View source for Natural product

{{short description|Chemical compound or substance produced by a living organism, found in nature}}
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A '''natural product''' is a natural [[Chemical compound|compound]] or [[chemical substance|substance]] produced by a living organism—that is, found in [[nature]].<ref name="url_Natural_product_Webster">{{cite web | url = http://www.thefreedictionary.com/natural+product | title = Natural product | year = 1913 | author = Webster's Revised Unabridged Dictionary  | publisher = Free Online Dictionary and C. & G. Merriam Co. | quote = A chemical substance produced by a living organism; – a term used commonly in reference to chemical substances found in nature that have distinctive pharmacological effects. Such a substance is considered a natural product even if it can be prepared by total synthesis. }}</ref><ref name="pmid17576412">{{cite journal | title = All natural | journal = Nature Chemical Biology | volume = 3 | issue = 7 | page = 351 | date = July 2007 | pmid = 17576412 | doi = 10.1038/nchembio0707-351 | quote = The simplest definition for a natural product is a small molecule that is produced by a biological source. | doi-access = free }}</ref> In the broadest sense, natural products include any substance produced by life.<ref name = "Samuelson_1999">{{cite book | title = Drugs of Natural Origin: A Textbook of Pharmacognosy | vauthors = Samuelson G | publisher = Taylor & Francis Ltd | year = 1999 | isbn = 978-91-86274-81-8 }}</ref><ref name="urlNatural Products Research—Information for Researchers | NCCAM">{{cite web | url = http://nccih.nih.gov/grants/naturalproducts | title = Natural Products Research—Information for Researchers &#124; NCCIH | author = National Center for Complementary and Integrative Health | date = 13 July 2013 | publisher = U.S. Department of Health & Human Services | quote = Natural products include a large and diverse group of substances from a variety of sources. They are produced by marine organisms, bacteria, fungi, and plants. The term encompasses complex extracts from these producers, but also the isolated compounds derived from those extracts. It also includes vitamins, minerals and probiotics.}}</ref> Natural products can also be prepared by [[chemical synthesis]] (both [[semisynthesis]] and [[total synthesis]]) and have played a central role in the development of the field of [[organic chemistry]] by providing challenging synthetic targets. The term ''natural product'' has also been extended for commercial purposes to refer to [[cosmetics]], [[dietary supplement]]s, and foods produced from natural sources without added artificial ingredients.<ref name="url_NPF_about_us">{{cite web | url = http://www.naturalproductsfoundation.org/index.php?src=gendocs&ref=about_us&category=About | title = About Us | publisher = Natural Products Foundation  | quote = Natural products are represented by a wide array of consumer goods that continue to grow in popularity each year. These products include natural and organic foods, dietary supplements, pet foods, health and beauty products, "green" cleaning supplies and more. Generally, natural products are considered those formulated without artificial ingredients and that are minimally processed. | access-date = 7 December 2013 }}</ref>

Within the field of organic chemistry, the definition of natural products is usually restricted to [[organic compound]]s isolated from natural sources that are produced by the  pathways of  [[secondary metabolite|secondary metabolism]].<ref name = "Hanson_2003">{{cite book | vauthors = Hanson JR | title = Natural Products: the Secondary Metabolite | date = 2003 | publisher = Royal Society of Chemistry | location = Cambridge | isbn = 0-85404-490-6 | quote = Natural products are organic compounds that are formed by living systems. }}</ref>  Within the field of [[medicinal chemistry]], the definition is often further restricted to secondary metabolites.<ref>{{cite web | url = http://www.medilexicon.com/medicaldictionary.php?t=72549 | work = [[Stedman's Medical Dictionary]] | publisher = Lippincott Williams & Wilkins | title = Natural Products | quote = Natural products: naturally occurring compounds that are end products of secondary metabolism; often, they are unique compounds for particular organisms or classes of organisms. | access-date = 7 December 2013 | archive-url = https://web.archive.org/web/20160803091030/http://www.medilexicon.com/medicaldictionary.php?t=72549 | archive-date = 3 August 2016  }}</ref><ref>{{cite book  | vauthors = Williams DA, Lemke TL | title = Foye's Principles of Medicinal Chemistry| date = 2002 | edition = 5th | publisher = Lippincott Williams Wilkins | location = Philadelphia | isbn = 0-683-30737-1 | page = 25 | chapter = Chapter 1: Natural Products | chapter-url = https://books.google.com/books?id=KGLF4ZudTyAC&q=Table+1.1&pg=PA25 | quote = Natural product: A single chemical compound that occurs naturally.  This term is typically used to refer to an organic compound of limited distribution in nature (often called secondary metabolites). }}</ref> Secondary metabolites (or specialized metabolites) are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage.<ref name="pmid1612430">{{cite journal | vauthors = Maplestone RA, Stone MJ, Williams DH | title = The evolutionary role of secondary metabolites—a review | journal = Gene | volume = 115 | issue = 1–2 | pages = 151–7 | date = June 1992 | pmid = 1612430 | doi = 10.1016/0378-1119(92)90553-2 }}</ref> Many secondary metabolites are [[cytotoxic]] and have been selected and optimized through evolution for use as "chemical warfare" agents against prey, predators, and competing organisms.<ref name="pmid18762775">{{cite journal | vauthors = Hunter P | title = Harnessing Nature's wisdom. Turning to Nature for inspiration and avoiding her follies | journal = EMBO Reports | volume = 9 | issue = 9 | pages = 838–40 | date = September 2008 | pmid = 18762775 | pmc = 2529361 | doi = 10.1038/embor.2008.160 }}</ref> Secondary or specialized metabolites are often unique to species, which is contrasted to primary metabolites which have broad use across kingdoms. Secondary metabolites are marked by chemical complexity which is why they are of such interest to chemists.

Natural sources may lead to [[basic research]] on potential bioactive components for commercial development as [[lead compound]]s in [[drug discovery]].<ref name="Li_2009">{{cite journal | vauthors = Li JW, Vederas JC | title = Drug discovery and natural products: end of an era or an endless frontier? | journal = Science | volume = 325 | issue = 5937 | pages = 161–5 | date = July 2009 | pmid = 19589993 | doi = 10.1126/science.1168243 | bibcode = 2009Sci...325..161L | s2cid = 207777087 }}</ref> Although natural products have inspired numerous  drugs, [[drug development]] from natural sources has received declining attention in the 21st century by pharmaceutical companies, partly due to unreliable access and supply, intellectual property, cost, and [[profit (economics)|profit]] concerns, seasonal or environmental variability of composition, and loss of sources due to rising [[extinction]] rates.<ref name=Li_2009/>

== Classes ==
The broadest definition of natural product is anything that is produced by life,<ref name = "Samuelson_1999"/><ref name = "Bhat_2005">{{cite book  | vauthors = Bhat SV, Nagasampagi BA, Sivakumar M | title = Chemistry of Natural Products | date = 2005 | publisher = Springer  | location = Berlin; New York | isbn = 81-7319-481-5 }}</ref> and includes the likes of [[biotic material]]s (e.g. wood, silk), [[bio-based material]]s (e.g. [[bioplastic]]s, cornstarch), [[bodily fluid]]s (e.g. milk, plant exudates), and [[Natural material|other natural material]]s (e.g. soil, coal).

Natural products may be classified according to their biological function, biosynthetic pathway, or source. Depending on the sources, the number of known natural product molecules ranges between 300,000<ref>{{cite journal | vauthors = Rutz A, Sorokina M, Galgonek J, Mietchen D, Willighagen E, Gaudry A, Graham JG, Stephan R, Page R, Vondrášek J, Steinbeck C, Pauli GF, Wolfender JL, Bisson J, Allard PM | display-authors = 6 | title = The LOTUS initiative for open knowledge management in natural products research | journal = eLife | volume = 11 | pages = e70780 | date = May 2022 | pmid = 35616633 | pmc = 9135406 | doi = 10.7554/eLife.70780 | doi-access = free }}</ref><ref name="pmid25300487">{{cite journal | vauthors = Banerjee P, Erehman J, Gohlke BO, Wilhelm T, Preissner R, Dunkel M | title = Super Natural II--a database of natural products | journal = Nucleic Acids Research | volume = 43 | issue = Database issue | pages = D935–D939 | date = January 2015 | pmid = 25300487 | pmc = 4384003 | doi = 10.1093/nar/gku886 }}</ref> and 400,000.<ref>{{cite journal | vauthors = Sorokina M, Steinbeck C | title = Review on natural products databases: where to find data in 2020 | journal = Journal of Cheminformatics | volume = 12 | issue = 1 | page = 20 | date = April 2020 | pmid = 33431011 | pmc = 7118820 | doi = 10.1186/s13321-020-00424-9 | doi-access = free }}</ref>

== Function ==

Following [[Albrecht Kossel]]'s original proposal in 1891,<ref name = "Kossel_1891">{{cite journal | vauthors = Kossel A | author-link1 = Albrecht Kossel | title = Ueber die chemische Zusammensetzung der Zelle | trans-title = The chemical composition of the cell | language = de | journal = Archiv für Physiologie | pages = 181–186 | year = 1891 | url = https://archive.org/stream/archivfrphysio1891berl#page/n7/mode/2up}}</ref> natural products are often divided into two major classes, the primary and secondary metabolites.<ref name = "Kliebenstein_2004">{{cite journal| vauthors = Kliebenstein DJ|title=Secondary metabolites and plant/environment interactions: a view through ''Arabidopsis thaliana'' tinged glasses | journal = Plant, Cell and Environment | year = 2004 | volume = 27 | issue = 6 | pages = 675–684 | doi = 10.1111/j.1365-3040.2004.01180.x | quote = In 1891, following Stahls work on plant biochemistry, Kossel suggested a distinction between basic and secondary metabolism (Stahl 1888). | doi-access = free }}</ref><ref name = "Karlovsky_2008">{{cite book |doi=10.1007/978-3-540-74543-3_1 |chapter=Secondary Metabolites in Soil Ecology |series=Soil Biology |year=2008 | vauthors = Karlovsky P |title=Soil Biology |volume=14 |pages=1–19 |isbn=978-3-540-74542-6 |quote = The current, generally accepted concept in line with Kossel's view is that primary metabolites are chemical components of living organisms that are vital for their normal functioning, while secondary metabolites are compounds which are dispensable.}}</ref> Primary metabolites have an intrinsic function that is essential to the survival of the organism that produces them.  Secondary metabolites in contrast have an extrinsic function that mainly affects other organisms.  Secondary metabolites are not essential to survival but do increase the competitiveness of the organism within its environment.  Because of their ability to modulate biochemical and [[signal transduction]] pathways, some secondary metabolites have useful medicinal properties.<ref>{{Cite journal | vauthors = Wink M |date=2015-09-08 |title=Modes of Action of Herbal Medicines and Plant Secondary Metabolites |journal=Medicines |volume=2 |issue=3 |pages=251–286 |doi=10.3390/medicines2030251 |issn=2305-6320 |pmc=5456217 |pmid=28930211|doi-access=free }}</ref>

Natural products especially within the field of [[organic chemistry]] are often defined as primary and secondary metabolites.  A more restrictive definition limiting natural products to secondary metabolites is commonly used within the fields of [[medicinal chemistry]] and [[pharmacognosy]].<ref name = "Bhat_2005"/>

