule. Liposomes, with an average diameter around 120 nm and 83% of encapsulation efficiency, were tested in two animal models of neuropathic pain and the performance of the liposomal verbascoside was compared with that of unformulated drug. Verbascoside possesses, in fact, various pharmacological activities for human health, including antioxidant, anti-inflammatory and antineoplastic properties in addition to numerous wound healing and neuroprotective properties. The paw pressure test was carried out administering verbascoside-loaded liposomes in chronic constriction injury rats by intraperitoneal injection at the dosage of 100 mg/kg, and presented a prolonged antihyperalgesic effect for loaded-verbascoside in comparison to the free drug. The effect has onset 15 min after the injection and persisted for 60 min (Isacchi et al. 2016 ).

Naringenin is a flavonoid with diverse pharmacological activities. However, upon ingestion it could be degraded into an active aglycone by the action of certain intestinal bacterial enzymes and the formulation in liposomes was proposed to stabilize the molecule and enhance its bioavailability, in addition to increase its water solubility. Developed liposomes had dimensions suitable for the oral route ( ca. 70 nm), whereas in vivo studies in mice showed an increased area under the curve, indicating a correspondent enhanced bioavailability (about 14-fold) of naringenin after oral administration. Also, studies of tissue distribution evidenced a predominant accumulation of liposomal naringenin in the liver, with respect to the free drug (Wan et al. 2017 ).

As conventional liposomes are at times unstable when exposed to endogenous chemicals and enzymes in the gastrointestinal environment, an interest study reports the effect of different pluronics (F127, F87 and P85), triblock copolymers many of which approved for use as food additives and pharmaceutical ingredients, on vesicle membranes and, consequently, on their stability. Pluronic-modified liposomes were then loaded with curcumin. It was observed that particle sizes and polydispersity of vesicles were significantly decreased after adding the diverse pluronics, whereas the in vitro release of curcumin was slower compared to the release from conventional liposomes. Pluronics were also able to enhance thermal and pH stability of vesicles, in addition to significantly increase the absorption of curcumin in in vitro simulated gastrointestinal tract studies (Lia et al. 2018 ).

Untargeted liposomes loaded with anticancer drugs are the most successful nano-drug delivery systems translated into clinical applications, including the treatment of hematological cancers. Nanoliposomes for the simultaneous delivery of berberine chloride, antineoplastic drug, and tariquidar, P-gp efflux pump modulator, were formulated to enhance berberine chloride intracellular concentration in doxorubicin-resistant human erythroleukemia cells (K562/DOXO) due to Pg-p overexpression and to contemporaneously reduce tariquidar toxicity. Developed nanoliposomes had sizes around 128 nm and good PdI ( ca. 0.20) and ζ-potential ( ca. -20 mV). The stability of nanoliposomes in the cell culture medium showed only a slight variance in average sizes, PdI and encapsulation efficiency of berberine chloride and tariquidar. Analysis by transmission electron microscopy also evidenced the ability of developed nanoliposomes to enter in both cell lines by receptor-mediated endocytosis, with significant increase in berberine chloride uptake by K562/DOXO cell line. Moreover, formulated tariquidar had less toxic effects (lower cell death by necrosis) than free molecule, as nanoliposomes controlled tariquidar release, with a potential benefit in clinical therapy (Vanti et al. 2021b ).

Nanoliposomes were also investigated to formulate the Serenoa repens L. (saw palmetto) carbon dioxide (CO 2 ) extract, complex mixture constituted of free fatty acids, sterols, phosphoglycerides, glycerides and carotenoids. The saw palmetto CO 2 extract has many biological properties, including anti-inflammation, anti-androgen and anti-proliferation activities, and it has been recently studied for the treatment of hair loss because of the inhibition of 5α-reductase enzyme, responsible of the conversion of testosterone to 5α-dihydrotestosterone. Nanoliposomes ( ca. 145 nm) loaded with 0.1% w/v of saw palmetto CO 2 extract were developed and fully characterized, in terms of Size, PdI, ζ-potential, morphology and encapsulation efficiency, for topical application (Vanti et al. 2021a ).

Some studies have also evidenced the possibility to load essential oils inside liposomes. Generally, essential oils are complex mixtures of volatile, liquid, odorous, flavor and strongly active compounds. Due to their various biological properties, principally antioxidant and antimicrobial, they have been widely used since the Middle Ages and currently they also may have several applications in different fields, from medicine and cosmetics to food. However, their high volatility and low stability to direct exposure to light, oxygen, heat, and humidity can limit their efficacy and potential use. Accordingly, nanocarriers which can definitely load the essential oils, represent an innovative challenge to optimise the essential oil formulation, overcoming these main limitations (Bilia et al. 2014a ; De Matos et al. 2019 ). The resulting nanocarriers are stable and efficient, easily and safely produced, capable of stabilizing the essential oil, modulating its release, optimising its activity and providing an innovative formulative approach to avoid irritancy in case of cutaneous administration (Bilia et al. 2019b ).

