A natural product is a natural compound or substance produced by a living organism—that is, found in

nature Nature, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans are ...

. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by

chemical synthesis As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In mod ...

(both

semisynthesis Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with ...

and total synthesis) and have played a central role in the development of the field of

organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J ...

by providing challenging synthetic targets. The term natural product has also been extended for commercial purposes to refer to cosmetics, dietary supplements, and foods produced from natural sources without added artificial ingredients. Within the field of

, the definition of natural products is usually restricted to

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...

s isolated from natural sources that are produced by the pathways of

primary Primary or primaries may refer to: Arts, entertainment, and media Music Groups and labels * Primary (band), from Australia * Primary (musician), hip hop musician and record producer from South Korea * Primary Music, Israeli record label Works ...

or secondary metabolism. Within the field of medicinal chemistry, the definition is often further restricted to secondary metabolites. Secondary metabolites (or specialized metabolites) are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage. 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. 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 compounds in

drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or b ...

. 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 Profit may refer to: Business and law * Profit (accounting), the difference between the purchase price and the costs of bringing to market * Profit (economics), normal profit and economic profit * Profit (real property), a nonpossessory inter ...

concerns, seasonal or environmental variability of composition, and loss of sources due to rising

extinction Extinction is the termination of a kind of organism or of a group of kinds (taxon), usually a species. The moment of extinction is generally considered to be the death of the Endling, last individual of the species, although the Functional ext ...

rates.

Classes

The broadest definition of natural product is anything that is produced by life, and includes the likes of biotic materials (e.g. wood, silk),

bio-based material A bio-based material is a material intentionally made from substances derived from living (or once-living) organisms. These materials are sometimes referred to as biomaterials, but this word also has another meaning. Strictly the definition could ...

s (e.g. bioplastics, cornstarch), bodily fluids (e.g. milk, plant exudates), and other natural materials (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 and 400,000.

Function

Following Albrecht Kossel's original proposal in 1891, natural products are often divided into two major classes, the primary and secondary metabolites. 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 Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

pathways, some secondary metabolites have useful medicinal properties. Natural products especially within the field of

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 Pharmacognosy is the study of medicinal plants and other natural substances as sources of drugs. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical, and biological properties of dru ...

Primary metabolites

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

phyla Phyla, the plural of ''phylum'', may refer to: * Phylum, a biological taxon between Kingdom and Class * by analogy, in linguistics, a large division of possibly related languages, or a major language family which is not subordinate to another Phy ...

and frequently more than one kingdom. Primary metabolites include the basic building blocks of life:

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

s, and

nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main ...

s. Primary metabolites that are involved with energy production include respiratory and photosynthetic

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s. Enzymes in turn are composed of

s and often non-peptidic

cofactors Cofactor may also refer to: * Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed * A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...

that are essential for enzyme function. The basic structure of cells and of organisms are also composed of primary metabolites. These include cell membranes (e.g.

phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

s), cell walls (e.g. peptidoglycan,

chitin Chitin ( C8 H13 O5 N)n ( ) is a long-chain polymer of ''N''-acetylglucosamine, an amide derivative of glucose. Chitin is probably the second most abundant polysaccharide in nature (behind only cellulose); an estimated 1 billion tons of chit ...

), and

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is co ...

s (proteins). 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 FMN and FAD which are necessary for many redox reactions.

Vitamin B3 Vitamin B3, colloquially referred to as niacin, is a vitamin family that includes three forms or vitamers: niacin (nicotinic acid), nicotinamide (niacinamide), and nicotinamide riboside. All three forms of vitamin B3 are converted within the b ...

(nicotinic acid or niacin), synthesized from tryptophan is a component of the coenzymes NAD and NADP which in turn are required for electron transport in the Krebs cycle,

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine t ...

, 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 Vitamin B6 is one of the B vitamins, and thus an essential nutrient. The term refers to a group of six chemically similar compounds, i.e., " vitamers", which can be interconverted in biological systems. Its active form, pyridoxal 5′-phosp ...