=== Primary metabolites ===
[[File:Building blocks of life.png|thumb|upright=1.9|Molecular building blocks of life]]

Primary metabolites as defined by Kossel are components of basic metabolic pathways that are required for life.  They are associated with essential cellular functions such as nutrient assimilation, energy production, and growth/development.  They have a wide species distribution that span many [[phylum|phyla]] and frequently more than one [[kingdom (biology)|kingdom]].  Primary metabolites include the basic building blocks of life: [[carbohydrate]]s, [[lipid]]s, [[amino acid]]s, and [[nucleic acid]]s.<ref name = "Rogers_2011">{{cite book | vauthors = Rogers K | title = The Components of Life: From Nucleic Acids to Carbohydrates | year = 2011 | publisher = Britannica Educational Publishing in association with Rosen Educational Services | location = New York, NY | isbn = 978-1-61530-324-3 | edition = 1st }}</ref>

Primary metabolites that are involved with energy production include [[respiratory]] and [[photosynthetic]] [[enzyme]]s. Enzymes in turn are composed of [[amino acid]]s and often non-peptidic [[cofactor (biochemistry)|cofactors]] that are essential for enzyme function.<ref name = "Lehninger_2013">{{cite book | vauthors = Cox DL, Nelson MM | title = Lehninger Principles of Biochemistry | year = 2013 | publisher = W.H. Freeman | location = New York, N.Y. | isbn = 978-1-4641-0962-1 | edition = 6th }}</ref> The basic structure of cells and of organisms are also composed of primary metabolites.  These include cell membranes (e.g. [[phospholipid]]s), cell walls (e.g. [[peptidoglycan]], [[chitin]]), and [[cytoskeleton]]s (proteins).<ref>{{cite book | vauthors = Boal D | title = Mechanics of the Cell | year = 2006 | publisher = Cambridge University Press | location = Cambridge, UK | isbn = 978-0-521-79681-1 | edition = 4th printing }}</ref>

Primary metabolite enzymatic cofactors include members of the [[vitamin B]] family. [[Vitamin B1]] as thiamine diphosphate is a coenzyme for [[pyruvate dehydrogenase]], [[2-oxoglutarate dehydrogenase]], and [[transketolase]] which are all involved in carbohydrate metabolism.  [[Vitamin B2]] (riboflavin) is a constituent of [[flavin mononucleotide|FMN]] and [[flavin adenine dinucleotide|FAD]] which are necessary for many redox reactions.  [[Vitamin B3]] (nicotinic acid or niacin), synthesized from tryptophan is a component of the coenzymes [[NAD+|NAD{{+}}]] and [[NADP+|NADP{{+}}]] which in turn are required for electron transport in the [[Krebs cycle]], [[oxidative phosphorylation]], as well as many other redox reactions. [[Vitamin B5]] (pantothenic acid) is a constituent of [[coenzyme A]], a basic component of carbohydrate and amino acid metabolism as well as the biosynthesis of fatty acids and polyketides. [[Vitamin B6]] ([[pyridoxol]], [[pyridoxal]], and [[pyridoxamine]]) as pyridoxal 5′-phosphate is a cofactor for many enzymes especially transaminases involve in amino acid metabolism. [[Vitamin B12]] (cobalamins) contain a [[corrin]] ring similar in structure to [[porphyrin]] and is an essential coenzyme for the catabolism of fatty acids as well for the biosynthesis of [[methionine]].<ref name = "Dewick_2009"/>{{rp|Ch. 2}}

[[DNA]] and [[RNA]], which store and transmit [[genetic information]], are composed of nucleic acid primary metabolites.<ref name = "Lehninger_2013"/>

[[Second messenger system|First messengers]] are signaling molecules that control [[metabolism]] or [[cellular differentiation]]. These signaling molecules include hormones and growth factors in turn are composed of peptides, [[biogenic amine]]s, [[steroid hormone]]s, [[auxin]]s, [[gibberellin]]s etc.  These first messengers interact with cellular receptors which are composed of proteins. Cellular receptors in turn activate [[second messenger system|second messengers]] are used to relay the extracellular message to intracellular targets.  These signaling molecules include the primary metabolites [[cyclic nucleotide]]s, [[diacyl glycerol]] etc.<ref name = "Sitaramayya_1999">{{cite book | vauthors = Sitaramayya A | title = Introduction to Cellular Signal Transduction | year = 1999 | publisher = Birkhäuser | location = Boston | isbn = 978-0-8176-3982-2 }}</ref>

=== Secondary metabolites ===
{{main|Secondary metabolite}}
[[File:Secondary metabolite class examples.svg|upright=2.1|thumb|Representative examples of each of the major classes of secondary metabolites]]

Secondary in contrast to primary metabolites are dispensable and not absolutely required for survival. Furthermore, secondary metabolites typically have a narrow species distribution.<ref>{{cite book | vauthors = Herbert RB |title=The Biosynthesis of Secondary Metabolites |date=1981 |publisher=Springer Netherlands |location=Dordrecht |isbn=94-009-5833-1 |pages=1–2 | chapter = Introduction | chapter-url = https://books.google.com/books?id=hRHtCAAAQBAJ&pg=PA1 | quote = Secondary metabolites are distinguished more precisely by the following criteria: they have a restricted distribution being found mostly in plants and microorganisms, and are often characteristic of individual genera, species, or strains; they are formed along specialized pathwasys from primary metabolites.  Primary metabolites, by contrast, have a broad distribution in all living things and are intimately involved in essential life processes. }}</ref>

Secondary metabolites have a broad range of functions.  These include [[pheromone]]s that act as social signaling molecules with other individuals of the same species, communication molecules that attract and activate [[symbiotic]] organisms, agents that solubilize and transport nutrients ([[siderophores]] etc.), and competitive weapons ([[allelochemicals|repellants]], [[venoms]], [[toxins]] etc.) that are used against competitors, prey, and predators.<ref name="pmid11036689">{{cite book | vauthors = Demain AL, Fang A | chapter = The natural functions of secondary metabolites | volume = 69 | pages = 1–39 | year = 2000 | pmid = 11036689 | doi = 10.1007/3-540-44964-7_1 | series = Advances in Biochemical Engineering/Biotechnology | isbn = 978-3-540-67793-2 | title = History of Modern Biotechnology I }}</ref> For many other secondary metabolites, the function is unknown. One hypothesis is that they confer a competitive advantage to the organism that produces them.<ref name="pmid2693613">{{cite journal | vauthors = Williams DH, Stone MJ, Hauck PR, Rahman SK | title = Why are secondary metabolites (natural products) biosynthesized? | journal = Journal of Natural Products | volume = 52 | issue = 6 | pages = 1189–208 | year = 1989 | pmid = 2693613 | doi = 10.1021/np50066a001 }}</ref> An alternative view is that, in analogy to the [[immune system]], these secondary metabolites have no specific function, but having the machinery in place to produce these diverse chemical structures is important and a few secondary metabolites are therefore produced and selected for.<ref name="Firn_2000">{{cite journal | vauthors = Firn RD, Jones CG | title = The evolution of secondary metabolism – a unifying model | journal = Molecular Microbiology | volume = 37 | issue = 5 | pages = 989–94 | date = September 2000 | pmid = 10972818 | doi = 10.1046/j.1365-2958.2000.02098.x | s2cid = 3827335 | url = http://www.caryinstitute.org/sites/default/files/public/reprints/Firn-Jones_2000.pdf | doi-access = free }}</ref>

General structural classes of secondary metabolites include [[alkaloid]]s, [[phenylpropanoid]]s, [[polyketide]]s, and [[terpenoid]]s.<ref name = "Hanson_2003"/>

== Biosynthesis ==
[[File:Building blocks of life 2.svg|thumb|upright=2.3|Biosynthesis of primary and secondary metabolites.<ref name = "Dewick_2009"/><!-- Structure of isoleucine is now correct. -->{{rp|Ch. 2}}]]

The biosynthetic pathways leading to the major classes of natural products are described below.<ref name = "Bhat_2005"/><ref name = "Dewick_2009">{{cite book | vauthors = Dewick PM | title = Medicinal Natural Products: A Biosynthetic Approach | year = 2009 | publisher = Wiley | location = Chichester | isbn = 978-0-470-74167-2 | edition = 3rd}}</ref>{{rp|Ch. 2}}
<!-- each bullet point below should be expanded into its own subsection -->
* [[Photosynthesis]] or [[gluconeogenesis]] → [[monosaccharide]]s → [[polysaccharide]]s ([[cellulose]], [[chitin]], [[glycogen]] etc.)
* Acetate pathway → [[fatty acid]]s and [[polyketide]]s
* [[Shikimate pathway]] → aromatic amino acids and [[phenylpropanoid]]s
* [[Mevalonate pathway]] and [[non-mevalonate pathway|methyletrythritol phosphate pathway]] → [[terpenoid]]s and [[steroid]]s
* Amino acids → [[alkaloid]]s

=== Carbohydrates ===
Carbohydrates are an essential energy source for most life forms. In addition, [[polysaccharide]]s formed from simpler carbohydrates are important structural components of many organisms such the [[cell wall]]s of bacteria and plants.{{Citation needed|date=February 2021}}

Carbohydrate are the products of plant [[photosynthesis]] and animal [[gluconeogenesis]]. Photosynthesis produces initially {{nowrap|[[3-phosphoglyceraldehyde]]}}, a three-carbon atom containing sugar (a [[triose]]).<ref name = "Dewick_2009"/>{{rp|Ch. 8}} This triose in turn may be converted into [[glucose]] (a six carbon atom containing sugar) or a variety of [[pentose]]s (five carbon atom containing sugars) through the [[Calvin cycle]]. In animals, the three carbon precursors [[lactic acid|lactate]] or [[glycerol]] can be converted into [[pyruvate]] which in turn can be converted into carbohydrates in the liver.{{Citation needed|date=February 2021}}

=== Fatty acids and polyketides ===
Through the process of [[glycolysis]] sugars are broken down into [[acetyl-CoA]]. In an ATP-dependent enzymatically catalyzed reaction, acetyl-CoA is carboxylated to form [[malonyl-CoA]]. Acetyl-CoA and malonyl-CoA undergo a [[Claisen condensation]] with lose of carbon dioxide to form [[acetoacetyl-CoA]]. Additional condensation reactions produce successively higher molecular weight poly-β-keto chains which are then converted into other polyketides.<ref name = "Dewick_2009"/>{{rp|Ch. 3}}  The polyketide class of natural products have diverse structures and functions and include [[prostaglandin]]s and [[macrolide antibiotic]]s.{{Citation needed|date=February 2021}}

One molecule of acetyl-CoA (the "starter unit") and several molecules malonyl-CoA (the "extender units") are condensed by [[fatty acid synthase]] to produce [[fatty acid]]s.<ref name = "Dewick_2009"/>{{rp|Ch. 3}} Fatty acid are essential components of lipid bilayers that form cell membranes as well as fat energy stores in animals.{{Citation needed|date=February 2021}}