The essential oil of Artemisia annua L. was loaded in conventional liposomes and its anti-fungal activity was evaluated against 10 different drug-resistant Candida strains. Formulated liposomes, containing 10 mg/mL of essential oil, had sizes around 250 nm, whereas the encapsulation efficiency of artemisia ketone, the marker constituent of the essential oil, was ca. 75%. The minimum fungicidal concentration of Artemisia annua essential oil loaded in liposomes, ranging 5 to 10 mg/mL, was much inferior than that of free essential oil (Risaliti et al. 2020b ). Another study investigated the antioxidant, anti-inflammatory and antibacterial properties of Salvia triloba L. and Rosmarinus officinalis L. essential oils formulated in liposomes. The obtained systems, loaded with 100 mg/mL of Salvia triloba L. or Rosmarinus officinalis L. essential oil, presented encapsulation efficiency of camphor, the marker constituent, around 57% for Salvia triloba L. and around 65% for Rosmarinus officinalis L. Liposomes were physically stable over time, when stored at +4°C, and very active against Klebsiella pneumoniae (Risaliti et al. 2019 ). Specifically, liposomes enhanced the antibacterial activity of both essential oils. Their antioxidant and anti-inflammatory activities, evaluated by in vitro tests, were also increased in comparison to those of unformulated essential oils.

Pegylated liposomes

Surface functionalization of liposomes has played an important role in formulation of liposomes as pharmaceutical carries, to improve their pharmacokinetics and effectiveness. For instance, conventional liposomes, when administered intravenously, are recognized by opsonin, a serum-protein, and phagocyted in the reticuloendothelial system. In order to increase the circulation time of liposomes, the bilayer surface can be coated with a hydrophilic polymer, such as the polyethylene glycol, increasing repulsive forces between liposomes and serum-components . Such surface modified liposomes have been defined as pegylated or stealth liposomes (Riaz et al. 2018 ).

Therefore, in a further study, pegylated liposomes, loaded with salvianolic acid B, were developed and tested in the same animal model of neuropathic pain reported for verbascoside (Isacchi et al. 2016 ). Salvianolic acid B was effective against mechanical hyperalgesia 15 min after administration, when injected intraperitoneally at a dose of 100 mg/kg. The antihyperalgesic activity prolonged for 30 min after administration, and the effect was still significant after 45 min (Isacchi et al. 2011b ).

Some studies report instead on the performance of conventional and long circulating liposomes (pegylated) loaded with artemisinin, a sesquiterpene lactone isolated from the Artemisia annua  L., well known as very active antimalarial drug. Conventional and long circulating liposomes, with sizes of 130–140 nm and encapsulation efficacy higher than 70%, were injected in healthy mice. Free artemisinin was quickly cleared from plasma and it was almost not more detectable 1 hour after the injection. By contrast, artemisinin was still detectable after 3 and 24 hours when formulated in conventional or pegylated liposomes, respectively. The area under the curve (0-24 h) was six times increased with respect to free artemisinin. In particular, artemisinin half-life was enhanced more than 5-fold with long circulating liposomes (Isacchi et al. 2011a ). The same liposomes were tested in Plasmodium berghei NK-65 infected mice, a successful malaria model, at the dose of 50 mg/kg/day for artemisinin and 100 mg/kg/day for artemisinin plus curcumin. In mice treated with artemisinin-loaded liposomes or artemisinin plus curcumin-loaded liposomes (conventional and pegylated) was observed an immediate antimalarian effect. Particularly, artemisinin-loaded long circulating liposomes showed the most conspicuous and statistically significant activity (Isacchi et al. 2012 ). As artemisinin attracted increasing interest over years also for its antitumor properties in a variety of cancer cells, in a further study it was loaded in long circulating liposomes decorated with transferrin, in order to increase the up-take in tumoral cells. Specifically, cell uptake and cytotoxicity of liposomes were explored using the human colon carcinoma (HCT-8) cell line, because of the overexpression of transferrin receptors. An improved delivery of artemisinin was found for transferrin decorated liposomes with respect to the long-circulating vesicles, and enhanced cytotoxicity was also observed due to iron ions, obtaining a synergic anticancer effect (Leto et al. 2016 ).

Conventional and pegylated liposomes were also loaded with dihydroartemisinin, the natural metabolite of artemisinin and one of the most potent anticancer compounds, able to induce cancer cell death by apoptotic pathways. Cellular uptake efficiency of liposomes was determined by flow cytometry in MCF-7 cells. Higher internalization occurred for conventional liposomes rather than for stealth liposomes, probably due to the hydrophilic steric barrier of polyethylene glycol molecules. Furthermore, cytotoxicity studies on these cancer cells evidenced an increased toxicity for the formulated dihydroartemisinin and absence of toxicity for blank formulations (Righeschi et al. 2014 ).

Stabilized nanovesicles

Liposomes mostly consist of phospholipids and cholesterol. However, some solvents (ethanol, glycerol, propylene glycol) can impart stability, deformability or elasticity to the bilayer membrane of liposomes, resulting in a considerable improved drug loading and permeability through biological barriers by several orders of magnitude (Carita et al. 2018 ; Fernández-García et al. 2019 ).

Glycerosomes are innovative liposomes for dermal and transdermal drug delivery, based on glycerol and characterized by high physical stability and excellent deformability (Manca et al. 2013 ). In a recent investigation Melissa officinalis L. essential oil was loaded inside glycerosomes containing 10% v/v of glycerol, and it was evaluated for its anti-herpetic activity against herpes simplex virus (HSV) type 1 (herpes labialis). The encapsulation efficiency of the essential oil in terms of citral and β-caryophyllene, major constituents, was found to be ca. 63% and 76%, respectively. Moreover, the developed glycerosomes loaded with Melissa officinalis L. essential oil showed extraordinary chemical and physical stability during 4 months of storage, and were very active in inhibiting HSV type 1 infection of mammalian cells in vitro , without producing cytotoxic effects (Vanti et al. 2020a ).