(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. DNA and RNA which store and transmit

genetic information A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequences are u ...

are composed of nucleic acid primary metabolites. First messengers are signaling molecules that control

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...

cellular differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...

. These signaling molecules include hormones and growth factors in turn are composed of peptides, biogenic amines, steroid hormones, auxins, gibberellins etc. These first messengers interact with cellular receptors which are composed of proteins. Cellular receptors in turn activate

second messengers Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first m ...

are used to relay the extracellular message to intracellular targets. These signaling molecules include the primary metabolites cyclic nucleotides, diacyl glycerol etc.

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. Secondary metabolites have a broad range of functions. These include pheromones that act as social signaling molecules with other individuals of the same species, communication molecules that attract and activate

symbiotic Symbiosis (from Greek , , "living together", from , , "together", and , bíōsis, "living") is any type of a close and long-term biological interaction between two different biological organisms, be it mutualistic, commensalistic, or para ...

organisms, agents that solubilize and transport nutrients ( siderophores etc.), and competitive weapons ( repellants, venoms, toxins etc.) that are used against competitors, prey, and predators. For many other secondary metabolites, the function is unknown. One hypothesis is that they confer a competitive advantage to the organism that produces them. An alternative view is that, in analogy to the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

, 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. General structural classes of secondary metabolites include

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of simila ...

s, phenylpropanoids, polyketides, and terpenoids.

Biosynthesis

The biosynthetic pathways leading to the major classes of natural products are described below. *

Photosynthesis Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored in ...

or gluconeogenesis →

monosaccharide Monosaccharides (from Greek '' monos'': single, '' sacchar'': sugar), also called simple sugars, are the simplest forms of sugar and the most basic units (monomers) from which all carbohydrates are built. They are usually colorless, water- so ...

s →

polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with w ...

s (

cellulose Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of β(1→4) linked D-glucose units. Cellulose is an important structural component of the primary cell wa ...

glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one of ...

etc.) * Acetate pathway →

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

s and polyketides * Shikimate pathway → aromatic amino acids and phenylpropanoids * Mevalonate pathway and methyletrythritol phosphate pathway → terpenoids and

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...

s * Amino acids →

Carbohydrates

Carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...

s are an essential energy source for most life forms. In addition,

s formed from simpler carbohydrates are important structural components of many organisms such the

cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...

s of bacteria and plants. Carbohydrate are the products of plant

photosynthesis Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored in ...

and animal gluconeogenesis. Photosynthesis produces initially 3-phosphoglyceraldehyde, a three carbon atom containing sugar (a

triose A triose is a monosaccharide, or simple sugar, containing three carbon atoms. There are only three possible trioses (including dihydroxyacetone): L-glyceraldehyde and D-glyceraldehyde, the two enantiomers of glyceraldehyde, which are aldotrio ...

). This triose in turn may be converted into

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

(a six carbon atom containing sugar) or a variety of

pentose In chemistry, a pentose is a monosaccharide (simple sugar) with five carbon atoms. The chemical formula of many pentoses is , and their molecular weight is 150.13 g/mol.Calvin cycle. In animals, the three carbon precursors

lactate Lactate may refer to: * Lactation, the secretion of milk from the mammary glands * Lactate, the conjugate base of lactic acid Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with w ...

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...

can be converted into

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic a ...

which in turn can be converted into carbohydrates in the liver.

Fatty acids and polyketides

Through the process of

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

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 Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ketone bodies digestion ...

. Additional condensation reactions produce successively higher molecular weight poly-β-keto chains which are then converted into other polyketides. The polyketide class of natural products have diverse structures and functions and include prostaglandins and

macrolide antibiotic The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...

s. One molecule of acetyl-CoA (the "starter unit") and several molecules malonyl-CoA (the "extender units") are condensed by fatty acid synthase to produce

s. Fatty acid are essential components of lipid bilayers that form cell membranes as well as fat energy stores in animals.

Sources

Natural products may be extracted from the cells, tissues, and

secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classic ...

s of

microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in old ...

s, plants and animals. A crude ( 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 drug discovery screens or bioassays. This effort to search for biologically active natural products is known as bioprospecting.

