Natural product

Chemical compound or substance produced by a living organism, found in nature

The anticancer drug paclitaxel is a natural product derived from the yew tree.[1]

A natural product is a natural compound or substance produced by a living organism—that is, found in nature.[2][3] In the broadest sense, natural products include any substance produced by life.[4][5] 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 supplements, and foods produced from natural sources without added artificial ingredients.[6]

Within the field of organic chemistry, the definition of natural products is usually restricted to organic compounds isolated from natural sources that are produced by the pathways of primary or secondary metabolism.[7] Within the field of medicinal chemistry, the definition is often further restricted to secondary metabolites.[8][9] Secondary metabolites (or specialized metabolites) are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage.[10] 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.[11] Secondary or specialized metabolites are often unique to specific species, whereas primary metabolites are commonly found across multiple 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.[12] 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 concerns, seasonal or environmental variability of composition, and loss of sources due to rising extinction rates.[12] Despite this, natural products and their derivatives still accounted for about 10% of new drug approvals between 2017 and 2019.[13]

## Classes

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The broadest definition of natural product is anything that is produced by life,[4][14] and includes the likes of biotic materials (e.g. wood, silk), bio-based materials (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[15][16] and 400,000.[17]

## Function

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Following Albrecht Kossel's original proposal in 1891,[18] natural products are often divided into two major classes, the primary and secondary metabolites.[19][20] 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. For instance, alkaloids like morphine and nicotine act as defense chemicals against herbivores, while flavonoids attract pollinators, and terpenes such as menthol serve to repel insects. Because of their ability to modulate biochemical and signal transduction pathways, some secondary metabolites have useful medicinal properties.[21]

Natural products especially within the field of organic chemistry are often defined as primary and secondary metabolites.[8][9] A more restrictive definition limiting natural products to secondary metabolites is commonly used within the fields of medicinal chemistry and pharmacognosy.[14]

### Primary metabolites

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Molecular building blocks of life Structures of representative primary metabolite vitamins

Main article: Primary metabolite

Primary metabolites, as defined by Kossel, are essential components of basic metabolic pathways required for life. They are associated with fundamental cellular functions such as nutrient assimilation, energy production, and growth and development. These metabolites have a wide distribution across many phyla and often span more than one kingdom. Primary metabolites include the basic building blocks of life: carbohydrates, lipids, amino acids, and nucleic acids.[22]

Primary metabolites involved in energy production include enzymes essential for respiratory and photosynthetic processes. These enzymes are composed of amino acids and often require non-peptidic cofactors for proper function.[23] The basic structures of cells and organisms are also built from primary metabolites, including components such as cell membranes (e.g., phospholipids), cell walls (e.g., peptidoglycan, chitin), and cytoskeletons (proteins).[24]

Enzymatic cofactors that are primary metabolites include several members of the vitamin B family. For instance, Vitamin B1 (thiamine diphosphate), synthesized from 1-deoxy-D-xylulose 5-phosphate, serves as a coenzyme for enzymes such as pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, and transketolase—all involved in carbohydrate metabolism. Vitamin B2 (riboflavin), derived from ribulose 5-phosphate and guanosine triphosphate, is a precursor to FMN and FAD, which are crucial for various redox reactions. Vitamin B3 (nicotinic acid or niacin), synthesized from tryptophan, is an essential part of the coenzymes NAD+ and NADP+, necessary for electron transport in the Krebs cycle, oxidative phosphorylation, and other redox processes. Vitamin B5 (pantothenic acid), derived from α,β-dihydroxyisovalerate (a precursor to valine) and aspartic acid, is a component of coenzyme A, which plays a vital role in carbohydrate and amino acid metabolism, as well as fatty acid biosynthesis. Vitamin B6 (pyridoxol, pyridoxal, and pyridoxamine, originating from erythrose 4-phosphate), functions as pyridoxal 5′-phosphate and acts as a cofactor for enzymes, particularly transaminases, involved in amino acid metabolism. Vitamin B12 (cobalamins) contains a corrin ring structure, similar to porphyrin, and serves as a coenzyme in fatty acid catabolism and methionine synthesis.[25]: Ch. 2

Other primary metabolite vitamins include retinol (vitamin A),[25]: 304–305 synthesized in animals from plant-derived carotenoids via the mevalonate pathway, and ascorbic acid (vitamin C),[25]: 492–493 which is synthesized from glucose in the liver of animals, though not in humans.

DNA and RNA, which store and transmit genetic information, are synthesized from primary metabolites, specifically nucleic acids and carbohydrates.[23]

First messengers are signaling molecules that regulate metabolism and cellular differentiation. These include hormones and growth factors composed of peptides, biogenic amines, steroid hormones, auxins, and gibberellins. These first messengers interact with cellular receptors, which are protein-based, and trigger the activation of second messengers to relay the extracellular signal to intracellular targets. Second messengers often include primary metabolites such as cyclic nucleotides and diacyl glycerol.[26]

### Secondary metabolites

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Main article: Secondary metabolite

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.[27]

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 organisms, agents that solubilize and transport nutrients (siderophores etc.), and competitive weapons (repellants, venoms, toxins etc.) that are used against competitors, prey, and predators.[28] For many other secondary metabolites, the function is unknown. One hypothesis is that they confer a competitive advantage to the organism that produces them.[29] 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.[30]

General structural classes of secondary metabolites include alkaloids, phenylpropanoids, polyketides, and terpenoids.[7]

## Biosynthesis

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Basic building blocks for secondary metabolites derived from primary metabolism.[25]: Ch. 2

The biosynthetic pathways leading to the major classes of natural products are described below.[14][25]: Ch. 2

### Carbohydrates

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Carbohydrates are organic molecules essential for energy storage, structural support, and various biological processes in living organisms. They are produced through photosynthesis in plants or gluconeogenesis in animals and can be converted into larger polysaccharides:[25]: Ch. 8

* Photosynthesis or gluconeogenesis → monosaccharides → polysaccharides (cellulose, chitin, glycogen, etc.)

Carbohydrates serve as a primary energy source for most life forms. Additionally, polysaccharides derived from simpler sugars are vital structural components, forming the cell walls of bacteria[31] and plants.[32][33]

During photosynthesis, plants initially produce 3-phosphoglyceraldehyde, a three-carbon triose.[25]: Ch. 8 This can be converted into glucose (a six-carbon sugar) or various pentoses (five-carbon sugars) through the Calvin cycle. In animals, three-carbon precursors like lactate or glycerol are converted into pyruvate, which can then be synthesized into carbohydrates in the liver.[34]

### Fatty acids and polyketides

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Fatty acid biosynthesis cycle. ACP: acyl carrier protein Enzyme abbreviations: ACC: acetyl-CoA carboxylase; ACS: acyl-CoA synthase; AT: acyltransferase; ER: enoyl reductase; HD: hydroxyacyl dehydratase; KR: ketoacyl reductase; KS: ketoacyl synthase; TE: thioesterase.[35]

Fatty acids and polyketides are synthesized via the acetate pathway, which starts from basic building blocks derived from sugars:[25]: Ch. 3

* Sugars → acetate pathway → fatty acids and polyketides

During glycolysis, sugars are broken down into acetyl-CoA. In an ATP-dependent enzymatic reaction, acetyl-CoA is carboxylated to form malonyl-CoA. Acetyl-CoA and malonyl-CoA then undergo a Claisen condensation, releasing carbon dioxide to form acetoacetyl-CoA which is used by the mevalonate pathway to produce steroids. In fatty acid synthesis, one molecule of acetyl-CoA (the "starter unit") and several molecules of malonyl-CoA (the "extender units") are condensed by fatty acid synthase.[25]: Ch. 3 After each round of elongation, the keto group is reduced, the intermediate alcohol dehydrated, and resulting enoyl-CoAs are reduced to acyl-CoAs. Fatty acids are essential components of lipid bilayers that form cell membranes[36] and serve as energy storage in the form of fat in animals.[37]

The plant-derived fatty acid linoleic acid is converted in animals through elongation and desaturation into arachidonic acid, which is then transformed into various eicosanoids, including leukotrienes, prostaglandins, and thromboxanes. These eicosanoids act as signaling molecules, playing key roles in inflammation and immune responses.[25]: Ch. 3

Alternatively the intermediates from additional condensation reactions are left unreduced to generate poly-β-keto chains, which are subsequently converted into various polyketides.[25]: Ch. 3 The polyketide class of natural products has diverse structures and functions[38] and includes important compounds such as macrolide antibiotics.[39]

### Aromatic amino acids and phenylpropanoids

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The shikimate pathway is a key metabolic route responsible for the production of aromatic amino acids and their derivatives in plants, fungi, bacteria, and some protozoans:[25]: Ch. 4

* Shikimate pathway → aromatic amino acids and phenylpropanoids

The shikimate pathway leads to the biosynthesis of aromatic amino acids (AAAs) — phenylalanine, tyrosine, and tryptophan.[40][41] This pathway is vital as it connects primary metabolism to specialized metabolic processes, directing an estimated 20-50% of all fixed carbon through its reactions.[40][42] It begins with the condensation of phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P), leading through several enzymatic steps to form chorismate, the precursor for all three AAAs.[41][43]

From chorismate, biosynthesis branches out to produce the individual AAAs. In plants, unlike in bacteria, the production of phenylalanine and tyrosine typically occurs via the intermediate arogenate.[43] Phenylalanine serves as the starting point for the phenylpropanoid pathway, which leads to a diverse array of secondary metabolites.[43]