== Sources ==
Natural products may be extracted from the [[Cell (biology)|cell]]s, [[Tissue (biology)|tissue]]s, and [[secretion]]s of [[microorganism]]s, plants and animals.<ref name="GB2003">{{cite journal | vauthors = Strobel G, Daisy B | title = Bioprospecting for microbial endophytes and their natural products | journal = Microbiology and Molecular Biology Reviews | volume = 67 | issue = 4 | pages = 491–502 | date = December 2003 | pmid = 14665674 | pmc = 309047 | doi = 10.1128/MMBR.67.4.491-502.2003 }}</ref><ref name="pmid32529587"/> A crude ([[Fractionation|unfractionated]]) extract from any one of these sources will contain a range of structurally diverse and often novel chemical compounds.  Chemical diversity in nature is based on biological diversity, so researchers collect samples from around the world to analyze and evaluate in [[high-throughput screening|drug discovery screens]] or [[bioassays]].  This effort to search for biologically active natural products is known as [[bioprospecting]].<ref name="GB2003"/><ref name="pmid32529587"/>

Pharmacognosy provides the tools to detect, isolate and identify bioactive natural products that could be developed for medicinal use.  When an [[Active ingredient#Herbal medicine|"active principle"]] is isolated from a traditional medicine or other biological material, this is known as a "hit".  Subsequent scientific and legal work is then performed to validate the hit (e.g. elucidation of [[mechanism of action]], confirmation that there is no intellectual property conflict).  This is followed by the [[hit to lead]] stage of drug discovery, where derivatives of the active compound are produced in an attempt to improve its [[Potency (pharmacology)|potency]] and [[Toxicity|safety]].<ref name="pmid22553861">{{cite book | vauthors = Markossian S, Grossman A, Brimacombe K, Arkin M, Auld D, Austin CP, Baell J, Chung TD, Coussens NP, Dahlin JL, Devanarayan V, Foley TL, Glicksman M, Hall MD, Haas JV, Hoare SR, Inglese J, Iversen PW, Kales SC, Lal-Nag M, Li Z, McGee J, McManus O, Riss T, Saradjian P, Sittampalam GS, Tarselli M, Trask Jr OJ, Wang Y, Weidner JR, Wildey MJ, Wilson K, Xia M, Xu X | display-authors = 6 |date=June 2020 |title= Assay Guidance Manual | url= https://www.ncbi.nlm.nih.gov/books/NBK53196/ |location=Bethesda |publisher= Eli Lilly & Company and the National Center for Advancing Translational Sciences |pmid=22553861  }}</ref><ref name="pmid26435527">{{cite journal | vauthors = Katsuno K, Burrows JN, Duncan K, Hooft van Huijsduijnen R, Kaneko T, Kita K, Mowbray CE, Schmatz D, Warner P, Slingsby BT | display-authors = 6 | title = Hit and lead criteria in drug discovery for infectious diseases of the developing world | journal = Nature Reviews. Drug Discovery | volume = 14 | issue = 11 | pages = 751–758 | date = November 2015 | pmid = 26435527 | doi = 10.1038/nrd4683 | s2cid = 25863919 }}</ref> In this and related ways, modern medicines can be developed directly from natural sources.{{Citation needed|date=February 2021}}

Although traditional medicines and other biological material are considered an excellent source of novel compounds, the extraction and isolation of these compounds can be a slow, expensive and inefficient process.  For large scale manufacture therefore, attempts may be made to produce the new compound by total synthesis or semisynthesis.<ref name="pmid24142193">{{cite journal | vauthors = Bauer A, Brönstrup M | title = Industrial natural product chemistry for drug discovery and development | journal = Natural Product Reports | volume = 31 | issue = 1 | pages = 35–60 | date = January 2014 | pmid = 24142193 | doi = 10.1039/c3np70058e }}</ref> Because natural products are generally [[secondary metabolite]]s with complex [[chemical structure]]s, their total/semisynthesis is not always commercially viable.  In these cases, efforts can be made to design simpler [[Analog (chemistry)|analogue]]s with comparable potency and safety that are amenable to total/semisynthesis.<ref name="pmid25829247">{{cite journal | vauthors = Maier ME | title = Design and synthesis of analogues of natural products | journal = Organic & Biomolecular Chemistry | volume = 13 | issue = 19 | pages = 5302–43 | date = May 2015 | pmid = 25829247 | doi = 10.1039/c5ob00169b | doi-access = free }}</ref>

=== Prokaryotic ===

==== Bacteria ====
[[Image:Clostridium botulinum 01.png|thumb|upright=1.25|[[Botulinum toxin]] types A and B (Botox, Dysport, Xeomin, MyoBloc), used both medicinally and cosmetically, are natural products from the bacterium ''[[Clostridium botulinum]]''.<ref name="MAD2013"/>]]

The serendipitous discovery and subsequent clinical success of [[penicillin]] prompted a large-scale search for other environmental [[microorganisms]] that might produce anti-infective natural products.  Soil and water samples were collected from all over the world, leading to the discovery of [[streptomycin]] (derived from ''[[Streptomyces griseus]]''), and the realization that bacteria, not just fungi, represent an important source of pharmacologically active natural products.<ref name="LJL2012">{{cite journal | vauthors = Zaffiri L, Gardner J, Toledo-Pereyra LH | s2cid = 30538825 | title = History of antibiotics. From salvarsan to cephalosporins | journal = Journal of Investigative Surgery | volume = 25 | issue = 2 | pages = 67–77 | date = April 2012 | pmid = 22439833 | doi = 10.3109/08941939.2012.664099 }}</ref> This, in turn, led to the development of an impressive arsenal of antibacterial and antifungal agents including [[amphotericin B]], [[chloramphenicol]], [[daptomycin]] and [[tetracycline]] (from ''[[Streptomyces]]'' [[species|spp.]]),<ref name="RIM2012">{{cite journal | vauthors = Procópio RE, Silva IR, Martins MK, Azevedo JL, Araújo JM | title = Antibiotics produced by Streptomyces | journal = The Brazilian Journal of Infectious Diseases | volume = 16 | issue = 5 | pages = 466–71 | year = 2012 | pmid = 22975171 | doi = 10.1016/j.bjid.2012.08.014 | doi-access = free }}</ref> the [[polymyxin]]s (from ''[[Paenibacillus polymyxa]]''),<ref name="SJ2015">{{cite journal | vauthors = Cochrane SA, Vederas JC | title = Lipopeptides from Bacillus and Paenibacillus spp.: A Gold Mine of Antibiotic Candidates | journal = Medicinal Research Reviews | volume = 36 | issue = 1 | pages = 4–31 | date = January 2016 | pmid = 24866700 | doi = 10.1002/med.21321 | s2cid = 46109250 }}</ref> and the [[rifamycins]] (from ''[[Amycolatopsis rifamycinica]]'').<ref name="ARU2014">{{cite journal | vauthors = Saxena A, Kumari R, Mukherjee U, Singh P, Lal R | title = Draft Genome Sequence of the Rifamycin Producer Amycolatopsis rifamycinica DSM 46095 | journal = Genome Announcements | volume = 2 | issue = 4 | pages = e00662–14 | date = July 2014 | pmid = 24994803 | pmc = 4082003 | doi = 10.1128/genomeA.00662-14 }}</ref> Antiparasitic and antiviral drugs have similarly been derived from bacterial metabolites.<ref>{{cite journal |last1=Saraiva |first1=Raúl G. |last2=Dimopoulos |first2=George |title=Bacterial natural products in the fight against mosquito-transmitted tropical diseases |journal=Natural Product Reports |date=2020 |volume=37 |issue=3 |pages=338–354 |doi=10.1039/C9NP00042A|pmid=31544193 |s2cid=202731385 }}</ref>

Although most of the drugs derived from bacteria are employed as anti-infectives, some have found use in other fields of medicine.  [[Botulinum toxin]] (from ''[[Clostridium botulinum]]'') and [[bleomycin]] (from ''[[Streptomyces verticillus]]'') are two examples.  Botulinum, the [[neurotoxin]] responsible for [[botulism]], can be injected into specific muscles (such as those controlling the eyelid) to prevent [[muscle spasm]].<ref name="MAD2013">{{cite journal | vauthors = Hallett M, Albanese A, Dressler D, Segal KR, Simpson DM, Truong D, Jankovic J | title = Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders | journal = Toxicon | volume = 67 | issue = June | pages = 94–114 | date = June 2013 | pmid = 23380701 | doi = 10.1016/j.toxicon.2012.12.004 }}</ref> Also, the [[glycopeptide]] bleomycin is used for the treatment of several cancers including [[Hodgkin's lymphoma]], [[head and neck cancer]], and [[testicular cancer]].<ref>{{cite web |url=https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682125.html|title=Bleomycin|publisher=US National Library of Medicine|access-date=28 January 2015}}</ref> Newer trends in the field include the metabolic profiling and isolation of natural products from novel bacterial species present in underexplored environments.  Examples include [[symbionts]] or [[endophytes]] from tropical environments,<ref name="AKB2014">{{cite journal | vauthors = Alvin A, Miller KI, Neilan BA | title = Exploring the potential of endophytes from medicinal plants as sources of antimycobacterial compounds | journal = Microbiological Research | volume = 169 | issue = 7–8 | pages = 483–95 | year = 2014 | pmid = 24582778 | doi = 10.1016/j.micres.2013.12.009 | pmc = 7126926 | doi-access = free }}</ref> subterranean bacteria found deep underground via mining/drilling,<ref name="XSK2014">{{cite journal | vauthors = Wang X, Elshahawi SI, Shaaban KA, Fang L, Ponomareva LV, Zhang Y, Copley GC, Hower JC, Zhan CG, Kharel MK, Thorson JS | display-authors = 6 | title = Ruthmycin, a new tetracyclic polyketide from Streptomyces sp. RM-4-15 | journal = Organic Letters | volume = 16 | issue = 2 | pages = 456–9 | date = January 2014 | pmid = 24341358 | pmc = 3964319 | doi = 10.1021/ol4033418 }}</ref><ref name="XKS2014">{{cite journal | vauthors = Wang X, Shaaban KA, Elshahawi SI, Ponomareva LV, Sunkara M, Copley GC, Hower JC, Morris AJ, Kharel MK, Thorson JS | display-authors = 6 | title = Mullinamides A and B, new cyclopeptides produced by the Ruth Mullins coal mine fire isolate Streptomyces sp. RM-27-46 | journal = The Journal of Antibiotics | volume = 67 | issue = 8 | pages = 571–5 | date = August 2014 | pmid = 24713874 | pmc = 4146655 | doi = 10.1038/ja.2014.37 }}</ref> and [[Marine (ocean)|marine]] bacteria.<ref name="DJD2012">{{cite journal | vauthors = Akey DL, Gehret JJ, Khare D, Smith JL | title = Insights from the sea: structural biology of marine polyketide synthases | journal = Natural Product Reports | volume = 29 | issue = 10 | pages = 1038–49 | date = October 2012 | pmid = 22498975 | pmc = 3709256 | doi = 10.1039/c2np20016c }}</ref>