Pharmacognosy Pharmacognosy is the study of medicinal plants and other natural substances as sources of drugs. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical, and biological properties of dru ...

provides the tools to detect, isolate and identify bioactive natural products that could be developed for medicinal use. When an "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 (eg. elucidation of mechanism of action, confirmation that there is no intellectual property conflict). This is followed by the

hit to lead Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compo ...

stage of drug discovery, where derivatives of the active compound are produced in an attempt to improve its

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...

and

safety Safety is the state of being "safe", the condition of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings There are two slightly di ...

. In this and related ways, modern medicines can be developed directly from natural sources. 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. Because natural products are generally secondary metabolites with complex

chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of ...

s, their total/semisynthesis is not always commercially viable. In these cases, efforts can be made to design simpler analogues with comparable potency and safety that are amenable to total/semisynthesis.

Prokaryotic

Bacteria

The serendipitous discovery and subsequent clinical success of

penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...

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. This, in turn, led to the development of an impressive arsenal of antibacterial and antifungal agents including

amphotericin B Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococcosis ...

chloramphenicol Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections. This includes use as an eye ointment to treat conjunctivitis. By mouth or by injection into a vein, it is used to treat meningitis, plague, chole ...

, daptomycin and tetracycline (from ''

Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positiv ...

'' spp.), the polymyxins (from '' Paenibacillus polymyxa''), and the

rifamycins The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium '' Amycolatopsis rifamycinica'' or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective aga ...

(from '' Amycolatopsis rifamycinica''). Antiparasitic and antiviral drugs have similarly been derived from bacterial metabolites. Although most of the drugs derived from bacteria are employed as anti-infectives, some have found use in other fields of medicine.

Botulinum toxin Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neurom ...

(from '' Clostridium botulinum'') and

bleomycin -13- (1''H''-imidazol-5-yl)methyl9-hydroxy-5- 1''R'')-1-hydroxyethyl8,10-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazapentadec-1-yl}-2,4'-bi-1,3-thiazol-4-yl)carbonyl]amino}propyl)(dimethyl)sulfonium , chemical_formula = , C=55 , H=84 , N=1 ...

(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 A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ such as the bladder. A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a muscle ...

. Also, the glycopeptide bleomycin is used for the treatment of several cancers including Hodgkin's lymphoma,

head and neck cancer Head and neck cancer develops from tissues in the lip and oral cavity (mouth), larynx (throat), salivary glands, nose, sinuses or the skin of the face. The most common types of head and neck cancers occur in the lip, mouth, and larynx. Symptom ...

, and

testicular cancer Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle, or swelling or pain in the scrotum. Treatment may result in infertility. Risk factors include a ...

. 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 Symbiosis (from Greek , , "living together", from , , "together", and , bíōsis, "living") is any type of a close and long-term biological interaction between two different biological organisms, be it mutualistic, commensalistic, or parasit ...

or endophytes from tropical environments, subterranean bacteria found deep underground via mining/drilling, and

marine Marine is an adjective meaning of or pertaining to the sea or ocean. Marine or marines may refer to: Ocean * Maritime (disambiguation) * Marine art * Marine biology * Marine debris * Marine habitats * Marine life * Marine pollution Military ...

bacteria.

Archaea

Because many

Archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaeba ...

have adapted to life in extreme environments such as

polar region The polar regions, also called the frigid zones or polar zones, of Earth are the regions of the planet that surround its geographical poles (the North and South Poles), lying within the polar circles. These high latitudes are dominated by flo ...

hot springs A hot spring, hydrothermal spring, or geothermal spring is a spring produced by the emergence of geothermally heated groundwater onto the surface of the Earth. The groundwater is heated either by shallow bodies of magma (molten rock) or by circ ...

, acidic springs, alkaline springs,

salt lakes A salt lake or saline lake is a landlocked body of water that has a concentration of salts (typically sodium chloride) and other dissolved minerals significantly higher than most lakes (often defined as at least three grams of salt per litre). ...