Beyond protein synthesis, AAAs and their derivatives have crucial roles in plant physiology, including pigment production, hormone synthesis, cell wall formation, and defense against various stresses.[40][41] Because animals cannot synthesize these amino acids, the shikimate pathway has also become a target for herbicides, most notably glyphosate, which inhibits one of the key enzymes in this pathway.[40][42]

### Terpenoids and steroids

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Terpenoid and steroid biosynthesis[25]: Ch. 5

The biosynthesis of terpenoids and steroids involves two primary pathways, which produce essential building blocks for these compounds:[25]: Ch. 5

* Mevalonate pathway and methylerythritol phosphate pathway → terpenoids and steroids

The mevalonate (MVA) and methylerythritol phosphate (MEP) pathways produce the five-carbon units isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are the building blocks for all terpenoids.[44][45]

The MVA pathway, discovered in the 1950s, functions in eukaryotes, some bacteria, and plants. It converts acetyl-CoA to IPP via HMG-CoA and mevalonate, and is essential for steroid biosynthesis. Statins, which lower cholesterol, work by inhibiting HMG-CoA reductase in this pathway.[44][45] The MEP pathway, found in bacteria, some parasites, and plant chloroplasts, starts with pyruvate and glyceraldehyde 3-phosphate to produce IPP and DMAPP. This pathway is crucial for the synthesis of plastid terpenoids like carotenoids and chlorophylls.[46][47] Both pathways converge at IPP and DMAPP, which combine to form longer prenyl diphosphates like geranyl (C10), farnesyl (C15), and geranylgeranyl (C20).[44] These compounds serve as precursors for a wide range of terpenoids, including monoterpenes, sesquiterpenes, and triterpenes.[45]

The diversity of terpenoids arises from modifications such as cyclization, oxidation, and glycosylation, enabling them to play roles in plant defense, pollinator attraction, and signaling.[48] Steroids, primarily synthesized via the MVA pathway, are derived from farnesyl diphosphate through intermediates like squalene and lanosterol, which are precursors to cholesterol and other steroid molecules.[45]

### Alkaloids

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Biosynthesis of the alkaloid cocaine depicting four key steps (labeled 1-4)[49]

Alkaloids are nitrogen-containing organic compounds produced by plants through complex biosynthetic pathways, starting from amino acids. The biosynthesis of alkaloids from amino acids is essential for producing many biologically active compounds in plants. These compounds range from simple cycloaliphatic amines to complex polycyclic nitrogen heterocycles.[50][25]: Ch. 6

Alkaloid biosynthesis generally follows four key steps: (i) synthesis of an amine precursor, (ii) synthesis of an aldehyde precursor, (iii) formation of an iminium cation, and (iv) a Mannich-like reaction. These steps form the core structure of many alkaloids and represent the initial committed steps in their production.[51] Amino acids such as tryptophan, tyrosine, lysine, arginine, and ornithine serve as essential precursors. Their accumulation is facilitated by mechanisms like increased gene expression, gene duplication, or the evolution of enzymes with broader substrate specificities.[51] The biosynthesis of the tropane alkaloid cocaine follows this general pathway.[49]

A key reaction in alkaloid biosynthesis is the Pictet-Spengler reaction, which is crucial for forming the β-carboline structure found in many alkaloids. This reaction involves the condensation of an aldehyde with an amine, as seen in the biosynthesis of strictosidine, a precursor to numerous monoterpene indole alkaloids.[52]

Oxidoreductases, including cytochrome P450s and flavin-containing monooxygenases, play a vital role in modifying the core alkaloid structures through oxidation, contributing to their structural diversity and bioactivity. For instance, in the biosynthesis of morphine, oxidative coupling is essential for forming the complex polycyclic structures typical of these alkaloids.[50] The biosynthetic pathways of alkaloids involve numerous enzymatic steps. For example, tropane alkaloids, derived from ornithine, undergo processes such as decarboxylation, oxidation, and cyclization. Similarly, the biosynthesis of isoquinoline alkaloids from tyrosine involves complex transformations, including the formation of (S)-reticuline, a key intermediate in the pathway.[50]

### Peptides, proteins, and other amino acid derivatives

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Biosynthesis of peptides, proteins, and other amino acid derivatives assembles amino acids into biologically active molecules, producing compounds like peptide hormones, modified peptides, and plant-derived substances.[25]: Ch. 8

Peptides and proteins are synthesized through protein synthesis or translation, a process involving transcription of DNA into messenger RNA (mRNA). The mRNA serves as a template for protein assembly on ribosomes. During translation, transfer RNA (tRNA) carries specific amino acids to match with mRNA codons, forming peptide bonds to create the protein chain.

Peptide hormones, such as oxytocin and vasopressin, are short amino acid chains that regulate physiological processes, including social bonding and water retention.[53] Modified peptides include antibiotics like penicillins and cephalosporins, characterized by their β-lactam ring structure, which is essential for their antibacterial activity.[54] These compounds undergo complex enzymatic modifications during biosynthesis.[55]

Cyanogenic glycosides are amino acid derivatives in plants that can release hydrogen cyanide when tissues are damaged, serving as a defense mechanism.[56] Their biosynthesis involves converting amino acids into cyanohydrins, which are then glycosylated.[57] Glucosinolates are sulfur-containing compounds in cruciferous vegetables like broccoli and mustard. Their biosynthesis starts with amino acids such as methionine or tryptophan and involves adding sulfur and glucose groups.[58] When tissues are damaged, glucosinolates break down into isothiocyanates, which contribute to the pungent flavors of these vegetables and offer potential health benefits.[58]

## Sources

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Natural products may be extracted from the cells, tissues, and secretions of microorganisms, plants and animals.[59][60] 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.[59][60]

Pharmacognosy 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 (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 and safety.[61][62] In this and related ways, modern medicines can be developed directly from natural sources.[63]

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.[64] Because natural products are generally secondary metabolites with complex chemical structures, 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.[65]

### Prokaryotic

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#### Bacteria

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Botulinum toxin types A and B (Botox, Dysport, Xeomin, MyoBloc), used both medicinally and cosmetically, are natural products from the bacterium Clostridium botulinum.[66]

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.[67] 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 spp.),[68] the polymyxins (from Paenibacillus polymyxa),[69] and the rifamycins (from Amycolatopsis rifamycinica).[70] Antiparasitic and antiviral drugs have similarly been derived from bacterial metabolites.[71]

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.[66] Also, the glycopeptide bleomycin is used for the treatment of several cancers including Hodgkin's lymphoma, head and neck cancer, and testicular cancer.[72] 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,[73] subterranean bacteria found deep underground via mining/drilling,[74][75] and marine bacteria.[76]

#### Archaea

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Because many Archaea have adapted to life in extreme environments such as polar regions, 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, chemical, and 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 amylases, pullulanases, cyclodextrin glycosyltransferases, cellulases, xylanases, chitinases, proteases, alcohol dehydrogenase, and esterases.[77] Archaea represent a source of novel chemical compounds also, for example isoprenyl glycerol ethers 1 and 2 from Thermococcus S557 and Methanocaldococcus jannaschii, respectively.[78]

### Eukaryotic

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#### Fungi

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The antibiotic penicillin is a natural product derived from the fungus Penicillium rubens.[79]

Several anti-infective medications have been derived from fungi including penicillin and the cephalosporins (antibacterial drugs from Penicillium rubens and Cephalosporium acremonium, respectively)[79][67] and griseofulvin (an antifungal drug from Penicillium griseofulvum).[80] Other medicinally useful fungal metabolites 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.[25]: 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.[81]

#### Plants

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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 (phytochemicals), this structural diversity attributed in part to the natural selection of organisms producing potent compounds to deter herbivory (feeding deterrents).[82] Major classes of phytochemical include phenols, polyphenols, tannins, terpenes, and alkaloids.[83] 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),[84] the antimalarial agent artemisinin (from Artemisia annua),[85] and the acetylcholinesterase inhibitor galantamine (from Galanthus spp.), used to treat Alzheimer's disease.[86] Other plant-derived drugs, used medicinally and/or recreationally include morphine, cocaine, quinine, tubocurarine, muscarine, and nicotine.[25]: Ch. 6

#### Animals

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The analgesic drug ω-conotoxin (ziconotide) is a natural product derived from the sea snail Conus magus.[87]

Animals also represent a source of bioactive natural products. In particular, venomous 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).[88][89] 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.[89]

Because of these specific chemical-target interactions, venom constituents have proved important tools for studying receptors, ion channels, 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.[89] 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.[90]

In addition to the terrestrial animals and amphibians described above, many marine animals have been examined for pharmacologically active natural products, with corals, sponges, tunicates, sea snails, and bryozoans yielding chemicals with interesting analgesic, antiviral, and anticancer activities.[91] Two examples developed for clinical use include ω-conotoxin (from the marine snail Conus magus)[92][87] and ecteinascidin 743 (from the tunicate Ecteinascidia turbinata).[93] The former, ω-conotoxin, is used to relieve severe and chronic pain,[87][92] while the latter, ecteinascidin 743 is used to treat metastatic soft tissue sarcoma.[94] Other natural products derived from marine animals and under investigation as possible therapies include the antitumour agents discodermolide (from the sponge Discodermia dissoluta),[95] eleutherobin (from the coral Erythropodium caribaeorum), and the bryostatins (from the bryozoan Bugula neritina).[95]

## Medical uses

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Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases.[96][97][98] 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.[99][100]