Glycerosomes and propylene glycol-nanovesicles loaded with essential oils of Origanum onites L. and Satureja thymbra L. were also investigated as safe and food-grade delivery systems. Essential oils represent in fact a valid alternative to synthetic preservatives in the food industry. However, in many cases their organoleptic impact in foodstuffs limits their usage, in addition to the high volatility and chemical instability which decrease their efficacy. Techniques such as the encapsulation in nanodelivery systems can address this problem. Both pure and formulated essential oils were evaluated against different food-borne pathogens and spoilage microorganisms. Propylene glycol‐nanovesicles loaded with Origanum onites L. essential oil were found to be the most active formulation against all tested strains. Additionally, in vitro studies on HaCaT cell line showed that nanovesicles loaded with the essential oils had no toxic effect. Overall, these studies unveiled that tested nanovesicles could represent potential biocontrol agents against fungal and bacterial food pathogens with promising GRAS status in mammalian systems, besides being an innovative and completely biodegradable approach for the prolonged and sustained release of the essential oils, preserving functional properties (Vanti et al. 2021c ).

Active nanovesicular carriers

Recently, innovative nanovesicular systems, escinosomes and ascosomes, were also investigated using natural bioactive molecules as vesicle bilayer components, and they were studied for the skin delivery of selected model drugs.

The first study was design to explore the conversion of the bioactive amphiphilic saponin escin, isolated from seeds of Aesculus hippocastanum L. and clinically used for its anti-inflammatory, anti-oedematous and venotonic properties, into vesicle bilayer forming component, because of the suited chemical structure and the fluidizing effect on phospholipid membranes. Escinosomes, the obtained nanovesicles made of phosphatidylcholine plus escin, retained escin inhibitory activity on hyaluronidase and were subsequently loaded with berberine chloride, salt of the natural quaternary isoquinoline alkaloid berberine isolated from several medicinal plants. Berberine chloride was selected as model drug of low skin absorption. Empty and berberine chloride-loaded escinosomes displayed optimal characteristics for skin delivery, with high deformability, optimal physical stability, good encapsulation efficiency of berberine chloride (about 67%) and proper release rate of drug (about 75% after 24 h), (Vanti et al. 2019 ). Subsequently, escinosomes were gelled using hydroxypropyl methylcellulose. Developed escinosome-hydrogels combined the benefits of a controlled release and improved transdermal permeability of both escin and berberine chloride, thanks to the escinosome components, with optimised viscosity properties thanks to the polysaccharide matrix. The escinosome-hydrogels also showed a very good safety profile with no potential skin irritation, evaluated by in vivo acute dermal irritation/corrosion test on Sprague-Dawley rats (Vanti et al. 2020b ).

Ascosomes represent a further innovative nanocarrier for cutaneous application made of phosphatidylcholine plus derivates of L-ascorbyl acid, ascorbyl octanoate or ascorbyl decanoate, investigated as bioactive constituents of the vesicle bilayer. L-ascorbic acid (vitamin C) plays in fact an important role in the prevention and treatment of a large number of chronic diseases, including skin disorders, but it hardly penetrate the stratum corneum. The synthesis of amphiphilic derivates is a promising approach to enhance its skin penetration. In addition, because of their amphiphilic nature, ascorbyl derivates form supramolecular assemblies in aqueous dispersions, and they have been investigated as potential constituents for drug delivery systems. Obtained nanovesicles, ascosomes, were thus investigated as potential nanocarriers for the skin delivery of khellin, a natural furanochromone with various applications in skin pathologies and selected as model lipophilic drug. Developed ascosomes increased the cutaneous absorption of khellin and retained the antioxidant properties of ascorbic acid (Risaliti et al. 2020a ). Subsequently, a hydrogel of khellin-loaded ascosomes was developed using hydroxyethyl cellulose, in order to overcome the short residence time of the liquid formulation upon application on the skin, and to enhance the stability of the vesicles preventing their aggregation. The hydrogel of khellin-loaded ascosomes demonstrated a good safety profile in rats by the acute dermal irritation/corrosion test. Liver and dermal histological and pathological analyses also indicated that khellin formulated in the ascosome-hydrogel had no toxic effects (Risaliti et al. 2021 ).

Perspectives of lipid vesicles

The development of vesicles as carriers for therapeutic molecules is an ever-growing research area. Conventional liposomes, stabilized nanovesicles (glycerosomes and propylene glycol-nanovesicles), active nanovesicular carriers (escinosomes and ascosomes) have shown excellent potential in (co-)delivering natural products which belong to different chemical classes, namely phenylpropanoids (verbascoside, curcumin), flavonoids (naringenin), sesquiterpene lactones (artemisinin), saponins (escin), alkaloids (berberine chloride), furanochromones (khellin), or carbon dioxide extracts ( Serenoa repens L.) and essential oils ( Artemisia annua L., Salvia triloba L., Rosmarinus officinalis L., Melissa officinalis L., Origanum onites L., Satureja thymbra L.). All these vesicular systems, besides being biocompatible and suitable for all the administration routes, demonstrated to improve the biopharmaceutical properties of loaded natural drugs or to increase their chemical stability, with the aim of reaching an effective pharmacological activity. Lipid vesicles are still the most widely studied colloidal drug delivery systems, which also find great application in the clinical practice.