, 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 Food is any substance consumed by an organism for nutritional support. Food is usually of plant, animal, or fungal origin, and contains essential nutrients, such as carbohydrates, fats, proteins, vitamins, or minerals. The substance is in ...

, chemical, and

pharmaceutical A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

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 amylases, pullulanases, cyclodextrin glycosyltransferases,

cellulase Cellulase (EC 3.2.1.4; systematic name 4-β-D-glucan 4-glucanohydrolase) is any of several enzymes produced chiefly by fungi, bacteria, and protozoans that catalyze cellulolysis, the decomposition of cellulose and of some related polysaccha ...

xylanase Endo-1,4-β-xylanase (EC 3.2.1.8, systematic name 4-β-D-xylan xylanohydrolase) is any of a class of enzymes that degrade the linear polysaccharide xylan into xylose, thus breaking down hemicellulose, one of the major components of plant cel ...

s, chitinases,

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

s, alcohol dehydrogenase, and esterases. Archaea represent a source of novel chemical compounds also, for example isoprenyl glycerol ethers 1 and 2 from ''

Thermococcus In taxonomy, ''Thermococcus'' is a genus of thermophilic Archaea in the family the Thermococcaceae. Members of the genus ''Thermococcus'' are typically irregularly shaped coccoid species, ranging in size from 0.6 to 2.0 μm in diameter. Some ...

'' S557 and ''

Methanocaldococcus jannaschii ''Methanocaldococcus jannaschii'' (formerly ''Methanococcus jannaschii'') is a thermophilic methanogenic archaean in the class Methanococci. It was the first archaeon to have its complete genome sequenced. The sequencing identified many genes un ...

'', respectively.

Eukaryotic

Fungi

Several anti-infective medications have been derived from fungi including

and the cephalosporins (antibacterial drugs from ''

Penicillium rubens ''Penicillium rubens'' is a species of fungus in the genus ''Penicillium'' and was the first species known to produce the antibiotic penicillin. It was first described by Philibert Melchior Joseph Ehi Biourge in 1923. For the discovery of penici ...

'' and ''

Cephalosporium acremonium ''Acremonium strictum'' is an environmentally widespread saprotroph species found in soil, plant debris, and rotting mushrooms. Isolates have been collected in North and Central America, Asia, Europe and Egypt. ''A. strictum'' is an agent of hya ...

'', respectively) and

griseofulvin Griseofulvin is an antifungal medication used to treat a number of types of dermatophytoses (ringworm). This includes fungal infections of the nails and scalp, as well as the skin when antifungal creams have not worked. It is taken by mouth. C ...

(an antifungal drug from '' Penicillium griseofulvum''). Other medicinally useful fungal

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

s include lovastatin (from '' Pleurotus ostreatus''), which became a lead for a series of drugs that lower

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...

levels, cyclosporin (from '' Tolypocladium inflatum''), which is used to suppress the

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which coul ...

after

organ transplant Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transpor ...

operations, and ergometrine (from '' Claviceps'' spp.), which acts as a

vasoconstrictor Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...

, and is used to prevent bleeding after childbirth. Asperlicin (from '' Aspergillus alliaceus'') is another example. Asperlicin is a novel antagonist of cholecystokinin, a

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...

thought to be involved in panic attacks, and could potentially be used to treat

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

Plants

Plants are a major source of complex and highly structurally diverse chemical compounds (

phytochemicals Phytochemicals are chemical compounds produced by plants, generally to help them resist fungi, bacteria and plant virus infections, and also consumption by insects and other animals. The name comes . Some phytochemicals have been used as pois ...

), this structural diversity attributed in part to the

natural selection Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Cha ...

of organisms producing potent compounds to deter herbivory ( feeding deterrents). Major classes of phytochemical include

phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it r ...

polyphenol Polyphenols () are a large family of naturally occurring organic compounds characterized by multiples of phenol units. They are abundant in plants and structurally diverse. Polyphenols include flavonoids, tannic acid, and ellagitannin, some ...

s, tannins,

terpene Terpenes () are a class of natural products consisting of compounds with the formula (C5H8)n for n > 1. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predominantly by plants, particularly conifers. Terpenes ...

s, and

s. 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 Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical ca ...

and omacetaxine mepesuccinate (from '' Taxus brevifolia'' and ''

Cephalotaxus harringtonii ''Cephalotaxus harringtonia'', commonly known as Japanese plum-yew, Harrington's cephalotaxus, or cowtail pine, is a coniferous bush or small tree in the family Taxaceae. It is native to Japan, but is occasionally utilised in western gardens ...