Representative examples of drugs based on natural products

### Modern natural product-derived drugs

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Many prescribed drugs have been either directly derived from or inspired by natural products.[1][101] Approximately 35% of the annual global market of medicine is either from natural products or related drugs.[102] This breaks down as 25% from plants, 13% from microorganisms, and 3% from animal sources.[102]

Between 1981 and 2019, the FDA approved 1,881 new chemical entities, of which 65 (3.5%) were unaltered natural products, 99 (5.3%) were defined mixture botanical drugs, 178 (9.5%) were natural product derivatives, and 164 (8.7%) were synthetic compounds containing natural product pharmacophores. Altogether, this accounts for 506 (26.9%) of all new approved drugs.[13] Additionally, natural products and their derivatives often show higher success rates in later clinical trial phases and may have lower toxicity profiles compared to synthetic compounds.[103]

Some of the oldest natural product based drugs are analgesics. The bark of the willow tree has been known since antiquity to have pain-relieving properties due to 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.[104] Another notable example is opium extracted from the latex of Papaver somniferous (a flowering poppy plant). The most potent narcotic component of opium is the alkaloid morphine, which acts as an opioid receptor agonist.[105] The N-type calcium channel blocker ziconotide is an analgesic based on a cyclic peptide cone snail toxin (ω-conotoxin MVIIA) from the species Conus magus.[106]

Numerous anti-infectives are based on natural products.[60] The first antibiotic to be discovered, penicillin, was isolated from the mold Penicillium. Penicillin and related beta lactams work by inhibiting the DD-transpeptidase enzyme that is required by bacteria to cross link peptidoglycan to form the cell wall.[107]

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.[108] 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).[109]

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.[110] 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).[111]

### Limiting and enabling factors

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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.[12][112] 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.[12][112]

The biological resource for drug discovery from natural products remains abundant, with small percentages of microorganisms, plant species, and insects assessed for bioactivity.[12] In enormous numbers, bacteria and marine microorganisms remain unexamined.[113][114] As of 2008, the field of metagenomics was proposed to examine genes and their function in soil microbes,[114][115] 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.[12]

## Isolation and purification

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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,[a] and others, Fleming recognized the antibacterial activity and clinical potential of "pen G", but was unable to purify or stabilize it.[116] Developments in chromatographic separations and freeze drying helped move progress forward in the production of commercial quantities of penicillin and other natural products.[117]

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.[112] 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,[118][119][120]

Structure determination refers to methods applied to determine the chemical structure of an isolated, pure natural product. For instance, the chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in 1945, work for which she later received a Nobel Prize in Chemistry (1964).[121]

Modern structure determination often involves a combination of advanced analytical techniques. Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography are commonly used as primary tools for structure elucidation. High-resolution tandem mass spectrometry (MS/MS) also plays a crucial role, providing information on molecular formula and fragmentation patterns. For complex structures, computational methods are increasingly employed to assist in structure determination. This may include computer-assisted structure elucidation (CASE) platforms and in silico fragmentation prediction tools. Determination of the absolute configuration often relies on a combination of NMR data (coupling constants and nuclear Overhauser effect (NOE), chemical derivatization methods (e.g., Mosher's ester analysis), and spectroscopic techniques like vibrational circular dichroism (VCD), and optical rotatory dispersion (ORD). In cases where traditional methods are insufficient, especially for novel compounds with unprecedented molecular skeletons, advanced computational chemistry approaches are used to predict and compare spectral data, helping to elucidate the complete structure including stereochemistry.[122]

## Synthesis

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Many natural products have complex structures. The complexity is determined by factors like molecular mass, arrangement of substructures (e.g., functional groups, rings), number and density of these groups, their stability, stereochemical elements, and physical properties, as well as the novelty of the structure and prior synthetic efforts.[123]

Less complex natural products can often be cost-effectively synthesized from simpler chemical ingredients through total synthesis. However, not all natural products are suitable for total synthesis. The most complex ones are often impractical to synthesize on a large scale due to high costs. In these cases, isolation from natural sources may be sufficient if it provides adequate quantities, as seen with drugs like penicillin, morphine, and paclitaxel, which were obtained at commercial scales without significant synthetic chemistry.[123]

### Semisynthesis

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Main article: Semisynthesis

Isolating a natural product from its source can be costly in terms of time and materials, and may impact the availability of the natural resource or have ecological consequences. For example, it is estimated that harvesting enough paclitaxel for a single dose of therapy would require the bark of an entire yew tree (Taxus brevifolia).[124] Additionally, the number of structural analogues available for structure–activity analysis (SAR) is limited by the biology of the organism, and thus beyond experimental control.[125]

When the desired product is difficult to obtain or modify to create analogs, a middle-to-late stage biosynthetic precursor or analog can sometimes be used to produce the final target. This approach, called semisynthesis or partial synthesis, involves extracting a biosynthetic intermediate and converting it into the final product using conventional chemical synthesis techniques.[125]

This strategy offers two advantages. First, the intermediate may be easier to extract and yield higher amounts than the final product. For instance, paclitaxel can be produced by extracting 10-deacetylbaccatin III from T. brevifolia needles, followed by a four-step synthesis.[126] Second, the semisynthetic process allows for the creation of analogues of the final product, as seen in the development of newer generation semisynthetic penicillins.[127]

### Total synthesis

[edit]

Main article: Total synthesis

Structural representation of cobalamin, a natural product isolated and structurally characterized.[128] The variable R group can be a methyl or 5'-adenosyl group, or a cyanide or hydroxide anion. The "proof" by synthesis of vitamin B12 was accomplished in 1972 by the groups of Robert Burns Woodward[129] and Albert Eschenmoser.[130]

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.[131][132] 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").[133] Early efforts in natural products synthesis targeted complex substances such as cobalamin (vitamin B12), an essential cofactor in cellular metabolism.[129][130]

### Biomimetic synthesis

[edit]

Main article: Biomimetic synthesis

Biomimetic synthesis is a branch of organic chemistry which aims at designing and preparing natural product compounds in the laboratory using the biosynthetic pathways as a blueprint. This method is based on the mechanisms used by the living organisms for the synthesis of various compounds, which is usually done in a stereoselective and regioselective manner.[134] Biomimetic synthetic strategies have emerged due to their ability to simplify the synthesis of complex structures, especially those containing unusual moieties like spiro-ring systems or quaternary carbon atoms.[135] These approaches mainly involve reactions such as Diels-Alder dimerizations, photocycloadditions, cyclizations, oxidative and radical reactions and these reactions can be used to efficiently construct complex molecular frameworks. Thus, mimicking the biosynthetic processes, chemists have been able to design more effective and economical processes for the synthesis of natural products that are of interest in drug discovery and chemical biology.[134][135]

### Symmetry

[edit]

Examination of dimerized and 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, Cs, or C2v 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 (DFT), the Hartree–Fock method, and 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.[136]

## Research and teaching

[edit]

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,[137] systems biology, molecular modeling, chemometrics, and chemoinformatics.[138]

### Chemistry

[edit]

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 chemical space.[139] To achieve this, many technological advances have been made, such as the evolution of technology associated with 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,[140][141][142] and the challenge of synthesising natural products has led to the development of new synthetic methodology, synthetic strategy, and tactics.[143] 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–Miyaura cross-coupling reactions).[144]

## History

[edit]

Antoine Lavoisier (1743–1794) Friedrich Wöhler (1800–1882) Hermann Emil Fischer (1852–1919)

### Foundations of organic and natural product chemistry

[edit]

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.[145]

### Isolation

[edit]

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, 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.[146] In 1815, Eugène Chevreul isolated cholesterol, a crystalline substance, from animal tissue that belongs to the class of steroids,[147] and in 1819 strychnine, an alkaloid was isolated.[148]

### Synthesis

[edit]

A second important step was the synthesis of organic compounds. While the synthesis of inorganic substances had been known for a long time, creating organic substances was a major challenge. In 1827, the Swedish chemist Jöns Jacob Berzelius argued that a vital force or life force was essential for synthesizing organic compounds. This idea, known as vitalism, had many supporters well into the 19th century, even after the introduction of atomic theory. Vitalism also aligned with traditional medicine, which often viewed disease as a result of imbalances in vital energies that distinguish life from nonlife.

The first significant challenge to vitalism came in 1828 when German chemist Friedrich Wöhler synthesized urea, a natural product found in urine, by heating ammonium cyanate, an inorganic substance:[149]

N H 4 O C N -> 60 ∘ C H 2 N C O N H 2 {\displaystyle \mathrm {NH_{4}OCN\ {\xrightarrow {\ \ 60^{\circ }C\ \ }}\ H_{2}NCONH_{2}} }

This reaction demonstrated that a life force was not needed to create organic substances. Initially, this idea faced skepticism, but it gained acceptance 20 years later when Adolph Wilhelm Hermann Kolbe synthesized acetic acid from carbon disulfide.[150] Since then, organic chemistry has developed into a distinct field focused on studying carbon-containing compounds, which were found to be prevalent in nature.

### Structural theories

[edit]

The third key development was the structure elucidation of organic substances. While the elemental composition of pure organic compounds could be determined accurately, their molecular structures remained unclear. This issue became evident in a dispute between Friedrich Wöhler and Justus von Liebig, who studied silver salts with identical compositions but different properties. Wöhler examined silver cyanate, a harmless compound, while von Liebig investigated the explosive silver fulminate.[151] Elemental analysis showed both salts had the same amounts of silver, carbon, oxygen, and nitrogen, yet their properties differed, contradicting the prevailing view that composition alone determined properties.