==== Archaea ====

Because many [[Archaea]] have adapted to life in extreme environments such as [[polar region]]s, [[hot springs]], acidic springs, alkaline springs, [[salt lakes]], and the [[high pressure]] of [[deep ocean water]], they possess enzymes that are functional under quite unusual conditions.  These enzymes are of potential use in the [[food industry|food]], [[chemical industry|chemical]], and [[pharmaceutical industry|pharmaceutical]] industries, where biotechnological processes frequently involve high temperatures, extremes of pH, high salt concentrations, and / or high pressure.  Examples of enzymes identified to date include [[amylase]]s, [[pullulanase]]s, [[cyclodextrin glycosyltransferase]]s, [[cellulase]]s, [[xylanase]]s, [[chitinase]]s, [[protease]]s, [[alcohol dehydrogenase]], and [[esterase]]s.<ref name="CG2011">{{cite book  | vauthors = Bertoldo C, Antranikian G | title = Biotechnology Vol. IX| date = 2011 | publisher = Encyclopedia of Life Support Systems (EOLSS) | location = Paris | chapter = Chapter 1: Biotechnology of Archaea| chapter-url = http://www.eolss.net/sample-chapters/c17/E6-58-08-08.pdf }}</ref>  Archaea represent a source of novel [[chemical compounds]] also, for example isoprenyl glycerol ethers 1 and 2 from ''[[Thermococcus]]'' S557 and ''[[Methanocaldococcus jannaschii]]'', respectively.<ref name="CTK2010">{{cite journal | vauthors = Thornburg CC, Zabriskie TM, McPhail KL | title = Deep-sea hydrothermal vents: potential hot spots for natural products discovery? | journal = Journal of Natural Products | volume = 73 | issue = 3 | pages = 489–99 | date = March 2010 | pmid = 20099811 | doi = 10.1021/np900662k }}</ref>

=== Eukaryotic ===
==== Fungi ====
[[Image: Penicillium rubens (type specimen).png|thumb|The antibiotic [[penicillin]] is a natural product derived from the fungus ''[[Penicillium rubens]]''.<ref name="pmid32973216">{{cite journal |vauthors=Pathak A, Nowell RW, Wilson CG, Ryan MJ, Barraclough TG|date=September 2020 |title=Comparative genomics of Alexander Fleming's original ''Penicillium'' isolate (IMI 15378) reveals sequence divergence of penicillin synthesis genes|journal=Scientific Reports|volume=10 |issue=1 |pages=Article 15705 |doi=10.1038/s41598-020-72584-5|pmid=32973216|pmc=7515868|bibcode=2020NatSR..1015705P }}</ref>]]

Several anti-infective medications have been derived from fungi including penicillin and the [[cephalosporins]] (antibacterial drugs from ''[[Penicillium rubens]]'' and ''[[Cephalosporium acremonium]]'', respectively)<ref name="pmid32973216"/><ref name="LJL2012" /> and [[griseofulvin]] (an antifungal drug from ''[[Penicillium griseofulvum]]'').<ref name="AR20154">{{cite journal | vauthors = Beekman AM, Barrow RA | title = Fungal metabolites as pharmaceuticals | journal = Aust J Chem | volume = 67 | issue =6| pages = 827–843| year = 2014| doi=10.1071/ch13639}}</ref> Other medicinally useful fungal [[metabolite]]s include [[lovastatin]] (from ''[[Pleurotus ostreatus]]''), which became a lead for a series of drugs that lower [[cholesterol]] levels, [[cyclosporin]] (from ''[[Tolypocladium inflatum]]''), which is used to suppress the [[immune response]] after [[organ transplant]] operations, and [[ergometrine]] (from ''[[Claviceps]]'' spp.), which acts as a [[vasoconstrictor]], and is used to prevent bleeding after childbirth.<ref name = "Dewick_2009"/>{{rp|Ch. 6}} [[Asperlicin]] (from ''[[Aspergillus alliaceus]]'') is another example.  Asperlicin is a novel antagonist of [[cholecystokinin]], a [[neurotransmitter]] thought to be involved in [[panic attacks]], and could potentially be used to treat [[anxiety]].{{Citation needed|date=February 2021}}

==== Plants ====
[[Image:Papaver somniferum 01.jpg|thumb|The opioid [[analgesic]] drug [[morphine]] is a natural product derived from the plant ''[[Papaver somniferum]]'']]

Plants are a major source of complex and highly structurally diverse chemical compounds ([[phytochemical]]s), this structural diversity attributed in part to the [[natural selection]] of organisms producing [[wikt:potent|potent]] compounds to deter [[herbivory]] ([[Plant defense against herbivory#Types|feeding deterrents]]).<ref name="LE2015">{{cite journal | vauthors = Dang L, Van Damme EJ | title = Toxic proteins in plants | journal = Phytochemistry | volume = 117 | pages = 51–64 | date = September 2015 | pmid = 26057229 | pmc = 7111729 | doi = 10.1016/j.phytochem.2015.05.020 | bibcode = 2015PChem.117...51D }}</ref> Major classes of phytochemical include [[natural phenol|phenol]]s, [[polyphenol]]s, [[tannin]]s, [[terpene]]s, and alkaloids.<ref name = "AMH2006">{{cite book | vauthors = Crozier A, Clifford MN, Ashihara H | title = Plant Secondary Metabolites: Occurrence, Structure and Role in the Human Diet | year = 2006 | publisher = Blackwell Publishing Ltd | location = Oxford, UK | isbn = 978-1-4051-2509-3| pages = 1–24, 47–136 | chapter = Chapters 1, 3 and 4}}</ref> Though the number of plants that have been extensively studied is relatively small, many pharmacologically active natural products have already been identified.  Clinically useful examples include the [[anticancer]] agents [[paclitaxel]] and [[omacetaxine mepesuccinate]] (from ''[[Taxus brevifolia]]'' and ''[[Cephalotaxus harringtonii]]'', respectively),<ref name="PCS2014">{{cite journal | vauthors = Kittakoop P, Mahidol C, Ruchirawat S | title = Alkaloids as important scaffolds in therapeutic drugs for the treatments of cancer, tuberculosis, and smoking cessation | journal = Current Topics in Medicinal Chemistry | volume = 14 | issue = 2 | pages = 239–52 | year = 2014 | pmid = 24359196 | doi = 10.2174/1568026613666131216105049 | url = https://www.researchgate.net/publication/259446333 }}</ref> the [[antimalarial]] agent [[artemisinin]] (from ''[[Artemisia annua]]''),<ref name="S2014">{{cite journal | vauthors = Kano S | title = Artemisinin-based combination therapies and their introduction in Japan | journal = Kansenshogaku Zasshi. The Journal of the Japanese Association for Infectious Diseases | volume = 88 | issue = 3 Suppl 9–10 | pages = 18–25 | date = May 2014 | pmid = 24979951 }}</ref> and the [[acetylcholinesterase inhibitor]] [[galantamine]] (from ''[[Galanthus]]'' spp.), used to treat [[Alzheimer's disease]].<ref name="PAA2013">{{cite journal | vauthors = Russo P, Frustaci A, Del Bufalo A, Fini M, Cesario A | title = Multitarget drugs of plants origin acting on Alzheimer's disease | journal = Current Medicinal Chemistry | volume = 20 | issue = 13 | pages = 1686–93 | year = 2013 | pmid = 23410167 | doi = 10.2174/0929867311320130008 }}</ref> Other plant-derived drugs, used medicinally and/or [[Recreational drug use|recreationally]] include [[morphine]], [[cocaine]], [[quinine]], [[tubocurarine]], [[muscarine]], and [[nicotine]].<ref name = "Dewick_2009"/>{{rp|Ch. 6}}

==== Animals ====
[[Image:Conus magus 001.jpg|thumb|upright=1.1|The analgesic drug {{nowrap|ω-conotoxin}} ([[ziconotide]]) is a natural product derived from the sea snail ''[[Conus magus]]''.<ref name="P2006"/>]]

Animals also represent a source of bioactive natural products.  In particular, [[venom]]ous animals such as snakes, spiders, scorpions, caterpillars, bees, wasps, centipedes, ants, toads, and frogs have attracted much attention.  This is because venom constituents (peptides, enzymes, nucleotides, lipids, biogenic amines etc.) often have very specific interactions with a [[macromolecular]] target in the body (e.g. α-bungarotoxin from [[cobra]]s).<ref name="chemical weaponry">{{cite journal | vauthors = Dossey AT | title = Insects and their chemical weaponry: new potential for drug discovery | journal = Natural Product Reports | volume = 27 | issue = 12 | pages = 1737–57 | date = January 2010 | pmid = 20957283 | doi = 10.1039/C005319H }}</ref><ref name="pmid32535105"/> As with plant feeding deterrents, this biological activity is attributed to natural selection, organisms capable of killing or paralyzing their prey and/or defending themselves against predators being more likely to survive and reproduce.<ref name="pmid32535105">{{cite journal | vauthors = Herzig V, Cristofori-Armstrong B, Israel MR, Nixon SA, Vetter I, King GF| title = Animal toxins – Nature's evolutionary-refined toolkit for basic research and drug discovery| journal = Biochemical Pharmacology | volume = 181| date = June 2020| page = 114096| pmid = 32535105 | pmc = 7290223 | doi = 10.1016/j.bcp.2020.114096}}</ref>

Because of these specific chemical-target interactions, venom constituents have proved important tools for studying [[Receptor (biochemistry)|receptors]], [[ion channel]]s, and enzymes.  In some cases, they have also served as leads in the development of novel drugs.  For example, teprotide, a peptide isolated from the venom of the Brazilian pit viper ''[[Bothrops jararaca]]'', was a lead in the development of the [[antihypertensive]] agents [[cilazapril]] and [[captopril]].<ref name="pmid32535105"/> Also, echistatin, a [[disintegrin]] from the venom of the saw-scaled viper ''[[Echis carinatus]]'' was a lead in the development of the [[antiplatelet drug]] [[tirofiban]].<ref name="pmid31137917">{{cite journal | vauthors = Lazarovici P, Marcinkiewicz C, Lelkes PI| title = From snake venom's disintegrins and C-type lectins to anti-platelet drugs| journal = Toxins | volume = 11 | issue = 5 | pages = Article 303 | date = May 2019| pmid = 31137917 | pmc = 6563238 | doi = 10.3390/toxins11050303| doi-access = free}}</ref>