'', respectively), the antimalarial agent

artemisinin Artemisinin () and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to '' Plasmodium falciparum''. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for h ...

(from ''

Artemisia annua ''Artemisia annua'', also known as sweet wormwood, sweet annie, sweet sagewort, annual mugwort or annual wormwood (), is a common type of wormwood native to temperate Asia, but naturalized in many countries including scattered parts of North Am ...

''), and the acetylcholinesterase inhibitor galantamine (from '' Galanthus'' spp.), used to treat

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

. Other plant-derived drugs, used medicinally and/or recreationally include

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...

quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...

, tubocurarine, muscarine, and

nicotine Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and '' Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is use ...

Animals

Animals also represent a source of bioactive natural products. In particular,

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a st ...

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 cobras). 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. Because of these specific chemical-target interactions, venom constituents have proved important tools for studying receptors,

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...

s, and

s. 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 ''Bothrops jararaca'' — known as the ''jararaca'' or ''yarara'' — is a highly venomous pit viper species endemic to South America in southern Brazil, Paraguay, and northern Argentina. The specific name, ''jararaca'', is derived from the Tu ...

'', was a lead in the development of the

antihypertensive Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests th ...

agents cilazapril and captopril. Also, echistatin, a

disintegrin Disintegrins are a family of small proteins (45–84 amino acids in length) from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion. Operation Disintegrins work by countering the ...

from the venom of the saw-scaled viper ''

Echis carinatus ''Echis carinatus'', known as the saw-scaled viper,Mallow D, Ludwig D, Nilson G (2003). ''True Vipers: Natural History and Toxinology of Old World Vipers''. Malabar, Florida: Krieger Publishing Company. 359 pp. . Indian saw-scaled viper, little I ...

'' was a lead in the development of the antiplatelet drug

tirofiban Tirofiban, sold under the brand name Aggrastat, is an antiplatelet medication. It belongs to a class of antiplatelets named glycoprotein IIb/IIIa inhibitors. Tirofiban is a small molecule inhibitor of the protein-protein interaction between fibri ...

. In addition to the terrestrial animals and

amphibian Amphibians are four-limbed and ectothermic vertebrates of the class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terrestrial, fossorial, arbo ...

s described above, many

animals have been examined for pharmacologically active natural products, with

coral Corals are marine invertebrates within the class Anthozoa of the phylum Cnidaria. They typically form compact colonies of many identical individual polyps. Coral species include the important reef builders that inhabit tropical oceans and se ...

sponges Sponges, the members of the phylum Porifera (; meaning 'pore bearer'), are a basal animal clade as a sister of the diploblasts. They are multicellular organisms that have bodies full of pores and channels allowing water to circulate through t ...

tunicate A tunicate is a marine invertebrate animal, a member of the subphylum Tunicata (). It is part of the Chordata, a phylum which includes all animals with dorsal nerve cords and notochords (including vertebrates). The subphylum was at one t ...

s, sea snails, and

bryozoa Bryozoa (also known as the Polyzoa, Ectoprocta or commonly as moss animals) are a phylum of simple, aquatic invertebrate animals, nearly all living in sedentary colonies. Typically about long, they have a special feeding structure called a ...

ns yielding chemicals with interesting

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

antiviral Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...

, and anticancer activities. Two examples developed for clinical use include ω- conotoxin (from the marine snail '' Conus magus'') and ecteinascidin 743 (from the tunicate ''

Ecteinascidia turbinata ''Ecteinascidia turbinata'', the mangrove tunicate, is a sea squirt species in the genus '' Ecteinascidia'', which was described to science in 1880 by William Abbott Herdman. The cancer drug trabectedin is isolated from ''E. turbinata''. Descrip ...