This discrepancy was explained by Berzelius's theory of isomers, which proposed that not only the number and type of elements but also the arrangement of atoms affects a compound's properties. This insight led to the development of structural theories, such as the radical theory of Jean-Baptiste Dumas and the substitution theory of Auguste Laurent.[152][153] A definitive structure theory was proposed in 1858 by August Kekulé, who suggested that carbon is tetravalent and can bond to itself, forming chains found in natural products.[154][153]

### Expanding the concept

[edit]

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.[146]

### Milestones

[edit]

By the 1930s, several major classes of natural products had been identified and studied extensively. Key milestones in the field of natural product research include:[146]

* Terpenes: First systematically studied by Otto Wallach (Nobel Prize 1910)[155] and later by Leopold Ružička (Nobel Prize 1939).
* Porphyrin-based dyes: Including chlorophyll and heme, investigated by Richard Willstätter (Nobel Prize 1915) and Hans Fischer (Nobel Prize 1930). These tetrapyrrole compounds play essential roles in various biological processes (including photosynthesis, respiration, electron transfer, and catalysis) and have been the subject of extensive research.[156]
* Steroids: Researched by Heinrich Otto Wieland (Nobel Prize 1927) and Adolf Windaus (Nobel Prize 1928). Their work contributed significantly to our understanding of sterol biosynthesis and structure.[157]
* Carotenoids: Studied by Paul Karrer (Nobel Prize 1937). These pigments are important for their antioxidant properties and roles in photosynthesis and vision.[158]
* Vitamins: Investigated by numerous scientists, including Paul Karrer, Robert R. Williams, Adolf Windaus (Nobel Prize 1928), Norman Haworth (Nobel Prize 1937), Richard Kuhn (Nobel Prize 1938), and Albert Szent-Györgyi (Nobel Prize 1937). The discovery and characterization of vitamins revolutionized our understanding of nutrition and health.[159]
* Steroid hormones: Studied by Adolf Butenandt (Nobel Prize 1939) and Edward Calvin Kendall (Nobel Prize 1950). Their work on steroid hormones paved the way for modern endocrinology.[160]
* Alkaloids and anthocyanins: Researched by Robert Robinson (Nobel Prize 1947) and others. These compounds, particularly alkaloids, have been crucial in the development of many pharmaceuticals.
* Polypeptide hormones: Investigated by Vincent du Vigneaud (Nobel Prize 1955) who completed the first total synthesis of the natural polypeptide oxytocin and vasopressin.[161]
* Total synthesis of natural products: Robert Burns Woodward was awarded a Nobel Prize in 1965 for synthesizing compounds including quinine, cholesterol, cortisone, strychnine, reserpine, chlorophyll, and vitamin B12. Elias James Corey received a Nobel Prize in 1990 for similar achievements, such as the synthesis of gibberellic acid, ginkgolide, and prostaglandins.

These pioneering studies laid the foundation for our understanding of natural product chemistry and biochemistry,[162] leading to numerous Nobel Prizes in Chemistry and Physiology or Medicine. The field of natural products has continued to evolve, with recent research focusing on the evolutionary and ecological roles of these compounds.[30]

## See also

[edit]

* Biogenic substance
* Pharmacognosy
* Phytotherapy

### Journals

[edit]

* Chemistry of Natural Compounds
* Journal of Natural Products
* Natural Product Reports
* Natural Product Research

## References

[edit]

Footnotes

1. ^ These three named scientists shared the 1945 Nobel Prize in Medicine for the work.