In addition to the [[terrestrial animal]]s and [[amphibian]]s described above, many [[Marine (ocean)|marine]] animals have been examined for pharmacologically active natural products, with [[coral]]s, [[sea sponge|sponges]], [[tunicate]]s, [[sea snail]]s, and [[bryozoa]]ns yielding chemicals with interesting [[analgesic]], [[Antiviral drug|antiviral]], and [[anticancer]] activities.<ref name="AKC2010">{{cite journal | vauthors = Mayer AM, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, McIntosh JM, Newman DJ, Potts BC, Shuster DE | display-authors = 6 | title = The odyssey of marine pharmaceuticals: a current pipeline perspective | journal = Trends in Pharmacological Sciences | volume = 31 | issue = 6 | pages = 255–65 | date = June 2010 | pmid = 20363514 | doi = 10.1016/j.tips.2010.02.005 }}</ref> Two examples developed for clinical use include ω-[[conotoxin]] (from the marine snail ''[[Conus magus]]'')<ref name="BL1998">{{cite journal | vauthors = Bowersox SS, Luther R | title = Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus | journal = Toxicon | volume = 36 | issue = 11 | pages = 1651–8 | date = November 1998 | pmid = 9792182 | doi = 10.1016/S0041-0101(98)00158-5 }}</ref><ref name="P2006">{{cite journal | vauthors = Prommer E | title = Ziconotide: a new option for refractory pain | journal = Drugs of Today | volume = 42 | issue = 6 | pages = 369–78 | date = June 2006 | pmid = 16845440 | doi = 10.1358/dot.2006.42.6.973534 }}</ref> and [[trabectedin|ecteinascidin 743]] (from the tunicate ''[[Ecteinascidia turbinata]]'').<ref name="R2000">{{cite journal | vauthors = Rinehart KL | title = Antitumor compounds from tunicates | journal = Medicinal Research Reviews | volume = 20 | issue = 1 | pages = 1–27 | date = January 2000 | pmid = 10608919 | doi = 10.1002/(SICI)1098-1128(200001)20:1<1::AID-MED1>3.0.CO;2-A | s2cid = 25117225 }}</ref> The former, ω-conotoxin, is used to relieve severe and chronic pain,<ref name="P2006"/><ref name=" BL1998" /> while the latter, ecteinascidin 743 is used to treat [[metastasis|metastatic]] [[soft tissue sarcoma]].<ref name="BES2015">{{cite journal | vauthors = Petek BJ, Loggers ET, Pollack SM, Jones RL | title = Trabectedin in soft tissue sarcomas | journal = Marine Drugs | volume = 13 | issue = 2 | pages = 974–83 | date = February 2015 | pmid = 25686274 | pmc = 4344612 | doi = 10.3390/md13020974 | doi-access = free }}</ref> Other natural products derived from marine animals and under investigation as possible therapies include the [[antitumour]] agents [[discodermolide]] (from the sponge ''[[Discodermia dissoluta]]''),<ref name="RMP2008">{{cite journal | vauthors = Singh R, Sharma M, Joshi P, Rawat DS | title = Clinical status of anti-cancer agents derived from marine sources | journal = Anti-Cancer Agents in Medicinal Chemistry | volume = 8 | issue = 6 | pages = 603–17 | date = August 2008 | pmid = 18690825 | doi = 10.2174/187152008785133074 }}</ref> [[eleutherobin]] (from the coral ''[[Erythropodium caribaeorum]]''), and the [[bryostatins]] (from the bryozoan ''[[Bugula neritina]]'').<ref name="RMP2008" />

== Medical uses ==

Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases.<ref name=Brahmachari_2010>{{cite book | vauthors = Brahmachari G | title = Handbook of Pharmaceutical Natural Products | year = 2010 | publisher = Wiley-VCH |location = Weinheim | isbn = 978-3-52732148-3 }}</ref><ref name="pmid18554253">{{cite journal | vauthors = Beghyn T, Deprez-Poulain R, Willand N, Folleas B, Deprez B | title = Natural compounds: leads or ideas? Bioinspired molecules for drug discovery | journal = Chemical Biology & Drug Design | volume = 72 | issue = 1 | pages = 3–15 | date = July 2008 | pmid = 18554253 | doi = 10.1111/j.1747-0285.2008.00673.x | s2cid = 20973633 | doi-access = free }}</ref><ref name="pmid15729362">{{cite journal | vauthors = Koehn FE, Carter GT | title = The evolving role of natural products in drug discovery | journal = Nature Reviews. Drug Discovery | volume = 4 | issue = 3 | pages = 206–20 | date = March 2005 | pmid = 15729362 | doi = 10.1038/nrd1657 | s2cid = 32749678 }}</ref> Moreover, synthetic analogs of natural products with improved potency and safety can be prepared and therefore natural products are often used as starting points for [[drug discovery]]. Natural product constituents have inspired numerous drug discovery efforts that eventually gained approval as new drugs<ref name="pmid17309302">{{cite journal | vauthors = Newman DJ, Cragg GM | title = Natural products as sources of new drugs over the last 25 years | journal = Journal of Natural Products | volume = 70 | issue = 3 | pages = 461–77 | date = March 2007 | pmid = 17309302 | doi = 10.1021/np068054v | citeseerx = 10.1.1.336.753 }}</ref><ref name="Gransalke_2011">{{cite journal | title = Mother Nature's Drug Cabinet | vauthors = Gransalke K | date = February 2011 | volume = 11 | issue = 1 | journal = Lab Times | pages = 16–19 | url = http://www.labtimes.org/labtimes/issues/lt2011/lt01/lt_2011_01_16_19.pdf | quote = Drug Discovery – Is Mother Nature still the number one source for promising new drugs? | access-date = 8 December 2013 | archive-url = https://web.archive.org/web/20160304091143/http://www.labtimes.org/labtimes/issues/lt2011/lt01/lt_2011_01_16_19.pdf | archive-date = 4 March 2016  }}</ref>

[[File:Natural product drugs.svg|thumb|upright=1.8|Representative examples of drugs based on natural products]]

=== Modern natural product-derived drugs ===
A large number of currently prescribed drugs have been either directly derived from or inspired by natural products.<ref name="CRC Press"/><ref name="pmid26281720">{{cite journal | vauthors = Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H | title = Discovery and resupply of pharmacologically active plant-derived natural products: A review | journal = Biotechnology Advances | volume = 33 | issue = 8 | pages = 1582–614 | date = December 2015 | pmid = 26281720 | doi = 10.1016/j.biotechadv.2015.08.001 | pmc=4748402}}</ref>

Some of the oldest natural product based drugs are analgesics. The bark of the [[willow]] tree has been known from antiquity to have pain relieving properties. This is due to presence of the natural product [[salicin]] which in turn may be hydrolyzed into [[salicylic acid]].  A synthetic derivative [[acetylsalicylic acid]] better known as ''[[aspirin]]'' is a widely used pain reliever.  Its mechanism of action is inhibition of the [[cyclooxygenase]] (COX) enzyme.<ref name = "Schrör_2008">{{cite book | vauthors = Schrör K | title = Acetylsalicylic Acid | year = 2008 | publisher = Wiley-VCH | location = Weinheim | isbn = 978-3-527-62600-7 | pages = 5–24 | chapter = Chapter 1.1: History | chapter-url = https://books.google.com/books?id=X5eKkljZtFIC&q=aspirin%20willow%20tree%20%20acetylsalicylic%20acid&pg=PA19 }}</ref> Another notable example is [[opium]] is extracted from the latex from ''Papaver somniferous'' (a flowering poppy plant). The most potent narcotic component of opium is the alkaloid morphine which acts as an [[opioid receptor]] agonist.<ref name=Busse_2006>{{cite book | vauthors = Busse GD, Triggle DJ | title = Morphine | year = 2006 | publisher = Chelsea House Publishers | location = New York | isbn = 978-1-4381-0211-5 | pages = 8–23 | chapter = The history of opium and morphine | chapter-url = https://books.google.com/books?id=sud4ORAMNkYC&q=opium%20morphine%20history&pg=PA8 }}</ref>  A more recent example is the [[N-type calcium channel]] blocker [[ziconotide]] analgesic which is based on a cyclic peptide cone snail toxin (ω-[[conotoxin]] MVIIA) from the species ''Conus magus''.<ref name="pmid22407615">{{cite journal | vauthors = Lewis RJ, Dutertre S, Vetter I, Christie MJ | title = Conus venom peptide pharmacology | journal = Pharmacological Reviews | volume = 64 | issue = 2 | pages = 259–98 | date = April 2012 | pmid = 22407615 | doi = 10.1124/pr.111.005322 | s2cid = 6115292 }}</ref>

A significant number of [[Infection#Treatments|anti-infectives]] are based on natural products.<ref name="pmid32529587">{{cite journal |vauthors=Cushnie TP, Cushnie B, Echeverría J, Fowsantear W, Thammawat S, Dodgson JL, Law S, Clow SM |date=June 2020 |title=Bioprospecting for antibacterial drugs: a multidisciplinary perspective on natural product source material, bioassay selection and avoidable pitfalls|journal=Pharmaceutical Research |volume=37 |issue=7 |pages=Article 125 |doi=10.1007/s11095-020-02849-1|pmid=32529587|s2cid=219590658 |url= https://zenodo.org/record/3909383}}</ref> The first antibiotic to be discovered, penicillin, was isolated from the mold ''[[Penicillium]]''.  Penicillin and related [[beta lactam]]s work by inhibiting [[DD-transpeptidase]] enzyme that is required by bacteria to cross link [[peptidoglycan]] to form the cell wall.<ref>{{cite book | vauthors = de la Bédoyère G | title = The discovery of penicillin | year = 2005 | publisher = Evans | location = London | isbn = 978-0-237-52739-6 }}</ref>

Several natural product drugs target [[tubulin]], which is a component of the [[cytoskeleton]].  These include the tubulin polymerization inhibitor [[colchicine]] isolated from the ''[[Colchicum autumnale]]'' (autumn crocus flowering plant), which is used to treat [[gout]].<ref name="pmid13198053">{{cite journal | vauthors = Hartung EF | title = History of the use of colchicum and related medicaments in gout; with suggestions for further research | journal = Annals of the Rheumatic Diseases | volume = 13 | issue = 3 | pages = 190–200 | date = September 1954 | pmid = 13198053 | pmc = 1006735 | doi = 10.1136/ard.13.3.190 }}</ref> Colchicine is biosynthesized from the amino acids [[phenylalanine]] and [[tryptophan]]. Paclitaxel, in contrast, is a tubulin polymerization stabilizer and is used as a [[chemotherapeutic]] drug.  Paclitaxel is based on the terpenoid natural product [[taxol]], which is isolated from  ''Taxus brevifolia'' (the pacific yew tree).<ref name=Sneader_2005a>{{cite book | vauthors = Sneader W | title = Drug Discovery: A History | year = 2005 | publisher = Wiley | location = Chichester | isbn = 978-0-471-89979-2 | pages = 112–113 | edition = Rev. and updated | chapter = Paclitaxel (taxol) | chapter-url = https://books.google.com/books?id=Cb6BOkj9fK4C&q=Paclitaxel+taxol+discovery+history&pg=PA112 }}</ref>

A class of drugs widely used to lower cholesterol are the [[HMG-CoA reductase]] inhibitors, for example [[atorvastatin]].  These were developed from [[mevastatin]], a polyketide produced by the fungus ''Penicillium citrinum''.<ref name=LI_2009>{{cite book | vauthors = Li JL | title = Triumph of the Heart: the Story of Statins | year = 2009 | publisher = Oxford University Press | location = New York, NY | isbn = 978-0-19-804351-5 | pages = 71–96 | chapter = Discovery of Lipitor | chapter-url = https://books.google.com/books?id=0IZwL8MJ3y4C&q=atorvastatin+discovery+history&pg=PA71}}</ref>  Finally, a number natural product drugs are used to treat hypertension and congestive heart failure.  These include the [[angiotensin-converting enzyme]] inhibitor [[captopril]].  Captopril is based on the peptidic bradykinin potentiating factor isolated from venom of the Brazilian arrowhead viper (''[[Bothrops jararaca]]'').<ref name=Sneader_2005b>{{cite book | vauthors = Sneader W | title = Drug Discovery: A History | year = 2005 | publisher = Wiley | location = Chichester | isbn = 978-0-471-89979-2 | pages = 280–283 | edition = Rev. and updated | chapter = ACE Inhibitors | chapter-url =https://books.google.com/books?id=Cb6BOkj9fK4C&q=captopril+discovery+history&pg=PA281 }}</ref>