''). The former, ω-conotoxin, is used to relieve severe and chronic pain, while the latter, ecteinascidin 743 is used to treat metastatic

soft tissue sarcoma A soft-tissue sarcoma (STS) is a malignant tumour, a type of cancer, that develops in soft tissue. A soft tissue sarcoma is often a painless mass that grows slowly over months or years. They may be superficial or deep-seated. Any such unexplained ...

. Other natural products derived from marine animals and under investigation as possible therapies include the antitumour agents discodermolide (from the sponge '' Discodermia dissoluta''), eleutherobin (from the coral '' Erythropodium caribaeorum''), and the bryostatins (from the bryozoan '' Bugula neritina'').

Medical uses

Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases. 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

. Natural product constituents have inspired numerous drug discovery efforts that eventually gained approval as new drugs

Traditional medicine

Indigenous peoples Indigenous peoples are culturally distinct ethnic groups whose members are directly descended from the earliest known inhabitants of a particular geographic region and, to some extent, maintain the language and culture of those original people ...

and

ancient civilizations A civilization (or civilisation) is any complex society characterized by the development of a state, social stratification, urbanization, and symbolic systems of communication beyond natural spoken language (namely, a writing system). Ci ...

experimented with various plant and animal parts to determine what effect they might have. Through trial and error in isolated cases, traditional healers or

shamans Shamanism is a religious practice that involves a practitioner (shaman) interacting with what they believe to be a spirit world through altered states of consciousness, such as trance. The goal of this is usually to direct spirits or spirit ...

found some sources to provide therapeutic effect, representing knowledge of a

crude drug Crude drugs are plant or animal drugs that contain natural substances that have undergone only the processes of collection and drying. The term natural substances refers to those substances found in nature that have not had man-made changes made i ...

that was passed down through generations in such practices as

traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative medical practice drawn from traditional medicine in China. It has been described as "fraught with pseudoscience", with the majority of its treatments having no logical mechanism of acti ...

and

Ayurveda Ayurveda () is an alternative medicine system with historical roots in the Indian subcontinent. The theory and practice of Ayurveda is pseudoscientific. Ayurveda is heavily practiced in India and Nepal, where around 80% of the population rep ...

. Extracts of some natural products led to modern discovery of their active constituents and eventually to the development of new drugs.

Modern natural product-derived drugs

A large number of currently prescribed drugs have been either directly derived from or inspired by natural products. Some of the oldest natural product based drugs are

s. The bark of the

willow Willows, also called sallows and osiers, from the genus ''Salix'', comprise around 400 speciesMabberley, D.J. 1997. The Plant Book, Cambridge University Press #2: Cambridge. of typically deciduous trees and shrubs, found primarily on moist so ...

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 Salicylic acid is an organic compound with the formula HOC6H4CO2H. A colorless, bitter-tasting solid, it is a precursor to and a metabolite of aspirin (acetylsalicylic acid). It is a plant hormone, and has been listed by the EPA Toxic Substa ...

. 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. 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

which acts as an opioid receptor agonist. 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''. A significant number of Infection#Treatments, anti-infectives are based on natural products. The first antibiotic to be discovered,

, was isolated from the mold ''Penicillium''. Penicillin and related beta lactams work by inhibiting DD-transpeptidase enzyme that is required by bacteria to cross link peptidoglycan to form the cell wall. Several natural product drugs target tubulin, which is a component of the

. These include the tubulin polymerization inhibitor colchicine isolated from the ''Colchicum autumnale'' (autumn crocus flowering plant), which is used to treat gout. 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). 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''. 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 (''

'').

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. 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

rates. The biological resource for drug discovery from natural products remains abundant, with small percentages of microorganisms, plant species, and insects assessed for bioactivity. In enormous numbers, bacteria and marine microorganisms remain unexamined. As of 2008, the field of metagenomics was proposed to examine genes and their function in soil microbes, 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.