Citations

1. ^ a b Cutler S, Cutler HG (2000). Biologically Active Natural Products: Pharmaceuticals. CRC Press. p. 5\. ISBN 978-0-8493-1887-0.
2. ^ Webster's Revised Unabridged Dictionary (1913). "Natural product". Free Online Dictionary and C. & G. Merriam Co. "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."
3. ^ "All natural". Nature Chemical Biology. 3 (7): 351. July 2007. doi:10.1038/nchembio0707-351. PMID 17576412. "The simplest definition for a natural product is a small molecule that is produced by a biological source."
4. ^ a b Samuelson G (1999). Drugs of Natural Origin: A Textbook of Pharmacognosy. Taylor & Francis Ltd. ISBN 978-91-86274-81-8.
5. ^ National Center for Complementary and Integrative Health (13 July 2013). "Natural Products Research—Information for Researchers | NCCIH". U.S. Department of Health & Human Services. Archived from the original on 5 April 2015. "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."
6. ^ "About Us". Natural Products Foundation. Retrieved 7 December 2013. "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."
7. ^ a b Hanson JR (2003). "The Classes of Natural Product and Their Isolation". Natural Products: the Secondary Metabolite. Cambridge: Royal Society of Chemistry. p. 1\. ISBN 0-85404-490-6. "Natural products are organic compounds that are formed by living systems."
8. ^ a b "Natural Products". Stedman's Medical Dictionary. Lippincott Williams & Wilkins. Archived from the original on 3 August 2016. Retrieved 7 December 2013. "Natural products: naturally occurring compounds that are end products of secondary metabolism; often, they are unique compounds for particular organisms or classes of organisms."
9. ^ a b Williams DA, Lemke TL (2002). "Chapter 1: Natural Products". Foye's Principles of Medicinal Chemistry (5th ed.). Philadelphia: Lippincott Williams Wilkins. p. 25\. ISBN 0-683-30737-1. "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)."
10. ^ Maplestone RA, Stone MJ, Williams DH (June 1992). "The evolutionary role of secondary metabolites—a review". Gene. 115 (1–2): 151–157\. doi:10.1016/0378-1119(92)90553-2. PMID 1612430.1–2&rft.pages=151-157&rft.date=1992-06&rft_id=info:doi/10.1016/0378-1119(92)90553-2&rft_id=info:pmid/1612430&rft.aulast=Maplestone&rft.aufirst=RA&rft.au=Stone,+MJ&rft.au=Williams,+DH&rfr_id=info:sid/en.wikipedia.org:Natural+product" class="Z3988">
11. ^ Hunter P (September 2008). "Harnessing Nature's wisdom. Turning to Nature for inspiration and avoiding her follies". EMBO Reports. 9 (9): 838–840\. doi:10.1038/embor.2008.160. PMC 2529361. PMID 18762775.
12. ^ a b c d e f Li JW, Vederas JC (July 2009). "Drug discovery and natural products: end of an era or an endless frontier?". Science. 325 (5937): 161–165\. Bibcode:2009Sci...325..161L. doi:10.1126/science.1168243. PMID 19589993. S2CID 207777087.
13. ^ a b Newman DJ, Cragg GM (March 2020). "Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019". Journal of Natural Products. 83 (3): 770–803\. doi:10.1021/acs.jnatprod.9b01285. PMID 32162523. "Figure 1. All new approved drugs 01JAN81 to 30SEP19; n = 1881. Figure 9. N/NB/ND & S* categories 01JAN81 to 30SEP19, n = 506." Natural products represent 100*(506/1881) = 27% of new drug approvals from 01JAN81 to 30SEP19. From Figure 9, the percentage was ~10% for 2017-2019.
14. ^ a b c Bhat SV, Nagasampagi BA, Sivakumar M (2005). Chemistry of Natural Products. Berlin; New York: Springer. ISBN 978-3-540-40669-3.
15. ^ Rutz A, Sorokina M, Galgonek J, Mietchen D, Willighagen E, Gaudry A, et al. (May 2022). "The LOTUS initiative for open knowledge management in natural products research". eLife. 11: e70780. doi:10.7554/eLife.70780. PMC 9135406. PMID 35616633.
16. ^ Banerjee P, Erehman J, Gohlke BO, Wilhelm T, Preissner R, Dunkel M (January 2015). "Super Natural II--a database of natural products". Nucleic Acids Research. 43 (Database issue): D935 – D939. doi:10.1093/nar/gku886. PMC 4384003. PMID 25300487.
17. ^ Sorokina M, Steinbeck C (April 2020). "Review on natural products databases: where to find data in 2020". Journal of Cheminformatics. 12 (1) 20. doi:10.1186/s13321-020-00424-9. PMC 7118820. PMID 33431011.
18. ^ Kossel A (1891). "Ueber die chemische Zusammensetzung der Zelle" [The chemical composition of the cell]. Archiv für Physiologie (in German): 181–186.
19. ^ Kliebenstein DJ (2004). "Secondary metabolites and plant/environment interactions: a view through Arabidopsis thaliana tinged glasses". Plant, Cell and Environment. 27 (6): 675–684\. Bibcode:2004PCEnv..27..675K. doi:10.1111/j.1365-3040.2004.01180.x. "In 1891, following Stahls work on plant biochemistry, Kossel suggested a distinction between basic and secondary metabolism (Stahl 1888)."
20. ^ Karlovsky P (2008). "Secondary Metabolites in Soil Ecology". Soil Biology. Vol. 14\. pp. 1–19\. doi:10.1007/978-3-540-74543-3_1. ISBN 978-3-540-74542-6. "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."
21. ^ Wink M (September 2015). "Modes of Action of Herbal Medicines and Plant Secondary Metabolites". Medicines. 2 (3): 251–286\. doi:10.3390/medicines2030251. PMC 5456217. PMID 28930211.
22. ^ Rogers K (2011). The Components of Life: From Nucleic Acids to Carbohydrates (1st ed.). New York, NY: Britannica Educational Publishing in association with Rosen Educational Services. ISBN 978-1-61530-324-3.
23. ^ a b Cox DL, Nelson MM (2013). Lehninger Principles of Biochemistry (6th ed.). New York, N.Y.: W.H. Freeman. ISBN 978-1-4641-0962-1.
24. ^ Boal D (2006). Mechanics of the Cell (4th printing ed.). Cambridge, UK: Cambridge University Press. ISBN 978-0-521-79681-1.
25. ^ a b c d e f g h i j k l m n o p q r Dewick PM (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). Chichester: Wiley. ISBN 978-0-470-74167-2.
26. ^ Sitaramayya A (1999). Introduction to Cellular Signal Transduction. Boston: Birkhäuser. ISBN 978-0-8176-3982-2.
27. ^ Herbert RB (1981). "Introduction". The Biosynthesis of Secondary Metabolites. Dordrecht: Springer Netherlands. pp. 1–2\. ISBN 94-009-5833-1. "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."
28. ^ Demain AL, Fang A (2000). "The natural functions of secondary metabolites". History of Modern Biotechnology I. Advances in Biochemical Engineering/Biotechnology. Vol. 69\. pp. 1–39\. doi:10.1007/3-540-44964-7_1. ISBN 978-3-540-67793-2. PMID 11036689.
29. ^ Williams DH, Stone MJ, Hauck PR, Rahman SK (1989). "Why are secondary metabolites (natural products) biosynthesized?". Journal of Natural Products. 52 (6): 1189–1208\. doi:10.1021/np50066a001. PMID 2693613.
30. ^ a b Firn RD, Jones CG (September 2000). "The evolution of secondary metabolism - a unifying model" (PDF). Molecular Microbiology. 37 (5): 989–994\. doi:10.1046/j.1365-2958.2000.02098.x. PMID 10972818. S2CID 3827335.
31. ^ van Heijenoort J (March 2001). "Formation of the glycan chains in the synthesis of bacterial peptidoglycan". Glycobiology. 11 (3): 25R – 36R. doi:10.1093/glycob/11.3.25r. PMID 11320055.
32. ^ Cosgrove DJ (November 2005). "Growth of the plant cell wall". Nature Reviews. Molecular Cell Biology. 6 (11): 850–61\. doi:10.1038/nrm1746. PMID 16261190.
33. ^ Seltmann G, Holst O (2013). "Further Cell Wall Components of Gram-Positive Bacteria". The Bacterial Cell Wall. Berlin Heidelberg: Springer. pp. 133–161\. ISBN 978-3-662-04878-8.
34. ^ Rui L (January 2014). "Energy metabolism in the liver". Comprehensive Physiology. 4 (1): 177–97\. doi:10.1002/cphy.c130024. ISBN 978-0-470-65071-4. PMC 4050641. PMID 24692138.
35. ^ Reilly P (2024). "Biosynthesis of Fatty Acids". AOCS Lipid Library. The American Oil Chemists' Society (AOCS).; Cantu DC, Chen Y, Lemons ML, Reilly PJ (January 2011). "ThYme: a database for thioester-active enzymes". Nucleic Acids Research. 39 (Database issue): D342 – D346. doi:10.1093/nar/gkq1072. PMC 3013676. PMID 21045059.
36. ^ Cooper GM (2000). "Cell Membranes". The Cell: A Molecular Approach (2nd ed.). Sinauer Associates. ISBN 978-1-60535-746-1.
37. ^ Young RA (November 1976). "Fat, energy and mammalian survival". American Zoologist. 16 (4): 699–710\. doi:10.1093/icb/16.4.699. "Adipose tissue plays a critical role in mammalian life history strategies, serving as an organ for the storage of food and energy, as a source of heat and water, and as thermal insulation."
38. ^ Rimando AM, Baerson SR, eds. (2007). Polyketides: biosynthesis, biological activity, and genetic engineering. Washington, DC: American Chemical Society. ISBN 978-0-8412-3978-4.
39. ^ Risdian C, Mozef T, Wink J (May 2019). "Biosynthesis of Polyketides in Streptomyces". Microorganisms. 7 (5): 124. doi:10.3390/microorganisms7050124. PMC 6560455. PMID 31064143.
40. ^ a b c d Tohge T, Watanabe M, Hoefgen R, Fernie AR (2013). "Shikimate and phenylalanine biosynthesis in the green lineage". Frontiers in Plant Science. 4: 62. doi:10.3389/fpls.2013.00062. PMC 3608921. PMID 23543266.
41. ^ a b c Maeda H, Dudareva N (2012). "The shikimate pathway and aromatic amino Acid biosynthesis in plants". Annual Review of Plant Biology. 63: 73–105\. doi:10.1146/annurev-arplant-042811-105439. PMID 22554242.