===Limiting and enabling factors===
Numerous challenges limit the use of natural products for drug discovery, resulting in 21st century preference by pharmaceutical companies to dedicate discovery efforts toward [[high-throughput screening]] of pure synthetic compounds with shorter timelines to refinement.<ref name=Li_2009/> Natural product sources are often unreliable to access and supply, have a high probability of duplication, inherently create intellectual property concerns about [[patent protection]], vary in composition due to sourcing season or environment, and are susceptible to rising [[extinction]] rates.<ref name=Li_2009/>

The biological resource for drug discovery from natural products remains abundant, with small percentages of microorganisms, plant species, and insects assessed for bioactivity.<ref name=Li_2009/> In enormous numbers, bacteria and marine microorganisms remain unexamined.<ref>{{cite journal | vauthors = Gomez-Escribano JP, Alt S, Bibb MJ | title = Next Generation Sequencing of Actinobacteria for the Discovery of Novel Natural Products | journal = Marine Drugs | volume = 14 | issue = 4 | page = 78 | date = April 2016 | pmid = 27089350 | pmc = 4849082 | doi = 10.3390/md14040078 | doi-access = free }}</ref><ref name="pawar">{{cite journal | vauthors = Pawar SV, Ho JC, Yadav GD, Yadav VG | title = The Impending Renaissance in Discovery & Development of Natural Products | journal = Current Topics in Medicinal Chemistry | volume = 17 | issue = 2 | pages = 251–267 | year = 2017 | pmid = 27237327 | doi = 10.2174/1568026616666160530154649 }}</ref> As of 2008, the field of [[metagenomics]] was proposed to examine genes and their function in soil microbes,<ref name=pawar/><ref name="blow">{{cite journal | vauthors = Blow N | title = Metagenomics: exploring unseen communities | journal = Nature | volume = 453 | issue = 7195 | pages = 687–90 | date = May 2008 | pmid = 18509446 | doi = 10.1038/453687a | bibcode = 2008Natur.453..687B | s2cid = 29079319 | doi-access = free }}</ref> but most pharmaceutical firms have not exploited this resource fully, choosing instead to develop "diversity-oriented synthesis" from libraries of known drugs or natural sources for lead compounds with higher potential for bioactivity.<ref name=Li_2009/>

== Isolation and purification ==
[[File:Penicillin-G.svg|thumb|upright=1.4|[[Penicillin G]], the first-of-its-class fungal antibiotic, first studied by Scottish microbiologist [[Alexander Fleming]] in the late 1920s, and made practical as a therapeutic via natural product isolation in the late 1930s by [[Ernst Boris Chain]], [[Howard Florey]],{{efn|These three named scientists shared the 1945 [[Nobel Prize in Medicine]] for the work.}} and others, Fleming recognized the antibacterial activity and clinical potential of "pen G", but was unable to purify or stabilize it.<ref name="KB2009">{{cite journal | vauthors = Brown K | year = 2009 | title = That's funny!': the discovery and development of penicillin | journal = Microbiology Today | volume = 36 | issue = 1 | pages = 12–15 | url = http://www.sgm.ac.uk/download.cfm/docid/C14AF892-74A1-4CD3-82402F6D0C4AC751 | access-date = 12 January 2015 | archive-url = https://web.archive.org/web/20150112152851/http://www.sgm.ac.uk/download.cfm/docid/C14AF892-74A1-4CD3-82402F6D0C4AC751 | archive-date = 12 January 2015  }}</ref> Developments in [[chromatography|chromatographic separations]] and [[freeze drying]] helped move progress forward in the production of commercial quantities of penicillin and other natural products.{{citation needed|date=July 2014}}]]

All natural products begin as mixtures with other compounds from the natural source, often very complex mixtures, from which the product of interest must be isolated and purified. The ''isolation'' of a natural product refers, depending on context, either to the isolation of sufficient quantities of pure chemical matter for chemical structure elucidation, derivitzation/degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but historically, often more),{{citation needed|date=July 2014}} or to the isolation of "analytical quantities" of the substance of interest, where the focus is on identification and quantitation of the substance (e.g. in biological tissue or fluid), and where the quantity isolated depends on the analytical method applied (but is generally always sub-microgram in scale).<ref name = MakinGower2010>{{cite book | veditors = Gower DB, Makin HL | title = Steroid Analysis | date = 2009 | publisher = Springer | location = Dordrecht | isbn = 978-1-4020-9774-4 | edition = 2nd }}</ref>{{page needed|date=July 2014}} The ease with which the active agent can be isolated and [[List of purification methods in chemistry|purified]] depends on the structure, stability, and quantity of the natural product. The methods of isolation applied toward achieving these two distinct scales of product are likewise distinct, but generally involve [[extraction (chemistry)|extraction]], precipitation, adsorptions, [[chromatography]], and sometimes [[crystallization]]s. In both cases, the isolated substance is purified to ''chemical homogeneity'', i.e. specific combined separation and analytical methods such as [[Liquid chromatography–mass spectrometry|LC-MS]] methods are chosen to be "orthogonal"—achieving their separations based on distinct modes of interaction between substance and isolating matrix—with the goal being repeated detection of only a single species present in the putative pure sample. Early isolation is almost inevitably followed by ''structure determination'', especially if an important pharmacologic activity is associated with the purified natural product.{{Citation needed|date=February 2021}}

Structure determination refers to methods applied to determine the [[chemical structure]] of an isolated, pure natural product, a process that involves an array of chemical and physical methods that have changed markedly over the history of natural products research; in earliest days, these focused on chemical transformation of unknown substances into known substances, and measurement of physical properties such as melting point and boiling point, and related methods for determining molecular weight.{{citation needed|date=July 2014}} In the modern era, methods focus on [[mass spectrometry]] and [[NMR|nuclear magnetic resonance methods]], often multidimensional, and, when feasible, small molecule [[crystallography]].{{citation needed|date=July 2014}} For instance, the chemical structure of penicillin was determined by [[Dorothy Hodgkin|Dorothy Crowfoot Hodgkin]] in 1945, work for which she later received a Nobel Prize in Chemistry (1964).<ref>{{cite web | url = https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1964/perspectives.html | title = Enhancing X-ray Vision | work = The Nobel Prize in Chemistry 1964 – Perspectives | vauthors = Hodgkin DC }}</ref>

== Synthesis ==
Many natural products have very complex structures. The perceived complexity of a natural product is a qualitative matter, consisting of consideration of its molecular mass, the particular arrangements of substructures ([[functional groups]], rings etc.) with respect to one another, the number and density of those functional groups, the stability of those groups and of the molecule as a whole, the number and type of [[chiral|stereochemical elements]], the physical properties of the molecule and its intermediates (which bear on the ease of its handling and purification), all of these viewed in the context of the novelty of the structure and whether preceding related synthetic efforts have been successful (see below for details).{{citation needed|date=July 2014}}

Some natural products, especially those less complex, are easily and cost-effectively prepared via complete chemical synthesis from readily available, simpler chemical ingredients, a process referred to as [[total synthesis]] (especially when the process involves no steps mediated by biological agents). Not all natural products are amenable to total synthesis, cost-effective or otherwise. In particular, those most complex often are not. Many are accessible, but the required routes are simply too expensive to allow synthesis on any practical or industrial scale. However, to be available for further study, all natural products must yield to isolation and purification. This may suffice if isolation provides appropriate quantities of the natural product for the intended purpose (e.g. as a drug to alleviate disease). Drugs such as penicillin, morphine, and paclitaxel proved to be affordably acquired at needed commercial scales solely via isolation procedures (without any significant synthetic chemistry contributing).{{citation needed|date=July 2014}} However, in other cases, needed agents are not available without synthetic chemistry manipulations.{{Citation needed|date=February 2021}}

=== Semisynthesis ===
{{main|Semisynthesis}}

The process of isolating a natural product from its source can be costly in terms of committed time and material expense, and it may challenge the availability of the relied upon natural resource (or have ecological consequences for the resource). For instance, it has been estimated that the [[bark (botany)|bark]] of an entire yew tree (''Taxus brevifolia'') would have to be harvested to extract enough paclitaxel for just a single dose of therapy.<ref name="urlStory of Taxol">{{cite web | url = http://www.pharmacognosy.us/wordpress/wp-content/uploads/The-Story-of-Taxol.pdf | title = The Story of Taxol | publisher = The American Society of Pharmacognosy  | archive-url = https://web.archive.org/web/20131212131838/http://www.pharmacognosy.us/wordpress/wp-content/uploads/The-Story-of-Taxol.pdf | archive-date = 12 December 2013 }}</ref> Furthermore, the number of [[structural analog]]ues obtainable for [[structure–activity relationship|structure–activity analysis]] (SAR) simply via harvest (if more than one structural analogue is even present) is limited by the biology at work in the organism, and so outside of the experimentalist's control.{{Citation needed|date=February 2021}}

In such cases where the ultimate target is harder to come by, or limits SAR, it is sometimes possible to source a middle-to-late stage biosynthetic precursor or analogue from which the ultimate target can be prepared. This is termed semisynthesis or ''partial synthesis''. With this approach, the related biosynthetic intermediate is harvested and then converted to the final product by conventional procedures of [[chemical synthesis]].{{Citation needed|date=February 2021}}

This strategy can have two advantages. Firstly, the intermediate may be more easily extracted, and in higher yield, than the ultimate desired product. An example of this is paclitaxel, which can be manufactured by extracting [[10-deacetylbaccatin III]] from ''T. brevifolia'' [[Needle (botany)|needles]], then carrying out a four-step synthesis.{{citation needed|date=July 2014}} Secondly, the route designed between semisynthetic starting material and ultimate product may permit analogues of the final product to be synthesized. The newer generation semisynthetic [[penicillins]] are an illustration of the benefit of this approach.{{citation needed|date=July 2014}}

===Total synthesis===
{{main|Total synthesis}}
[[File:Cobalamin.svg|thumb|upright=1.1|Structural representation of [[Vitamin B12|cobalamin]], a natural product isolated and structurally characterized.<ref name="pmid13348621">{{cite journal | vauthors = Hodgkin DC, Kamper J, Mackay M, Pickworth J, Trueblood KN, White JG | title = Structure of vitamin B12 | journal = Nature | volume = 178 | issue = 4524 | pages = 64–6 | date = July 1956 | pmid = 13348621 | doi = 10.1038/178064a0 | bibcode = 1956Natur.178...64H | s2cid = 4210164 }}</ref> The variable R group can be a [[methyl]] or 5'-adenosyl group, or a cyanide or hydroxide anion. The "proof" by synthesis of vitamin B<sub>12</sub> was accomplished in 1972 by the groups of [[Robert Burns Woodward]]<ref name="Woodward_1973">{{cite journal | vauthors = Woodward RB | title = The total synthesis of vitamin B 12 | journal = Pure and Applied Chemistry | volume = 33 | issue = 1 | pages = 145–77 | year = 1973 | pmid = 4684454 | doi = 10.1351/pac197333010145 | s2cid = 30641959 | doi-access = free }}</ref> and [[Albert Eschenmoser]].<ref name="Eschenmoser_1988">{{cite journal | vauthors = Eschenmoser A | title = Vitamin B12: Experiments Concerning the Origin of Its Molecular Structure | journal = Angewandte Chemie International Edition in English |date=January 1988 | volume = 27 | issue = 1 | pages = 5–39 | doi = 10.1002/anie.198800051 }}</ref>]]