Nanocochleates

Nanocochleates represent an alternative platform to vesicles in order to overcome their main limitations, such as possible drug leakage, due to release processes, and low stability of the colloid in biological fluids. Cochleates were firstly observed when phosphatidylserine liposomes were treated with divalent metal cations, mainly magnesium and calcium. They are characterized by an exceptional stability due to their cylindrical shape and distinctive multi-layered structure (Fig. 2 ) (Bozó et al. 2017 ; Tilawat & Bonde 2021 ) and they were studied to formulate different kind of natural products.

Thymus vulgaris L. essential oil was loaded in nanocochleates (1 mg/mL), obtaining an encapsulation efficiency of the major constituents, thymol and carvacrol, of about 46% and 51%, respectively. Developed nanocochleates, ranging from ca. 210 to 250 nm, preserved the strong antioxidant activity of the unformulated Thymus vulgaris essential oil and were found to be suitable to provide a practical dosage form (Asprea et al. 2017 ). Nanocochleates have been also investigated as delivery systems of andrographolide, extensively studied for its wide spectrum of biological activities and selected as model drug because of its low water solubility and gastrointestinal instability. The developed andrographolide-loaded nanocochleates were found to be stable after lyophilisation and resuspension in distilled water, as well as after incubation in simulated gastric and intestinal media. They also demonstrated an elevated safety profile both in macrophages and 3T3 fibroblasts even at high concentrations, in addition to extraordinary uptake properties in macrophages, evaluated by a fluorescent probe (Asprea et al. 2019 ).

Nanocochleate is an extremely biocompatible system with excellent stability due to the unique compact structure, gaining increasing interest in pharmaceutical research as nanocarrier.

There is an increasing interest for nano-drug delivery systems for their potential application in clinic, both for local and systemic administration of drugs. Concurrently, natural products, which include a large and diverse group of substances from various natural sources, have assumed an exceptional importance for the prevention and cure of many diseases. This is due to their unique structure and their pleiotropic effects by targeting and modulating multiple pathways. For these reasons, natural products could represent the ideal drugs to a realistic approach of many diseases, especially those with emerging resistance to monofunctional agents, and they are suitable approaches against multifactorial and complex diseases, especially cancer and diabetes. By contrast, natural products suffer of many limitations and the majority of constituents are not “drug like”. Accordingly, the various nanovectors have been attempted as potential delivery systems for natural products, increasing the stability and solubility of loaded drugs and, thus, making them suitable for the administration. These nanostructures are also able to improve the biodistribution, with a consequent increased efficacy, as well as to favour the accumulation at target sites, reducing the adverse effects. Furthermore, the selection of biocompatible nanomaterials allow to decrease the formulation toxicity.

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Vanti, G. Recent strategies in nanodelivery systems for natural products: a review. Environ Chem Lett 19 , 4311–4326 (2021). https://doi.org/10.1007/s10311-021-01276-x

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DOI : https://doi.org/10.1007/s10311-021-01276-x

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Natural products from the Lithistida: a review of the literature since 2000

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• 1 Harbor Branch Oceanographic Institution at Florida Atlantic University, Center for Marine Biomedical and Biotechnology Research, 5600 US 1 North, Fort Pierce, FL 34946, USA.
• PMID: 22363244
• PMCID: PMC3280575
• DOI: 10.3390/md9122643

Lithistid sponges are known to produce a diverse array of compounds ranging from polyketides, cyclic and linear peptides, alkaloids, pigments, lipids, and sterols. A majority of these structurally complex compounds have very potent and interesting biological activities. It has been a decade since a thorough review has been published that summarizes the literature on the natural products reported from this amazing sponge order. This review provides an update on the current taxonomic classification of the Lithistida, describes structures and biological activities of 131 new natural products, and discusses highlights from the total syntheses of 16 compounds from marine sponges of the Order Lithistida providing a compilation of the literature since the last review published in 2002.

Keywords: Lithistida; Theonella; desmas; lithistid; natural product.

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The Traditional Medicine and Modern Medicine from Natural Products

Haidan yuan.

1 College of Pharmacy, Yanbian University, Yanji 133002, China; nc.ude.uby@nauydh (H.Y.); moc.361@8193naiqnaiq (Q.M.); nc.ude.uby@1260104102 (L.Y.)

2 Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University, Yanji 133002, China

Qianqian Ma

Guangchun piao.

Natural products and traditional medicines are of great importance. Such forms of medicine as traditional Chinese medicine, Ayurveda, Kampo, traditional Korean medicine, and Unani have been practiced in some areas of the world and have blossomed into orderly-regulated systems of medicine. This study aims to review the literature on the relationship among natural products, traditional medicines, and modern medicine, and to explore the possible concepts and methodologies from natural products and traditional medicines to further develop drug discovery. The unique characteristics of theory, application, current role or status, and modern research of eight kinds of traditional medicine systems are summarized in this study. Although only a tiny fraction of the existing plant species have been scientifically researched for bioactivities since 1805, when the first pharmacologically-active compound morphine was isolated from opium, natural products and traditional medicines have already made fruitful contributions for modern medicine. When used to develop new drugs, natural products and traditional medicines have their incomparable advantages, such as abundant clinical experiences, and their unique diversity of chemical structures and biological activities.