42. ^ a b Tzin V, Galili G, Aharoni A (August 2012). "Shikimate pathway and aromatic amino acid biosynthesis". eLS. 8: 32.
43. ^ a b c Peled-Zehavi H, Oliva M, Xie Q, Tzin V, Oren-Shamir M, Aharoni A, et al. (November 2015). "Metabolic Engineering of the Phenylpropanoid and Its Primary, Precursor Pathway to Enhance the Flavor of Fruits and the Aroma of Flowers". Bioengineering. 2 (4). Basel, Switzerland: 204–212\. doi:10.3390/bioengineering2040204. PMC 5597090. PMID 28952478.
44. ^ a b c Bergman ME, Davis B, Phillips MA (November 2019). "Medically Useful Plant Terpenoids: Biosynthesis, Occurrence, and Mechanism of Action". Molecules. 24 (21): 3961. doi:10.3390/molecules24213961. PMC 6864776. PMID 31683764.
45. ^ a b c d Rinner U. "The mevalonate and methylerythritol phosphate pathway" (PDF). Universität Wien.
46. ^ Kuzuyama T (July 2017). "Biosynthetic studies on terpenoids produced by Streptomyces". The Journal of Antibiotics. 70 (7): 811–818\. doi:10.1038/ja.2017.12. PMC 5509993. PMID 28196976.
47. ^ Perez-Gil J, Behrendorff J, Douw A, Vickers CE (June 2024). "The methylerythritol phosphate pathway as an oxidative stress sense and response system". Nature Communications. 15 (1) 5303. Bibcode:2024NatCo..15.5303P. doi:10.1038/s41467-024-49483-8. PMC 11192765. PMID 38906898.
48. ^ Dewick PM (2009). "The mevalonate and methylerythritol phosphate pathways: Terpenoids and steroids.". Medicinal Natural Products. pp. 187–310\. doi:10.1039/9781837671472-00077. ISBN 978-1-83767-045-1.
49. ^ a b Chavez BG, Leite Dias S, D'Auria JC (October 2024). "The evolution of tropane alkaloids: Coca does it differently". Current Opinion in Plant Biology. 81 102606\. Bibcode:2024COPB...8102606C. doi:10.1016/j.pbi.2024.102606. PMID 39067083.
50. ^ a b c Morrow GW (2016). "Biosynthesis of Alkaloids and Related Compounds.". Bioorganic Synthesis. Oxford University Press. doi:10.1093/oso/9780199860531.003.0010. ISBN 978-0-19-756322-9.
51. ^ a b Lichman BR (January 2021). "The scaffold-forming steps of plant alkaloid biosynthesis". Natural Product Reports. 38 (1): 103–129\. doi:10.1039/d0np00031k. PMID 32745157.
52. ^ Kishimoto S, Sato M, Tsunematsu Y, Watanabe K (August 2016). "Evaluation of Biosynthetic Pathway and Engineered Biosynthesis of Alkaloids". Molecules. 21 (8): 1078. doi:10.3390/molecules21081078. PMC 6274189. PMID 27548127.
53. ^ Carter CS (2017). "The Oxytocin-Vasopressin Pathway in the Context of Love and Fear". Frontiers in Endocrinology. 8: 356. doi:10.3389/fendo.2017.00356. PMC 5743651. PMID 29312146.
54. ^ Tahlan K, Jensen SE (July 2013). "Origins of the β-lactam rings in natural products". The Journal of Antibiotics. 66 (7): 401–10\. doi:10.1038/ja.2013.24. PMID 23531986.
55. ^ Martín JF, Casqueiro J, Kosalková K, Marcos AT, Gutiérrez S (1999). "Penicillin and cephalosporin biosynthesis: mechanism of carbon catabolite regulation of penicillin production". Antonie van Leeuwenhoek. 75 (1–2): 21–31\. doi:10.1023/a:1001820109140. PMID 10422579.1–2&rft.pages=21-31&rft.date=1999&rft_id=info:doi/10.1023/a:1001820109140&rft_id=info:pmid/10422579&rft.aulast=Martín&rft.aufirst=JF&rft.au=Casqueiro,+J&rft.au=Kosalková,+K&rft.au=Marcos,+AT&rft.au=Gutiérrez,+S&rfr_id=info:sid/en.wikipedia.org:Natural+product" class="Z3988">
56. ^ Gleadow RM, Møller BL (2014). "Cyanogenic glycosides: synthesis, physiology, and phenotypic plasticity". Annual Review of Plant Biology. 65: 155–85\. doi:10.1146/annurev-arplant-050213-040027. PMID 24579992.
57. ^ Zagrobelny M, de Castro ÉC, Møller BL, Bak S (May 2018). "Cyanogenesis in Arthropods: From Chemical Warfare to Nuptial Gifts". Insects. 9 (2): 51. doi:10.3390/insects9020051. PMC 6023451. PMID 29751568.
58. ^ a b Halkier BA, Gershenzon J (2006). "Biology and biochemistry of glucosinolates". Annual Review of Plant Biology. 57: 303–33\. doi:10.1146/annurev.arplant.57.032905.105228. PMID 16669764.
59. ^ a b Strobel G, Daisy B (December 2003). "Bioprospecting for microbial endophytes and their natural products". Microbiology and Molecular Biology Reviews. 67 (4): 491–502\. doi:10.1128/MMBR.67.4.491-502.2003. PMC 309047. PMID 14665674.
60. ^ a b c Cushnie TP, Cushnie B, Echeverría J, Fowsantear W, Thammawat S, Dodgson JL, et al. (June 2020). "Bioprospecting for Antibacterial Drugs: a Multidisciplinary Perspective on Natural Product Source Material, Bioassay Selection and Avoidable Pitfalls". Pharmaceutical Research. 37 (7) 125. doi:10.1007/s11095-020-02849-1. PMID 32529587. S2CID 219590658.
61. ^ Markossian S, Grossman A, Brimacombe K, Arkin M, Auld D, Austin CP, et al. (June 2020). Assay Guidance Manual. Bethesda: Eli Lilly & Company and the National Center for Advancing Translational Sciences. PMID 22553861.
62. ^ Katsuno K, Burrows JN, Duncan K, Hooft van Huijsduijnen R, Kaneko T, Kita K, et al. (November 2015). "Hit and lead criteria in drug discovery for infectious diseases of the developing world". Nature Reviews. Drug Discovery. 14 (11): 751–758\. doi:10.1038/nrd4683. PMID 26435527. S2CID 25863919.
63. ^ Calixto JB (2019). "The role of natural products in modern drug discovery". Anais da Academia Brasileira de Ciências. 91 Supplement 3: e20190105. doi:10.1590/0001-3765201920190105. PMID 31166478.
64. ^ Bauer A, Brönstrup M (January 2014). "Industrial natural product chemistry for drug discovery and development". Natural Product Reports. 31 (1): 35–60\. doi:10.1039/c3np70058e. PMID 24142193.
65. ^ Maier ME (May 2015). "Design and synthesis of analogues of natural products". Organic & Biomolecular Chemistry. 13 (19): 5302–5343\. doi:10.1039/c5ob00169b. PMID 25829247.
66. ^ a b Hallett M, Albanese A, Dressler D, Segal KR, Simpson DM, Truong D, et al. (June 2013). "Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders". Toxicon. 67 (June): 94–114\. Bibcode:2013Txcn...67...94H. doi:10.1016/j.toxicon.2012.12.004. PMID 23380701.
67. ^ a b Zaffiri L, Gardner J, Toledo-Pereyra LH (April 2012). "History of antibiotics. From salvarsan to cephalosporins". Journal of Investigative Surgery. 25 (2): 67–77\. doi:10.3109/08941939.2012.664099. PMID 22439833. S2CID 30538825.
68. ^ Procópio RE, Silva IR, Martins MK, Azevedo JL, Araújo JM (2012). "Antibiotics produced by Streptomyces". The Brazilian Journal of Infectious Diseases. 16 (5): 466–471\. doi:10.1016/j.bjid.2012.08.014. PMID 22975171.
69. ^ Cochrane SA, Vederas JC (January 2016). "Lipopeptides from Bacillus and Paenibacillus spp.: A Gold Mine of Antibiotic Candidates". Medicinal Research Reviews. 36 (1): 4–31\. doi:10.1002/med.21321. PMID 24866700. S2CID 46109250.
70. ^ Saxena A, Kumari R, Mukherjee U, Singh P, Lal R (July 2014). "Draft Genome Sequence of the Rifamycin Producer Amycolatopsis rifamycinica DSM 46095". Genome Announcements. 2 (4): e00662–14. doi:10.1128/genomeA.00662-14. PMC 4082003. PMID 24994803.
71. ^ Saraiva RG, Dimopoulos G (March 2020). "Bacterial natural products in the fight against mosquito-transmitted tropical diseases". Natural Product Reports. 37 (3): 338–354\. doi:10.1039/C9NP00042A. PMID 31544193. S2CID 202731385.
72. ^ "Bleomycin". US National Library of Medicine. Retrieved 28 January 2015.
73. ^ Alvin A, Miller KI, Neilan BA (2014). "Exploring the potential of endophytes from medicinal plants as sources of antimycobacterial compounds". Microbiological Research. 169 (7–8): 483–495\. doi:10.1016/j.micres.2013.12.009. PMC 7126926. PMID 24582778.7–8&rft.pages=483-495&rft.date=2014&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126926#id-name=PMC&rft_id=info:pmid/24582778&rft_id=info:doi/10.1016/j.micres.2013.12.009&rft.aulast=Alvin&rft.aufirst=A&rft.au=Miller,+KI&rft.au=Neilan,+BA&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126926&rfr_id=info:sid/en.wikipedia.org:Natural+product" class="Z3988">
74. ^ Wang X, Elshahawi SI, Shaaban KA, Fang L, Ponomareva LV, Zhang Y, et al. (January 2014). "Ruthmycin, a new tetracyclic polyketide from Streptomyces sp. RM-4-15". Organic Letters. 16 (2): 456–459\. doi:10.1021/ol4033418. PMC 3964319. PMID 24341358.
75. ^ Wang X, Shaaban KA, Elshahawi SI, Ponomareva LV, Sunkara M, Copley GC, et al. (August 2014). "Mullinamides A and B, new cyclopeptides produced by the Ruth Mullins coal mine fire isolate Streptomyces sp. RM-27-46". The Journal of Antibiotics. 67 (8): 571–575\. doi:10.1038/ja.2014.37. PMC 4146655. PMID 24713874.
76. ^ Akey DL, Gehret JJ, Khare D, Smith JL (October 2012). "Insights from the sea: structural biology of marine polyketide synthases". Natural Product Reports. 29 (10): 1038–1049\. doi:10.1039/c2np20016c. PMC 3709256. PMID 22498975.
77. ^ Bertoldo C, Antranikian G (2011). "Chapter 1: Biotechnology of Archaea" (PDF). Biotechnology Vol. IX. Paris: Encyclopedia of Life Support Systems (EOLSS).
78. ^ Thornburg CC, Zabriskie TM, McPhail KL (March 2010). "Deep-sea hydrothermal vents: potential hot spots for natural products discovery?". Journal of Natural Products. 73 (3): 489–499\. doi:10.1021/np900662k. PMID 20099811.