In general, the total synthesis of natural products is a non-commercial research activity, aimed at deeper understanding of the synthesis of particular natural product frameworks, and the development of fundamental new synthetic methods. Even so, it is of tremendous commercial and societal importance. By providing challenging synthetic targets, for example, it has played a central role in the development of the field of organic chemistry.<ref name = "Heathcock_1996">{{cite book | title = Chemical Synthesis | vauthors = Heathcock CH | chapter = As We Head into the 21st Century, Is there Still Value in Total Synthesis of Natural Products as a Research Endeavor? | series = NATO ASI Series | volume = 320 | pages = 223–243 | year = 1996 | doi = 10.1007/978-94-009-0255-8_9 | chapter-url = http://heathcock.org/chhgrp/Ravello/Ravello.ms.html | isbn = 978-94-010-6598-6 }}</ref><ref name="Nicolaou_2000">{{cite journal | vauthors = Nicolaou KC, Vourloumis D, Winssinger N, Baran PS | title = The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century | journal = Angewandte Chemie | volume = 39 | issue = 1 | pages = 44–122 | date = January 2000 | pmid = 10649349 | doi = 10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L | author-link4 = Phil S. Baran | author-link1 = K. C. Nicolaou }}</ref> Prior to the development of [[analytical chemistry]] methods in the twentieth century, the structures of natural products were affirmed by total synthesis (so-called "structure proof by synthesis").<ref name="DAL2013">{{cite book |url=https://books.google.com/books?id=tCG4BAAAQBAJ&q=%22proof+by+synthesis%22+natural+product&pg=PA371 |title=Bilirubin: Jekyll and Hyde Pigment of Life: Pursuit of Its Structure Through Two World Wars to the New Millenium | vauthors = Lightner DA | year = 2013 | publisher = Springer | page = 371 | isbn = 978-3-7091-1637-1 }}</ref> Early efforts in natural products synthesis targeted complex substances such as cobalamin (vitamin B<sub>12</sub>), an essential [[cofactor (biochemistry)|cofactor]] in cellular [[metabolism]].<ref name="Woodward_1973"/><ref name="Eschenmoser_1988"/>

===Symmetry===
Examination of [[Dimer (chemistry)|dimerized]] and [[Dimer (chemistry)|trimerized]] natural products has shown that an element of bilateral symmetry is often present. Bilateral symmetry refers to a molecule or system that contains a C<sub>2</sub>, C<sub>s</sub>, or C<sub>2v</sub> point group identity. C<sub>2</sub> symmetry tends to be much more abundant than other types of bilateral symmetry. This finding sheds light on how these compounds might be mechanistically created, as well as providing insight into the thermodynamic properties that make these compounds more favorable. [[Density functional theory]] (DFT), the [[Hartree–Fock method]], and [[Semi-empirical quantum chemistry method|semiempirical]] calculations also show some favorability for dimerization in natural products due to evolution of more energy per bond than the equivalent trimer or tetramer. This is proposed to be due to [[steric hindrance]] at the core of the molecule, as most natural products dimerize and trimerize in a head-to-head fashion rather than head-to-tail.<ref name="pmid15270568">{{cite journal | vauthors = Voloshchuk T, Farina NS, Wauchope OR, Kiprowska M, Haberfield P, Greer A | title = Molecular bilateral symmetry of natural products: prediction of selectivity of dimeric molecules by density functional theory and semiempirical calculations | journal = Journal of Natural Products | volume = 67 | issue = 7 | pages = 1141–6 | date = July 2004 | pmid = 15270568 | doi = 10.1021/np049899e }}</ref>

== Research and teaching ==

Research and teaching activities related to natural products fall into a number of diverse academic areas, including organic chemistry, medicinal chemistry, pharmacognosy, [[ethnobotany]], [[traditional medicine]], and [[ethnopharmacology]]. Other biological areas include [[chemical biology]], [[chemical ecology]], [[chemogenomics]],<ref>{{cite journal | vauthors = Bredel M, Jacoby E | title = Chemogenomics: an emerging strategy for rapid target and drug discovery | journal = Nature Reviews. Genetics | volume = 5 | issue = 4 | pages = 262–75 | date = April 2004 | pmid = 15131650 | doi = 10.1038/nrg1317 | s2cid = 11952369 | url = http://cbio.ensmp.fr/~jvert/svn/bibli/local/Bredel2004Chemogenomics.pdf | citeseerx = 10.1.1.411.9671 }}</ref> [[systems biology]], [[molecular modeling]], [[chemometrics]], and [[chemoinformatics]].<ref>{{cite journal | vauthors = Galúcio JM, Monteiro EF, de Jesus DA, Costa CH, Siqueira RC, Santos GB, Lameira J, Costa KS | display-authors = 6 | title = In silico identification of natural products with anticancer activity using a chemo-structural database of Brazilian biodiversity | journal = Computational Biology and Chemistry | volume = 83 | page = 107102 | date = August 2019 | pmid = 31487609 | doi = 10.1016/j.compbiolchem.2019.107102 | s2cid = 201845232 }}</ref>

=== Chemistry ===

Natural products chemistry is a distinct area of chemical research which was important in the development and [[history of chemistry]]. Isolating and identifying natural products has been important to source substances for early preclinical drug discovery research, to understand traditional medicine and ethnopharmacology, and to find pharmacologically useful areas of [[Drug discovery#Chemical diversity|chemical space]].<ref>{{cite journal | vauthors = Harvey AL | title = Natural products in drug discovery | journal = Drug Discovery Today | volume = 13 | issue = 19–20 | pages = 894–901 | date = October 2008 | pmid = 18691670 | doi = 10.1016/j.drudis.2008.07.004 }}</ref> To achieve this, many technological advances have been made, such as the evolution of technology associated with [[Liquid chromatography–mass spectrometry|chemical separations]], and the development of modern methods in [[chemical structure determination]] such as [[NMR]]. Early attempts to understand the biosynthesis of natural products, saw chemists employ first radiolabelling and more recently stable isotope labeling combined with NMR experiments. In addition, natural products are prepared by [[organic synthesis]], to provide confirmation of their structure, or to give access to larger quantities of natural products of interest. In this process, the structure of some natural products have been revised,<ref>{{cite journal | vauthors = Chhetri BK, Lavoie S, Sweeney-Jones AM, Kubanek J | title = Recent trends in the structural revision of natural products | journal = Natural Product Reports | volume = 35 | issue = 6 | pages = 514–531 | date = June 2018 | pmid = 29623331 | doi = 10.1039/C8NP00011E | pmc = 6013367 }}</ref><ref>{{cite journal | vauthors = Heard DM, Tayler ER, Cox RJ, Simpson TJ, Willis CL |title=Structural and synthetic studies on maleic anhydride and related diacid natural products |journal=Tetrahedron |date=January 2020 |volume=76 |issue=1 |page=130717 |doi=10.1016/j.tet.2019.130717|hdl=1983/53998d06-9017-4cfb-822b-c6453348000a |s2cid=209714625 |url=https://research-information.bris.ac.uk/ws/files/217963504/Maleidrides_Tricladics_final.pdf }}</ref><ref>{{cite journal | vauthors = Wu J, Lorenzo P, Zhong S, Ali M, Butts CP, Myers EL, Aggarwal VK | title = Synergy of synthesis, computation and NMR reveals correct baulamycin structures | journal = Nature | volume = 547 | issue = 7664 | pages = 436–440 | date = July 2017 | pmid = 28748934 | doi = 10.1038/nature23265 | url = https://research-information.bris.ac.uk/ws/files/143720044/Baulamycin_Letter_format_final.pdf | hdl = 1983/85161235-ea9f-4568-9f8a-19b42f4dff67 | s2cid = 205258282 | hdl-access = free }}</ref> and the challenge of synthesising natural products has led to the development of new synthetic methodology, synthetic strategy, and tactics.<ref>{{cite journal | vauthors = Corsello MA, Kim J, Garg NK | title = Indole diterpenoid natural products as the inspiration for new synthetic methods and strategies | journal = Chemical Science | volume = 8 | issue = 9 | pages = 5836–5844 | date = September 2017 | pmid = 28970940 | doi = 10.1039/C7SC01248A | pmc = 5618777 | doi-access = free }}</ref> In this regard, natural products play a central role in the training of new synthetic organic chemists, and are a principal motivation in the development of new variants of old chemical reactions (e.g., the [[Evans aldol]] reaction), as well as the discovery of completely new chemical reactions (e.g., the [[Woodward cis-hydroxylation]], [[Sharpless epoxidation]], and [[Suzuki reaction|Suzuki–Miyaura]] cross-coupling reactions).<ref>{{cite journal | vauthors = Baran PS | title = Natural Product Total Synthesis: As Exciting as Ever and Here To Stay | journal = Journal of the American Chemical Society | volume = 140 | issue = 14 | pages = 4751–4755 | date = April 2018 | pmid = 29635919 | doi = 10.1021/jacs.8b02266 | doi-access = free }}</ref>

== History ==
[[File:Antoine Laurent Lavoisier. Lithograph by Z. Belliard after J Wellcome V0003416.jpg|thumb|[[Antoine Lavoisier]] (1743–1794)]]
[[File:Friedrich woehler.jpg|thumb|upright=.9|[[Friedrich Wöhler]] (1800–1882)]]
[[File:Hermann Emil Fischer c1895.jpg|thumb|upright=.7|[[Hermann Emil Fischer]] (1852–1919)]]

=== Foundations of organic and natural product chemistry ===

The concept of natural products dates back to the early 19th century, when the foundations of organic chemistry were laid. Organic chemistry was regarded at that time as the chemistry of substances that plants and animals are composed of. It was a relatively complex form of chemistry and stood in stark contrast to [[inorganic chemistry]], the principles of which had been established in 1789 by the Frenchman [[Antoine Lavoisier]] in his work ''[[Traité Élémentaire de Chimie]]''.<ref name="ACS_ Lavoisier_Landmark">{{cite web | url = http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/lavoisier.html  | title = Antoine Laurent Lavoisier The Chemical Revolution | work = International Historic Chemical Landmark | publisher = American Chemical Society }}</ref>