1. Introduction

Since prehistoric times, humans have used natural products, such as plants, animals, microorganisms, and marine organisms, in medicines to alleviate and treat diseases. According to fossil records, the human use of plants as medicines may be traced back at least 60,000 years [ 1 , 2 ]. The use of natural products as medicines must, of course, have presented a tremendous challenge to early humans. It is highly probable that when seeking food, early humans often consumed poisonous plants, which led to vomiting, diarrhea, coma, or other toxic reactions—perhaps even death. However, in this way, early humans were able to develop knowledge about edible materials and natural medicines [ 3 ]. Subsequently, humans invented fire, learned how to make alcohol, developed religions, and made technological breakthroughs, and they learned how to develop new drugs.

Traditional medicines (TMs) make use of natural products and are of great importance. Such forms of medicine as traditional Chinese medicine (TCM), Ayurveda, Kampo, traditional Korean medicine (TKM), and Unani employ natural products and have been practiced all over the world for hundreds or even thousands of years, and they have blossomed into orderly-regulated systems of medicine. In their various forms, they may have certain defects, but they are still a valuable repository of human knowledge [ 2 , 4 ].

In the case of China, Western medicine was introduced in the sixteenth century, but it did not undergo any development until the nineteenth century. Before that, TCM was the dominant form of medical care in the country [ 5 ]. Now TCM still plays an important role in China, and it is constantly being developed. TCM is based on 5000 years of medical practice and experience, and is rich in data from “clinical experiments” which guarantee its effectiveness and efficacy. It has developed techniques with respect to such areas as correct dosage, methods of preparing and processing materials, and the appropriate time to collect the various medicinal parts of plants. It is notable that there is increasing convergence between TCM and modern medicine. With the development of modern technology, it has become possible to determine the pharmacology and mechanisms of action of many Chinese herbs, and TCM has become comprehensible in terms of modern medicine [ 6 , 7 , 8 , 9 ]. With advances in the theoretical background, therapeutic principles, associated technologies, and understanding of the life sciences, a clearer understanding of the active compounds of TCM has become possible [ 5 ].

At the beginning of the nineteenth century, the era of “modern” drugs began. In 1805, the first pharmacologically-active compound morphine was isolated by a young German pharmacist, Friedrich Sertürner, from the opium plant [ 10 , 11 ]. Subsequently, countless active compounds have been separated from natural products. Among them, some follow their traditional uses and the others do not. Later, the development of synthetic techniques led to a significant reduction in the importance of natural products, and there were concerns that the use of some natural products for medicinal purposes might be completely banned. However, natural products are important for the development of new drugs, and these products have been in constant use. Some type of medicines, such as anticancer, antihypertensive, and antimigraine medication, have benefited greatly from natural products [ 10 , 12 ].

The development of new drugs relying purely on modern technology appears to be reaching something of a limit. In developing new drugs, the pharmaceutical industry has tended to adopt high-throughput synthesis and combinatorial chemistry-based drug development since the 1980s; however, the considerable efforts made in this direction have not resulted in the expected drug productivity. Some large pharmaceutical companies are facing great challenges to develop new products. Over the past dozen years, increasing attention has accordingly been paid to natural products in the search for novel drugs in combination with new technology, such as high-throughput selection [ 13 , 14 ].

Natural products, which have evolved over millions of years, have a unique chemical diversity, which results in diversity in their biological activities and drug-like properties. Those products have become one of the most important resources for developing new lead compounds and scaffolds. Natural products will undergo continual use toward meeting the urgent need to develop effective drugs, and they will play a leading role in the discovery of drugs for treating human diseases, especially critical diseases [ 15 ].

2. Natural Products

Natural products have a wide range of diversity of multi-dimensional chemical structures; in the meantime, the utility of natural products as biological function modifiers has also won considerable attention. Subsequently, they have been successfully employed in the discovery of new drugs and have exerted a far-reaching impact on chemicobiology [ 16 , 17 , 18 ]. From the past century, the high structural diversity of natural products have been realized from the perspective of physical chemistry. Their efficacy is related to the complexity of their well-organized three-dimensional chemical and steric properties, which offer many advantages in terms of efficiency and selectivity of molecular targets. As a successful example of drug development from natural products, artemisinin and its analogs are presently in wide use for the anti-malaria treatment. This shows how research using natural products has made a significant contribution in drug development [ 19 , 20 ].

Among anticancer drugs approved in the time frame of about 1940–2002, approximately 54% were derived natural products or drugs inspired from knowledge related to such. For instance, the Vinca alkaloids from Catharanthus roseus , and the terpene paclitaxel from Taxus baccata , are among successful anticancer drugs originally derived from plants [ 12 , 21 ]. During the period between 1981 and 2002, the application of natural products in the development of new drugs—especially in the search for novel chemical structures—showed conspicuous success. In that 22-year time frame, drugs derived from natural products have been significant. That is especially true in the case of antihypertensives, where about 64% of newly-synthesized drugs have their origins in natural product structures [ 12 ].

Considering their incomparable chemical diversity and novel mechanisms of action, natural products have continued to play a pivotal role in many drug development and research programs. With time, those natural products have undergone interesting and meaningful developments in their ability to interact with numerous, varied biological targets, and some have become the most important drugs in health care system [ 14 , 22 , 23 ]. For example, plants, microorganisms, and animals manufacture small molecules, which have played a major role in drug discovery. Among 69 small-molecule new drugs approved from 2005 to 2007 worldwide, 13 were natural products or originated from natural products, which underlines the importance of such products in drug research and development [ 12 , 13 ].