79. ^ a b Pathak A, Nowell RW, Wilson CG, Ryan MJ, Barraclough TG (September 2020). "Comparative genomics of Alexander Fleming's original Penicillium isolate (IMI 15378) reveals sequence divergence of penicillin synthesis genes". Scientific Reports. 10 (1) 15705. Bibcode:2020NatSR..1015705P. doi:10.1038/s41598-020-72584-5. PMC 7515868. PMID 32973216.
80. ^ Beekman AM, Barrow RA (2014). "Fungal metabolites as pharmaceuticals". Aust J Chem. 67 (6): 827–843\. doi:10.1071/ch13639.
81. ^ Evans BE, Bock MG, Rittle KE, DiPardo RM, Whitter WL, Veber DF, et al. (July 1986). "Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin". Proceedings of the National Academy of Sciences of the United States of America. 83 (13): 4918–4922\. Bibcode:1986PNAS...83.4918E. doi:10.1073/pnas.83.13.4918. PMC 323855. PMID 3014519.
82. ^ Dang L, Van Damme EJ (September 2015). "Toxic proteins in plants". Phytochemistry. 117: 51–64\. Bibcode:2015PChem.117...51D. doi:10.1016/j.phytochem.2015.05.020. PMC 7111729. PMID 26057229.
83. ^ Crozier A, Clifford MN, Ashihara H (2006). "Chapters 1, 3 and 4". Plant Secondary Metabolites: Occurrence, Structure and Role in the Human Diet. Oxford, UK: Blackwell Publishing Ltd. pp. 1–24, 47–136\. ISBN 978-1-4051-2509-3.
84. ^ Kittakoop P, Mahidol C, Ruchirawat S (2014). "Alkaloids as important scaffolds in therapeutic drugs for the treatments of cancer, tuberculosis, and smoking cessation". Current Topics in Medicinal Chemistry. 14 (2): 239–252\. doi:10.2174/1568026613666131216105049. PMID 24359196.
85. ^ Kano S (May 2014). "Artemisinin-based combination therapies and their introduction in Japan". Kansenshogaku Zasshi. The Journal of the Japanese Association for Infectious Diseases. 88 (3 Suppl 9-10): 18–25\. PMID 24979951.
86. ^ Russo P, Frustaci A, Del Bufalo A, Fini M, Cesario A (2013). "Multitarget drugs of plants origin acting on Alzheimer's disease". Current Medicinal Chemistry. 20 (13): 1686–1693\. doi:10.2174/0929867311320130008. PMID 23410167.
87. ^ a b c Prommer E (June 2006). "Ziconotide: a new option for refractory pain". Drugs of Today. 42 (6): 369–378\. doi:10.1358/dot.2006.42.6.973534. PMID 16845440.
88. ^ Dossey AT (January 2010). "Insects and their chemical weaponry: new potential for drug discovery". Natural Product Reports. 27 (12): 1737–1757\. doi:10.1039/C005319H. PMID 20957283.
89. ^ a b c Herzig V, Cristofori-Armstrong B, Israel MR, Nixon SA, Vetter I, King GF (November 2020). "Animal toxins - Nature's evolutionary-refined toolkit for basic research and drug discovery". Biochemical Pharmacology. 181 114096\. doi:10.1016/j.bcp.2020.114096. PMC 7290223. PMID 32535105.
90. ^ Lazarovici P, Marcinkiewicz C, Lelkes PI (May 2019). "From Snake Venom's Disintegrins and C-Type Lectins to Anti-Platelet Drugs". Toxins. 11 (5) 303. doi:10.3390/toxins11050303. PMC 6563238. PMID 31137917.
91. ^ Mayer AM, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, et al. (June 2010). "The odyssey of marine pharmaceuticals: a current pipeline perspective". Trends in Pharmacological Sciences. 31 (6): 255–265\. doi:10.1016/j.tips.2010.02.005. PMID 20363514.
92. ^ a b Bowersox SS, Luther R (November 1998). "Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus". Toxicon. 36 (11): 1651–1658\. Bibcode:1998Txcn...36.1651B. doi:10.1016/S0041-0101(98)00158-5. PMID 9792182.
93. ^ Rinehart KL (January 2000). "Antitumor compounds from tunicates". Medicinal Research Reviews. 20 (1): 1–27\. doi:10.1002/(SICI)1098-1128(200001)20:1<1::AID-MED1>3.0.CO;2-A. PMID 10608919. S2CID 25117225.
94. ^ Petek BJ, Loggers ET, Pollack SM, Jones RL (February 2015). "Trabectedin in soft tissue sarcomas". Marine Drugs. 13 (2): 974–983\. doi:10.3390/md13020974. PMC 4344612. PMID 25686274.
95. ^ a b Singh R, Sharma M, Joshi P, Rawat DS (August 2008). "Clinical status of anti-cancer agents derived from marine sources". Anti-Cancer Agents in Medicinal Chemistry. 8 (6): 603–617\. doi:10.2174/187152008785133074. PMID 18690825.
96. ^ Brahmachari G (2010). Handbook of Pharmaceutical Natural Products. Weinheim: Wiley-VCH. ISBN 978-3-52732148-3.
97. ^ Beghyn T, Deprez-Poulain R, Willand N, Folleas B, Deprez B (July 2008). "Natural compounds: leads or ideas? Bioinspired molecules for drug discovery". Chemical Biology & Drug Design. 72 (1): 3–15\. doi:10.1111/j.1747-0285.2008.00673.x. PMID 18554253. S2CID 20973633.
98. ^ Koehn FE, Carter GT (March 2005). "The evolving role of natural products in drug discovery". Nature Reviews. Drug Discovery. 4 (3): 206–220\. doi:10.1038/nrd1657. PMID 15729362. S2CID 32749678.
99. ^ Newman DJ, Cragg GM (March 2007). "Natural products as sources of new drugs over the last 25 years". Journal of Natural Products. 70 (3): 461–477\. CiteSeerX 10.1.1.336.753. doi:10.1021/np068054v. PMID 17309302.
100. ^ Gransalke K (February 2011). "Mother Nature's Drug Cabinet" (PDF). Lab Times. 11 (1): 16–19\. Archived from the original (PDF) on 4 March 2016. Retrieved 8 December 2013. "Drug Discovery – Is Mother Nature still the number one source for promising new drugs?"
101. ^ Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, et al. (December 2015). "Discovery and resupply of pharmacologically active plant-derived natural products: A review". Biotechnology Advances. 33 (8): 1582–1614\. doi:10.1016/j.biotechadv.2015.08.001. PMC 4748402. PMID 26281720.
102. ^ a b Najmi A, Javed SA, Al Bratty M, Alhazmi HA (January 2022). "Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents". Molecules. 27 (2): 349. doi:10.3390/molecules27020349. PMC 8779633. PMID 35056662.
103. ^ Domingo-Fernández D, Gadiya Y, Preto AJ, Krettler CA, Mubeen S, Allen A, et al. (July 2024). "Natural Products Have Increased Rates of Clinical Trial Success throughout the Drug Development Process". Journal of Natural Products. 87 (7): 1844–1851\. doi:10.1021/acs.jnatprod.4c00581. PMC 11287737. PMID 38970498.
104. ^ Schrör K (2008). "Chapter 1.1: History". Acetylsalicylic Acid. Weinheim: Wiley-VCH. pp. 5–24\. ISBN 978-3-527-62600-7.
105. ^ Busse GD, Triggle DJ (2006). "The history of opium and morphine". Morphine. New York: Chelsea House Publishers. pp. 8–23\. ISBN 978-1-4381-0211-5.
106. ^ Lewis RJ, Dutertre S, Vetter I, Christie MJ (April 2012). "Conus venom peptide pharmacology". Pharmacological Reviews. 64 (2): 259–298\. doi:10.1124/pr.111.005322. PMID 22407615. S2CID 6115292.
107. ^ de la Bédoyère G (2005). The discovery of penicillin. London: Evans. ISBN 978-0-237-52739-6.
108. ^ Hartung EF (September 1954). "History of the use of colchicum and related medicaments in gout; with suggestions for further research". Annals of the Rheumatic Diseases. 13 (3): 190–200\. doi:10.1136/ard.13.3.190. PMC 1006735. PMID 13198053.
109. ^ Sneader W (2005). "Paclitaxel (taxol)". Drug Discovery: A History (Rev. and updated ed.). Chichester: Wiley. pp. 112–113\. ISBN 978-0-471-89979-2.
110. ^ Li JL (2009). "Discovery of Lipitor". Triumph of the Heart: the Story of Statins. New York, NY: Oxford University Press. pp. 71–96\. ISBN 978-0-19-804351-5.
111. ^ Sneader W (2005). "ACE Inhibitors". Drug Discovery: A History (Rev. and updated ed.). Chichester: Wiley. pp. 280–283\. ISBN 978-0-471-89979-2.
112. ^ a b c Berida TI, Adekunle YA, Dada-Adegbola H, Kdimy A, Roy S, Sarker SD (May 2024). "Plant antibacterials: The challenges and opportunities". Heliyon. 10 (10) e31145. Bibcode:2024Heliy..1031145B. doi:10.1016/j.heliyon.2024.e31145. PMC 11128932. PMID 38803958.
113. ^ Gomez-Escribano JP, Alt S, Bibb MJ (April 2016). "Next Generation Sequencing of Actinobacteria for the Discovery of Novel Natural Products". Marine Drugs. 14 (4): 78. doi:10.3390/md14040078. PMC 4849082. PMID 27089350.
114. ^ a b Pawar SV, Ho JC, Yadav GD, Yadav VG (2017). "The Impending Renaissance in Discovery & Development of Natural Products". Current Topics in Medicinal Chemistry. 17 (2): 251–267\. doi:10.2174/1568026616666160530154649. PMID 27237327.
115. ^ Blow N (May 2008). "Metagenomics: exploring unseen communities". Nature. 453 (7195): 687–690\. Bibcode:2008Natur.453..687B. doi:10.1038/453687a. PMID 18509446. S2CID 29079319.
116. ^ Brown K (2009). "That's funny!': the discovery and development of penicillin". Microbiology Today. 36 (1): 12–15\. Archived from the original on 12 January 2015. Retrieved 12 January 2015.
117. ^ "Discovery and Development of Penicillin". International Historic Chemical Landmarks. American Chemical Society.
118. ^ Linington RG, Kubanek J, Luesch H (July 2019). "New methods for isolation and structure determination of natural products". Natural Product Reports. 36 (7): 942–943\. doi:10.1039/c9np90023c. PMID 31250867.
119. ^ Abdelmohsen UR, Sayed AM, Elmaidomy AH (May 2022). "Natural products' extraction and isolation-between conventional and modern techniques". Frontiers in Natural Products. 1: 873808. doi:10.3389/fntpr.2022.873808.
120. ^ Sarker SD, Nahar L (2012). "An introduction to natural products isolation". Natural Products Isolation. Methods in Molecular Biology. Vol. 864\. Clifton, N.J.: Humana Press. pp. 1–25\. doi:10.1007/978-1-61779-624-1_1. ISBN 978-1-61779-623-4. PMID 22367891.