Isolation and purification

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), 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). 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 crystallizations. 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. Structure determination refers to methods applied to determine the

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. In the modern era, methods focus on mass spectrometry and NMR, nuclear magnetic resonance methods, often multidimensional, and, when feasible, small molecule crystallography. For instance, the

of penicillin was determined by Dorothy Hodgkin, Dorothy Crowfoot Hodgkin in 1945, work for which she later received a Nobel Prize in Chemistry (1964).

Synthesis

Many natural products have very complex chemical structure, 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). 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

, and

proved to be affordably acquired at needed commercial scales solely via isolation procedures (without any significant synthetic chemistry contributing). However, in other cases, needed agents are not available without synthetic chemistry manipulations.

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 Taxus brevifolia, yew tree (''Taxus brevifolia'') would have to be harvested to extract enough

for just a single dose of therapy. Furthermore, the number of structural analogues 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. 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

or ''partial synthesis''. With this approach, the related biosynthetic intermediate is harvested and then converted to the final product by conventional procedures of

. 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. 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.

Total synthesis

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

. 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"). Early efforts in total synthesis, natural products synthesis targeted complex substances such as Vitamin B12, cobalamin (vitamin B₁₂), an essential cofactor (biochemistry), cofactor in cellular

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 C₂, C_s, or C_2v point group identity. C₂ 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, Density functional theoretical (DFT), Hartree–Fock method, Hartree Fock, 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.

Research and teaching

Research and teaching activities related to natural products fall into a number of diverse academic areas, including

, medicinal chemistry,

, ethnobotany, traditional medicine, and ethnopharmacology. Other biological areas include chemical biology, chemical ecology, chemogenomics, systems biology, molecular modeling, chemometrics, and chemoinformatics.

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 of natural products, chemical space. 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, and the challenge of synthesising natural products has led to the development of new synthetic methodology, total synthesis, synthetic strategy, and tactics. 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).

History

Foundations of organic and natural product chemistry

The concept of natural products dates back to the early 19th century, when the foundations of

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''.

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 glycosides. It was long been known that opium, a sticky mixture of alkaloids (including codeine,

, 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. In 1815, Eugène Chevreul isolated

, a crystalline substance, from animal tissue that belongs to the class of steroids, and in 1819 strychnine, an alkaloid was isolated.

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: :

\mathrm

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).

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. 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 isomers, 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. 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.

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

and mannose. After the discovery of

by Alexander Fleming in 1928, fungi and other micro-organisms were added to the arsenal of sources of natural products.

Milestones

By the 1930s, several large classes of natural products were known. Important milestones included: * Terpenes, first systematically studied by Otto Wallach (Nobel Prize 1910) and later by Leopold Ružička (Nobel Prize 1939) * Dyes based on porphins (including chlorophyll and heme), studied by Richard Willstätter (Nobel Prize 1915) and Hans Fischer (Nobel Prize 1930) * Steroids, studied by Heinrich Otto Wieland (Nobel Prize 1927) and Adolf Windaus (Nobel Prize 1928) * Carotenoids, studied by Paul Karrer (Nobel Prize 1937) * Vitamins, 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 * Hormones studied by Adolf Butenandt (Nobel Prize 1939) and Edward Calvin Kendall (Nobel Prize 1950) * Alkaloids and anthocyanins, studied by, among others, Robert Robinson (organic chemist), Robert Robinson (Nobel Prize 1947)

References

External links

* * * {{Authority control Natural products Chemistry Nature

Classes

Function

Primary metabolites

Secondary metabolites

Biosynthesis

Carbohydrates

Fatty acids and polyketides

Sources

Prokaryotic

Bacteria

Archaea

Eukaryotic

Fungi

Plants

Animals

Medical uses

Traditional medicine

Modern natural product-derived drugs

Limiting and enabling factors

Isolation and purification

Synthesis

Semisynthesis

Total synthesis

Symmetry

Research and teaching

Chemistry

History

Foundations of organic and natural product chemistry

Isolation

Synthesis

Structural theories

Expanding the concept

Milestones

See also

Journals

References

Further reading

External links