Over the past 50 years, there has been a great diversity of new drugs developed using high-throughput screening methods and combinatorial chemistry; however, natural products and their derived compounds have continued to be highly-important components in pharmacopoeias. Of the reckoned 250,000–500,000 existing plant species, only a tiny proportion has been scientifically researched for bioactivities [ 13 ]. Therefore, there is great potential for future discoveries from plants and other natural products which, thus, offer huge potential in deriving useful information about novel chemical structures and their new types of action related to new drug development.

3. Traditional Medicines

TM is the oldest form of health care in the world and is used in the prevention, and treatment of physical and mental illnesses. Different societies historically developed various useful healing methods to combat a variety of health- and life-threatening diseases. TM is also variously known as complementary and alternative, or ethnic medicine, and it still plays a key role in many countries today [ 24 , 25 ].

The medicaments used in TM are mostly derived from natural products. In TM, “clinical trials” have been conducted since ancient times. In the case of TCM, considerable experience and advances have been accumulated and developed over the past thousands of years with respect to methods of preparation, selection of herbs, identification of medicinal materials, and the best time for obtaining various different plants. Appropriate processing and dose regulation are urgently needed in TCM to improve drug efficacy and reduce drug toxicity. Considerable amounts of data have been acquired through clinical experiments, and in this way TM has assisted in the development of modern drugs. Through its use of natural products, TM offers merits over other forms of medicine in such areas as the following: discovery of lead compounds and drug candidates; examining drug-like activity; and exploring physicochemical, biochemical, pharmacokinetic, and toxicological characteristics. If any form of TM is applied successfully, it may surprisingly assist in the development of new drugs, thereby resulting in many benefits, such as significant cost reductions.

TCM is now an inseparable part of the Chinese public health system. In recent years, TCM has gradually gained considerable approval as a complementary or alternative medicine in Western countries. Chinese herbal medicine, which is the most important component of TCM, is currently used in the health care of an estimated 1.5 billion people worldwide [ 26 , 27 ]. It should be noted that in TCM, several herbs and ingredients are combined according to strict rules to form prescriptions, which are referred to as formulas ( fang ji in Chinese). Commonly, a classic formula is composed of four elements—the “monarch”, “minister”, “assistant”, and “servant”—according to their different roles in the formula, each of which consists of one to several drugs. Ideally, these drugs constitute an organic group to produce the desired therapeutic effect and reduce adverse reactions [ 28 ].

Kampo is the TM of Japan. Between the fifth and sixth centuries, TCM was introduced to Japan from China; since then, TCM has been significantly altered and adapted by Japanese practitioners to meet their particular circumstances and gradually evolved into Kampo [ 29 ]. A recent study has found that some physicians in Japan use Kampo medicines in their daily practice—sometimes as the preferred medication [ 29 , 30 , 31 ]. Together with radiotherapy or chemotherapy, some Japanese physicians frequently utilize Kampo medicines in treating cancer patients. This indicates how modern Western medicine can be well integrated with TM [ 30 , 32 ]. As the use of Kampo continues to rise in conjunction with Western medicine, there is growing realization of the urgent need to study the interactions between these two types of medicines [ 28 ].

Unani is an ancient Greek holistic medical system with a history that can be traced back 2500 years [ 33 ]. Since the mid-1970s, when the WHO began to place a greater focus on TM, Unani has attracted considerable attention all over the world, especially in India, where it has been integrated into the national health care system [ 34 ].

It was reckoned by WHO that a large quantity of people in the world still depend on TMs for health care [ 35 ]. The current status of TM differs in different countries. In 2012, the total value of the TCM industry was equivalent to around one-third of the total for China’s pharmaceutical industry [ 36 ]. It has been determined that 80% of the population in Africa makes use of TM—either alone or in conjunction with conventional medicine [ 37 ]. By contrast, traditional Aboriginal medicine in Australia is in danger of vanishing owing to the prevalence of conventional medicine [ 38 ]. In the case of Israel with its ethnic diversity, modern medicine is prevailing, and TM is declining [ 39 ]. Many practitioners of Western medical science think such TM systems as being short of reliability; however, they are adopted by the majority of people in the world [ 35 ]. It is possible to produce remarkable synergy and yield great benefits in developing reformed medicines and new drugs by connecting powerful modern scientific techniques and methods with the reasonable ethnobotanical and ethnomedical experiences of TM. Characteristics of several TM systems are summarized in Table 1 .

Characteristics of several important traditional medicine systems.

4. Drugs Developed from Traditional Medicines that Follow the Traditional Uses

TM is too valuable to be ignored in the research and development of modern drugs. Though it has an enigmatic character, there are also wide contexts for its use in terms of non-Western medical technology or activities. In TM, a single herb or formula may contain many phytochemical constituents, such as alkaloids, terpenoids, flavonoids, etc. Generally speaking, these chemicals function alone or in conjunction with one another to produce the desired pharmacological effect [ 35 ]. It is notable that a lot of plant-originated drugs in clinical medicine today were derived from TM [ 21 ]. In addition, it has been demonstrated that the many valuable drugs derived from plants were discovered through their application in TM [ 2 ].

Almost 20 years ago, a thorough investigation of the pharmacopoeias of developed and developing nations and the associated world scientific literature was conducted as part of the WHO’s TM Program. The aim of that study was to determine whether TM really had inspired modern drug discoveries and whether there was any correlation between the current use of various compounds and their application in TM. The study focused on various compounds used in drugs derived from plants in different countries, and it established that TM had indeed played a significant role in developing effective new drugs. That study focused on 122 compounds, 80% of which were found to be related to pharmaceutical effects in folk medicine, and it was determined that these compounds originated from 94 plant species [ 2 ].