=== Isolation ===
Lavoisier showed at the end of the 18th century that organic substances consisted of a limited number of elements: primarily carbon and hydrogen and supplemented by oxygen and nitrogen. He quickly focused on the isolation of these substances, often because they had an interesting pharmacological activity. Plants were the main source of such compounds, especially alkaloids and [[glycoside]]s. It was long been known that opium, a sticky mixture of alkaloids (including [[codeine]], morphine, [[noscapine]], [[thebaine]], and [[papaverine]]) from the opium poppy (''[[Papaver somniferum]]''), possessed a narcotic and at the same time mind-altering properties. By 1805, morphine had already been isolated by the German chemist [[Friedrich Sertürner]] and in the 1870s it was discovered that boiling morphine with [[acetic anhydride]] produced a substance with a strong pain suppressive effect: heroin.<ref name="Dias_2012">{{cite journal | vauthors = Dias DA, Urban S, Roessner U | title = A historical overview of natural products in drug discovery | journal = Metabolites | volume = 2 | issue = 4 | pages = 303–36 | year = 2012 | pmid = 24957513 | pmc = 3901206 | doi = 10.3390/metabo2020303 | doi-access = free }}</ref> In 1815, [[Eugène Chevreul]] isolated [[cholesterol]], a crystalline substance, from animal tissue that belongs to the class of steroids,<ref>{{cite book |title=Recherches chimiques sur les corps gras d'origine animale |language=fr |year=1823 | vauthors = Chevreul ME  |chapter-url=https://archive.org/details/b28992817/page/30/mode/2up |chapter=IX — De la cholestérine |pages=153–160 }}</ref> and in 1819 [[strychnine]], an alkaloid was isolated.<ref>{{cite journal | vauthors = Pelletier PP, Caventou JB | date = 1819 | url = https://books.google.com/books?id=sSE4AQAAIAAJ&pg=PA142 | title = Mémoire sur un nouvel alcali vegetal (la strychnine) trouvé dans la feve de Saint-Ignace, la noix vomique, etc. | trans-title = Memoir on a new vegetable alkali (strychnine) found in the St. Ignatius bean, the nux-vomica, etc) | language = French | journal = Annales de Chimie et de Physique | volume = 10 | pages = 142–176 }}</ref>

=== Synthesis ===

A second important step was the synthesis of organic compounds. Whereas the synthesis of inorganic substances had been known for a long time, the synthesis of organic substances was a difficult hurdle. In 1827 the Swedish chemist [[Jöns Jacob Berzelius]] held that an indispensable force of nature for the synthesis of organic compounds, called vital force or life force, was needed. This philosophical idea, [[vitalism]], well into the 19th century had many supporters, even after the introduction of the [[atomic theory]]. The idea of vitalism especially fitted in with beliefs in medicine; the most traditional healing practices believed that disease was the result of some imbalance in the vital energies that distinguishes life from nonlife. A first attempt to break the vitalism idea in science was made in 1828, when the German chemist [[Friedrich Wöhler]] succeeded in synthesizing [[urea]], a natural product found in [[urine]], by heating [[ammonium cyanate]], an inorganic substance:<ref>{{cite journal | vauthors = Wöhler F | title = Ueber künstliche Bildung des Harnstoffs | trans-title = About the artificial formation of urea | journal = Annalen der Physik und Chemie | date = 1828 | volume = 88 | issue = 2 |pages = 253–256 | doi = 10.1002/andp.18280880206 | language = de | bibcode = 1828AnP....88..253W | url = https://www.biodiversitylibrary.org/itempdf/127264 }}</ref>

:<math>\mathrm{NH_4OCN\ \xrightarrow {\ \ 60^{\circ}C \ \ }\ H_2NCONH_2}</math>

This reaction showed that there was no need for a life force in order to prepare organic substances. This idea, however, was initially met with a high degree of skepticism, and only 20 years later, with the synthesis of acetic acid from carbon by [[Adolph Wilhelm Hermann Kolbe]], was the idea accepted. Organic chemistry has since developed into an independent area of research dedicated to the study of carbon-containing compounds, since that element in common was detected in a variety of nature-derived substances. An important factor in the characterization of organic materials was on the basis of their physical properties (such as melting point, boiling point, solubility, crystallinity, or color).{{Citation needed|date=February 2021}}

=== Structural theories ===

A third step was the structure elucidation of organic substances: although the elemental composition of pure organic substances (irrespective of whether they were of natural or synthetic origin) could be determined fairly accurately, the molecular structure was still a problem. The urge to do structural elucidation resulted from a dispute between Friedrich Wöhler and [[Justus von Liebig]], who both studied a silver salt of the same composition but had different properties. Wöhler studied [[silver cyanate]], a harmless substance, while von Liebig investigated [[silver fulminate]], a salt with explosive properties.<ref name="Justus von Liebig and Friedrich Wöhler">{{cite web | url = https://www.sciencehistory.org/historical-profile/justus-von-liebig-and-friedrich-w%C3%B6hler | title = Justus von Liebig and Friedrich Wöhler | work = Science History Institute | date = June 2016 | access-date = 21 March 2018 | archive-date = 20 June 2018 | archive-url = https://web.archive.org/web/20180620232155/https://www.sciencehistory.org/historical-profile/justus-von-liebig-and-friedrich-w%C3%B6hler | url-status = dead }}</ref> The elemental analysis shows that both salts contain equal quantities of silver, carbon, oxygen and nitrogen. According to the then prevailing ideas, both substances should possess the same properties, but this was not the case. This apparent contradiction was later solved by [[Berzelius]]'s theory of [[isomer]]s, whereby not only the number and type of elements are of importance to the properties and chemical reactivity, but also the position of atoms in within a compound. This was a direct cause for the development of structure theories, such as the [[radical theory]] of [[Jean-Baptiste Dumas]] and the substitution theory of [[Auguste Laurent]].<ref>{{cite journal | vauthors = Liebig J | title = Ueber Laurent's Theorie der organischen Verbindungen | trans-title = About Laurent 's theory of organic compounds | language = de | journal = Annalen der Pharmacie | date= 1838 | volume = 25 | issue = 1 | pages = 1–31 | doi = 10.1002/jlac.18380250102 | url = https://zenodo.org/record/1426927 }}</ref>{{Better source needed|date=March 2021}}  However, it took until 1858 before by [[August Kekulé]] formulated a definite structure theory. He posited that carbon is tetravalent and can bind to itself to form carbon chains as they occur in natural products.<ref>{{cite journal | vauthors = Kekulé A | title = Ueber die Constitution und die Metamorphosen der chemischen Verbindungen und über die chemische Natur des Kohlenstoffs | trans-title = Concerning the constitution and the metamorphosis of the chemical compounds and the chemical nature of the carbon | journal = Annalen der Chemie und Pharmacie | date = 1858 | volume = 106 | issue = 2 | pages = 129–159 | doi = 10.1002/jlac.18581060202 | language = de | url = https://zenodo.org/record/1427102 }}</ref>{{Better source needed|date=March 2021}}

=== Expanding the concept ===

The concept of natural product, which initially based on organic compounds that could be isolated from plants, was extended to include animal material in the middle of the 19th century by the German [[Justus von Liebig]]. [[Hermann Emil Fischer]] in 1884, turned his attention to the study of carbohydrates and purines, work for which he was awarded the Nobel Prize in 1902. He also succeeded to make synthetically in the laboratory in a variety of carbohydrates, including [[glucose]] and [[mannose]]. After the discovery of penicillin by [[Alexander Fleming]] in 1928, fungi and other micro-organisms were added to the arsenal of sources of natural products.<ref name="Dias_2012"/>

=== Milestones ===
{{Unreferenced section|date=January 2021}}
By the 1930s, several large classes of natural products were known. Important milestones included:{{according to whom|date=January 2021}}
* [[Terpene]]s, first systematically studied by [[Otto Wallach]] (Nobel Prize 1910) and later by [[Leopold Ružička]] (Nobel Prize 1939)
* Dyes based on [[porphin]]s (including [[chlorophyll]] and [[heme]]), studied by [[Richard Willstätter]] (Nobel Prize 1915) and Hans Fischer (Nobel Prize 1930)
* [[Steroid]]s, studied by [[Heinrich Otto Wieland]] (Nobel Prize 1927) and [[Adolf Windaus]] (Nobel Prize 1928)
* [[Carotenoid]]s, studied by [[Paul Karrer]] (Nobel Prize 1937)
* [[Vitamin]]s, studied among others by [[Paul Karrer]], Adolf Windaus, [[Robert R. Williams]], [[Norman Haworth]] (Nobel Prize 1937), [[Richard Kuhn]] (Nobel Prize 1938) and [[Albert Szent-Györgyi]]
* [[Hormone]]s studied by [[Adolf Butenandt]] (Nobel Prize 1939) and Edward Calvin Kendall (Nobel Prize 1950)
* Alkaloids and [[anthocyanin]]s, studied by, among others, [[Robert Robinson (organic chemist)|Robert Robinson]] (Nobel Prize 1947)

== See also ==
* [[Biogenic substance]]
* [[Pharmacognosy]]
* [[Phytotherapy]]

=== Journals ===
* ''[[Chemistry of Natural Compounds]]''
* ''[[Journal of Natural Products]]''
* ''[[Natural Product Reports]]''
* ''[[Natural Product Research]]''
{{clear}}

== References ==
'''Footnotes'''
{{notelist}}

'''Citations'''
{{reflist|30em}}

== Further reading ==
{{refbegin}}
* {{cite book | vauthors = Bhat SV, Nagasampagi BA, Sivakumar M | title = Chemistry of Natural Products | year = 2005 | publisher = Springer |location = Berlin | isbn = 3-540-40669-7 | edition = 2 }}
* {{cite book | vauthors = Hanson JR | title = Natural Products: The Secondary Metabolites | year = 2003 | publisher = Royal Society of Chemistry | isbn =0-85404-490-6}}
* {{cite book | vauthors = Kaufman PB | title = Natural Products from Plants | year = 1999 | publisher = CRC Press | isbn = 0-8493-3134-X | url-access = registration | url = https://archive.org/details/naturalproductsf00kauf_0 }}
* {{cite book |veditors=Liang XT, Fang WS | title = Medicinal Chemistry of Bioactive Natural Products | year = 2006 | publisher = Wiley-Interscience | isbn = 0-471-73933-2 }}
* {{cite book |author=V. K. Ahluwalia |author2=Lalita S. Kumar |author3=Sanjiv Kumar | title = Chemistry of natural products: amino acids, peptides, proteins and enzymes | year = 2022 | publisher = Springer | isbn = 978-3-030-86697-6}}
* {{cite book | editor=Mayuri Napagoda, Lalith Jayasinghe |title = Chemistry of natural products: phytochemistry and pharmacognosy of medicinal plants | year = 2022 | publisher = De Gruyter | isbn = 978-3-11-059589-5}}
{{refend}}

==External links==
{{Commons category|Natural products}}
* {{cite web | url = http://www.cem.msu.edu/~reusch/VirtualText/biomol.htm | archive-url = https://web.archive.org/web/20070203050704/http://www.cem.msu.edu/~reusch/VirtualText/biomol.htm | archive-date = 3 February 2007  | title = Natural Products page | vauthors = Reusch W | date = 2010 | work = Virtual Textbook of Organic Chemistry | location = Ann Arbor, Mich. | publisher = Michigan State University, Department of Chemistry }}
* {{cite web | url = http://c13.usal.es | title = NAPROC-13 Base de datos de Carbono 13 de Productos Naturales y Relacionados (''Carbon-13 Database of Natural Products and Related Substances'') | work = Spanish language tools to facilitate structural identification of natural products }}
* {{WD1913|no-prescript=1|title=Natural product|name-list-style=vanc}}

{{Authority control}}

[[Category:Natural products]]
[[Category:Chemistry]]
[[Category:Nature]]