The acceptability, convenience, and accessibility of TMs have been, and will be, helpful for new drug research [ 13 ]. As noted above, artemisinin and other antimalarial drugs are examples of modern drugs based on TMs. Early in China’s Jin Dynasty, Doctor Hong Ge (AD 284–384) recorded the efficacy and related details of Artemisia annua L. in treating malaria in his book Zhou Hou Bei Ji Fang . That is the earliest record anywhere of treating malaria with Artemisia annua L., and it shows that Chinese physicians 1700 years ago had reached a sophisticated level of medical treatment [ 53 , 54 ].

Artemisinin is known as qinghaosu in Chinese, and its study has made significant progress, including the synthesis of new artemisinin analogs and derivatives, and research efforts into the biological activities and related mechanisms. As a result, artemisinin, as well as its effective derivatives, are extensively applied throughout the world as new-type anti-malarial drugs [ 55 ].

The discovery of artemisinin can be traced back to the 1960s, when tropical malaria was a serious problem during the Vietnam War. North Vietnam requested China to help tackle the malaria problem. The Chinese government approved a project for malaria control and drug research in 1967. The research group made its investigations and carried out a large-scale search of the literature on the subject. As part of the phytochemical and pharmacological research effort, a lot of Chinese herbal medicines were screened and investigated with respect to their toxicity or efficacy. Eventually artemisinin was derived from Artemisia annua L. in 1972 [ 53 , 55 , 56 ]. Artemisinin is quite different from previously-used antimalarial drugs, such as chloroquine, in that it has a novel structure, with a sesquiterpene lactone bearing a peroxy group, and it does not contain nitrogen heterocycles. Compared with previous antimalarial drugs, artemisinin has the merit of high efficiency, quick effect, and low toxicity. Artemisinin is effective in treating various forms of malaria, such as falciparum and cerebral malaria, which are resistant to chloroquine, and its mechanism of action is different from traditional antimalarial drugs. The discovery of artemisinin was a great success for TCM at a special period in China’s history, and it was achieved through a well-organized team of hundreds of researchers [ 56 ]. Since that breakthrough, scientists have conducted comprehensive research in such areas as pharmaceutical chemistry, organic synthetic chemistry, and chemical biology. Through etherification and esterification, they have produced a series of well-known new drugs, such as artemether and artesunate. Those drugs have improved efficacy and solubility, which are of benefit for patients receiving oral or intravenous administration and have overcome the high parasite recrudescence rate and low solubility of artemisinin [ 55 , 56 , 57 ]. Most importantly, one of these scientists, Youyou Tu, was just awarded the 2015 Nobel Medicine Prize for her significant devotion in discovering artemisinin.

The discovery of artemisinin illustrates how TCM constitutes a great store of knowledge about natural products, such as Chinese herbs, and holds much future promise. The discovery of successful new drugs can proceed by profiting from this knowledge [ 56 ]. Some drugs or compounds isolated from Chinese herbal medicines which follow the ethnomedical uses are summarized in Table 2 .

Some drugs or compounds isolated from Chinese herbal medicines which follow the traditional uses.

5. Drugs Developed from Natural Products

In clinical practice in China in the 1960s, it was found that Schisandra chinensis (Turcz.) Baill.—a traditional Chinese herb—had obvious enzyme-reducing and hepatoprotective effects. Chinese scientists then began isolating the chemical constituents of S. chinensis . In the subsequent total chemical synthesis and pharmacodynamic study of schisandrin C (which is one of the compounds of S. chinensis ), researchers found that the intermediate compound bifendate had a stronger pharmacological activity and that the cost of preparation was low. They discovered that it may be used to lower the enzyme content in the treatment of hepatitis B virus [ 57 ].

Since the end of the 1980s, chemists and pharmacologists at the Chinese Academy of Medical Sciences have been closely cooperating in studying the structure and activity relationships of bifendate and its analogs. As part of their research, a series of novel derivatives were synthesized. After screening using a number of chemical and pharmaceutical liver injury models, it was found that the hepatoprotective activities of the derivatives were closely related to the locations of dimethylenedioxy in two benzene rings, the length of the side-chain carboxylic acid, and the heterocycle between the two benzene rings. Finally, a new compound, bicyclol—formulated as 4,4″-dimethoxy-5,6,5′,6′-bis(methylene-dioxy)-2-hydroxy-methyl-2′-methoxycarbonyl biphenyl—was designed and synthesized. Bicyclol had greater in vivo absorption, and better bioavailability and biological activity, than bifendate owing to the introduction of the 6-hydroxymethyl group and 6′-carbomethoxy in the side chain [ 72 ]. Pharmacological results of bicyclol showed antifibrotic and hepatoprotective effects against liver injury and liver fibrosis induced by CCl 4 or other hepatotoxins in mice and rats; it also exhibited the antihepatitis virus effect in the 2.2.15 cell line and duck model with viral hepatitis [ 73 , 74 ].

In clinical trials, it was found that the increased levels of serum alanine aminotransferase and aspartate aminotransferase were dramatically decreased by bicyclol. It was also found that bicyclol prohibited hepatitis B virus replication in chronic hepatitis B patients [ 75 ]. Compared with previous anti-hepatitis drugs, bicyclol exhibited a more consolidated effect after the drug was discontinued; the rebound rate was low, with fewer adverse reactions and higher oral bioavailability [ 76 ]. Based on previous studies in such areas as synthesis, pharmacology, toxicology, pharmacokinetics, preparation, and quality control, researchers determined that the new antihepatitis drug bicyclol offered significant hepatoprotective effects, antihepatitis virus activity, and fewer adverse reactions [ 57 ]. Bicyclol has been approved for the treatment of chronic viral hepatitis in China since 2004 [ 73 ]. Bicyclol has independent intellectual property rights and belongs to Class 1 of China’s New Chemical Drug. The drug is one of the anti-inflammatory and hepatoprotective drugs recommended by the “Guidelines on Liver Disease Clinical Diagnosis and Treatment” in China, and it has been exported to many countries [ 57 , 76 ].

In the same decade in which Chinese scientists found that S. chinensis (Turcz.) Baill. had obvious enzyme-reducing and hepatoprotective effects, a program screening for cancer drugs from plants began in 1960 at the National Cancer Institute in the United States. Neither China nor the United States knew what the other was doing in this area. In that US project, 650 plant samples were gathered in three states. After the initial cytotoxicity tests were carried out using crude extracts, Taxus brevifolia was chosen for further research.

Taxol was isolated as a new compound from T. Brevifolia . Taxol has an unusual chemical structure and radically distinctive mechanism of action and was developed as a novel anticancer drug in subsequent decades. Nevertheless, the drug attracted little attention during the early stage of its development because of its poor solubility in water, low yield from natural products, and other disadvantages, particularly by the medical society. The story of Taxol involved many events that nearly resulted in discontinuation of the research. Fortunately, it underwent extraction, isolation, and structural determination; its activity against solid tumors and its mechanism of action were established, and it became developed for clinical practice. Finally, Taxol was approved by the US Food and Drug Administration for treating ovarian cancer in 1992—21 years after the initial breakthrough paper recording its isolation and structural identification. Taxol has remained a basic drug for treating various forms of cancer, and is still being used to develop new synergistic groups of anticancer drugs [ 77 , 78 , 79 ]. Some drugs or compounds isolated or developed from natural products are summarized in Table 3 .

Some drugs or compounds isolated or developed from natural products.

6. Discussion

Human history is also the history of medicines used to treat and prevent various diseases. To counter the danger from serious illnesses and to guarantee survival of the species, it is necessary to continually produce better drugs. With time, the use of these natural products as TM increased. Modern medicine has benefited considerably from TM in two areas: drugs with similar effects and drugs with different effects from those of TM. From the history of drug development, it is evident that many drugs have been derived as a result of inspiration from TM.

The application of, and research into, natural products are far from satisfactory. A number of problems need to be addressed in the future. For example, synergistic effects may exist among the compounds that occur in natural products; however, the modes and mechanisms of action are seldom very clear. It is, therefore, necessary to make full use of such synergetic effects toward improving the effectiveness of drugs. However, it is also requisite that any adverse effects of natural products be properly reduced to meet safety standards.

With the riches of modern technology, such as in synthesis, fermentation, pharmacology, pharmacodynamics—together with biological diversity, chemodiversity, and great breakthroughs in evolutionary techniques or concepts—combined with a wealth of knowledge about natural products, it will be possible to establish a large compound library for drug screening [ 89 ]. This will enhance the possibilities for individual treatment and prevention of disease. Humankind needs to learn more from natural products and traditional medicines.

In order to further promote the development of modern medical research on natural products, humans have to face up to various difficulties and challenges. Valuable information on natural products and TMs is mixed in a large number of documents, data, and useless rumors. Furthermore, one plant or formula of natural products and TMs contains a large number of chemical constituents, including active, invalid, and possible synergistic components. Therefore, great effort should be made at first to remove the dross and take the essence—precious experience of natural products and TMs. Furthermore, in many cases, the role of single compound from natural products and TMs is paid much attention to. However, as a matter of fact, one advantage of TM’s therapeutics is the “synergism”; that is, often multiple components in TMs play a synergistic role which is greater than that of the individual drug. In the meantime, the “1 disease, 1 target, 1 drug” mode cannot treat some complex diseases effectively, such as cardiovascular disease and diabetes. Thus, the treatment has seen a shift to the “multi-drugs and multi-targets” mode for combination therapies. Therefore, in the future, multidisciplinary collaborative research, closely cooperated with new ideas, such as network pharmacology and big data, will be possible to explain the synergism and other mechanisms of natural products and TMs from which more and better new drugs and treatment will be discovered and inspired.

Acknowledgments

This review was supported in part by research grants (No. 81260669 and 81560698) from National Natural Science Foundation of China, respectively.

Conflicts of Interest

The authors declare no conflict of interest.

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Natural Product Reports

Marine natural products †.

* Corresponding authors

a School of Environment and Science, Griffith University, Gold Coast, Australia E-mail: [email protected]

b Griffith Institute for Drug Discovery, Griffith University, Brisbane, Australia

c School of Chemical Sciences, University of Auckland, Auckland, New Zealand

d Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, and Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA

e Centre for Biodiscovery, and School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand

f School of Science, University of Waikato, Hamilton, New Zealand

Covering: January to the end of December 2022

This review covers the literature published in 2022 for marine natural products (MNPs), with 645 citations (633 for the period January to December 2022) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, the submerged parts of mangroves and other intertidal plants. The emphasis is on new compounds (1417 in 384 papers for 2022), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of NP structure class diversity in relation to biota source and biome is discussed.

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