121. ^ Hodgkin DC. "Enhancing X-ray Vision". The Nobel Prize in Chemistry 1964 – Perspectives.
122. ^ Přichystal J, Schug KA, Lemr K, Novák J, Havlíček V (November 2016). "Structural Analysis of Natural Products". Analytical Chemistry. 88 (21): 10338–10346\. doi:10.1021/acs.analchem.6b02386. PMID 27661090.
123. ^ a b Fay N, Kouklovsky C, de la Torre A (December 2023). "Natural Product Synthesis: The Endless Quest for Unreachable Perfection". ACS Organic & Inorganic Au. 3 (6): 350–363\. doi:10.1021/acsorginorgau.3c00040. PMC 10704578. PMID 38075446.
124. ^ "The Story of Taxol" (PDF). The American Society of Pharmacognosy. Archived from the original (PDF) on 12 December 2013.
125. ^ a b Maier ME (May 2015). "Design and synthesis of analogues of natural products". Organic & Biomolecular Chemistry. 13 (19): 5302–43\. doi:10.1039/c5ob00169b. PMID 25829247.
126. ^ Zhang S, Ye T, Liu Y, Hou G, Wang Q, Zhao F, et al. (November 2023). "Research Advances in Clinical Applications, Anticancer Mechanism, Total Chemical Synthesis, Semi-Synthesis and Biosynthesis of Paclitaxel". Molecules. 28 (22). Basel, Switzerland: 7517. doi:10.3390/molecules28227517. PMC 10673093. PMID 38005238.
127. ^ Sambyal K, Singh RV (October 2021). "Exploitation of E. coli for the production of penicillin G amidase: a tool for the synthesis of semisynthetic β-lactam antibiotics". Journal, Genetic Engineering & Biotechnology. 19 (1) 156. doi:10.1186/s43141-021-00263-7. PMC 8521562. PMID 34652570.
128. ^ Hodgkin DC, Kamper J, Mackay M, Pickworth J, Trueblood KN, White JG (July 1956). "Structure of vitamin B12". Nature. 178 (4524): 64–66\. Bibcode:1956Natur.178...64H. doi:10.1038/178064a0. PMID 13348621. S2CID 4210164.
129. ^ a b Woodward RB (1973). "The total synthesis of vitamin B 12". Pure and Applied Chemistry. 33 (1): 145–177\. doi:10.1351/pac197333010145. PMID 4684454. S2CID 30641959.
130. ^ a b Eschenmoser A (January 1988). "Vitamin B12: Experiments Concerning the Origin of Its Molecular Structure". Angewandte Chemie International Edition in English. 27 (1): 5–39\. doi:10.1002/anie.198800051.
131. ^ Heathcock CH (1996). "As We Head into the 21st Century, Is there Still Value in Total Synthesis of Natural Products as a Research Endeavor?". Chemical Synthesis. NATO ASI Series. Vol. 320\. pp. 223–243\. doi:10.1007/978-94-009-0255-8_9. ISBN 978-94-010-6598-6.
132. ^ Nicolaou KC, Vourloumis D, Winssinger N, Baran PS (January 2000). "The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century". Angewandte Chemie. 39 (1): 44–122\. doi:10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L. PMID 10649349.
133. ^ Lightner DA (2013). Bilirubin: Jekyll and Hyde Pigment of Life: Pursuit of Its Structure Through Two World Wars to the New Millenium. Springer. p. 371\. ISBN 978-3-7091-1637-1.
134. ^ a b Bulger PG, Bagal SK, Marquez R (April 2008). "Recent advances in biomimetic natural product synthesis". Natural Product Reports. 25 (2): 254–297\. doi:10.1039/b705909b. PMID 18389138.
135. ^ a b Shakour N, Mohadeszadeh M, Iranshahi M (2024). "Biomimetic Synthesis of Biologically Active Natural Products: An Updated Review". Mini Reviews in Medicinal Chemistry. 24 (1): 3–25\. doi:10.2174/1389557523666230417083143. PMID 37073153.
136. ^ Voloshchuk T, Farina NS, Wauchope OR, Kiprowska M, Haberfield P, Greer A (July 2004). "Molecular bilateral symmetry of natural products: prediction of selectivity of dimeric molecules by density functional theory and semiempirical calculations". Journal of Natural Products. 67 (7): 1141–1146\. doi:10.1021/np049899e. PMID 15270568.
137. ^ Bredel M, Jacoby E (April 2004). "Chemogenomics: an emerging strategy for rapid target and drug discovery". Nature Reviews. Genetics. 5 (4): 262–275\. CiteSeerX 10.1.1.411.9671. doi:10.1038/nrg1317. PMID 15131650. S2CID 11952369.
138. ^ Galúcio JM, Monteiro EF, de Jesus DA, Costa CH, Siqueira RC, Santos GB, et al. (December 2019). "In silico identification of natural products with anticancer activity using a chemo-structural database of Brazilian biodiversity". Computational Biology and Chemistry. 83 107102\. doi:10.1016/j.compbiolchem.2019.107102. PMID 31487609. S2CID 201845232.
139. ^ Harvey AL (October 2008). "Natural products in drug discovery". Drug Discovery Today. 13 (19–20): 894–901\. doi:10.1016/j.drudis.2008.07.004. PMID 18691670.19–20&rft.pages=894-901&rft.date=2008-10&rft_id=info:doi/10.1016/j.drudis.2008.07.004&rft_id=info:pmid/18691670&rft.aulast=Harvey&rft.aufirst=AL&rfr_id=info:sid/en.wikipedia.org:Natural+product" class="Z3988">
140. ^ Chhetri BK, Lavoie S, Sweeney-Jones AM, Kubanek J (June 2018). "Recent trends in the structural revision of natural products". Natural Product Reports. 35 (6): 514–531\. doi:10.1039/C8NP00011E. PMC 6013367. PMID 29623331.
141. ^ Heard DM, Tayler ER, Cox RJ, Simpson TJ, Willis CL (January 2020). "Structural and synthetic studies on maleic anhydride and related diacid natural products" (PDF). Tetrahedron. 76 (1) 130717. doi:10.1016/j.tet.2019.130717. hdl:1983/53998d06-9017-4cfb-822b-c6453348000a. S2CID 209714625.
142. ^ Wu J, Lorenzo P, Zhong S, Ali M, Butts CP, Myers EL, et al. (July 2017). "Synergy of synthesis, computation and NMR reveals correct baulamycin structures". Nature. 547 (7664): 436–440\. doi:10.1038/nature23265. hdl:1983/85161235-ea9f-4568-9f8a-19b42f4dff67. PMID 28748934. S2CID 205258282.
143. ^ Corsello MA, Kim J, Garg NK (September 2017). "Indole diterpenoid natural products as the inspiration for new synthetic methods and strategies". Chemical Science. 8 (9): 5836–5844\. doi:10.1039/C7SC01248A. PMC 5618777. PMID 28970940.
144. ^ Baran PS (April 2018). "Natural Product Total Synthesis: As Exciting as Ever and Here To Stay". Journal of the American Chemical Society. 140 (14): 4751–4755\. Bibcode:2018JAChS.140.4751B. doi:10.1021/jacs.8b02266. PMID 29635919.
145. ^ "Antoine Laurent Lavoisier The Chemical Revolution". International Historic Chemical Landmark. American Chemical Society.
146. ^ a b c Dias DA, Urban S, Roessner U (April 2012). "A historical overview of natural products in drug discovery". Metabolites. 2 (2): 303–336\. doi:10.3390/metabo2020303. PMC 3901206. PMID 24957513.
147. ^ Chevreul ME (1823). "IX — De la cholestérine". Recherches chimiques sur les corps gras d'origine animale (in French). pp. 153–160.
148. ^ Pelletier PP, Caventou JB (1819). "Mémoire sur un nouvel alcali vegetal (la strychnine) trouvé dans la feve de Saint-Ignace, la noix vomique, etc" [Memoir on a new vegetable alkali (strychnine) found in the St. Ignatius bean, the nux-vomica, etc)]. Annales de Chimie et de Physique (in French). 10: 142–176.
149. ^ Wöhler F (1828). "Ueber künstliche Bildung des Harnstoffs" [About the artificial formation of urea]. Annalen der Physik und Chemie (in German). 88 (2): 253–256\. Bibcode:1828AnP....88..253W. doi:10.1002/andp.18280880206.
150. ^ Rocke AJ (23 September 2024). "Hermann Kolbe – German chemist". Encyclopedia Britannica.
151. ^ "Justus von Liebig and Friedrich Wöhler". Science History Institute. June 2016. Archived from the original on 20 June 2018. Retrieved 21 March 2018.
152. ^ Liebig J (1838). "Ueber Laurent's Theorie der organischen Verbindungen" [About Laurent 's theory of organic compounds]. Annalen der Pharmacie (in German). 25 (1): 1–31\. doi:10.1002/jlac.18380250102.
153. ^ a b Lewis DE (2019). "1860–1861: Magic Years in the Development of the Structural Theory of Organic Chemistry". Bulletin for the History of Chemistry. 44 (2): 77–91.
154. ^ Kekulé A (1858). "Ueber die Constitution und die Metamorphosen der chemischen Verbindungen und über die chemische Natur des Kohlenstoffs" [Concerning the constitution and the metamorphosis of the chemical compounds and the chemical nature of the carbon]. Annalen der Chemie und Pharmacie (in German). 106 (2): 129–159\. doi:10.1002/jlac.18581060202.
155. ^ Christmann M (December 2010). "Otto Wallach: founder of terpene chemistry and Nobel Laureate 1910". Angewandte Chemie. 49 (50): 9580–9586\. doi:10.1002/anie.201003155. PMID 21110354.
156. ^ Battersby AR (December 2000). "Tetrapyrroles: the pigments of life". Natural Product Reports. 17 (6): 507–526\. doi:10.1039/b002635m. PMID 11152419.
157. ^ Nes WD (October 2011). "Biosynthesis of cholesterol and other sterols". Chemical Reviews. 111 (10): 6423–6451\. doi:10.1021/cr200021m. PMC 3191736. PMID 21902244.
158. ^ Britton G (December 1995). "Structure and properties of carotenoids in relation to function". FASEB Journal. 9 (15): 1551–1558\. doi:10.1096/fasebj.9.15.8529834. PMID 8529834.
159. ^ Rosenfeld L (April 1997). "Vitamine--vitamin. The early years of discovery". Clinical Chemistry. 43 (4): 680–685\. doi:10.1093/clinchem/43.4.680. PMID 9105273.
160. ^ Tata JR (June 2005). "One hundred years of hormones". EMBO Reports. 6 (6): 490–496\. doi:10.1038/sj.embor.7400444. PMC 1369102. PMID 15940278.
161. ^ "The Nobel Prize in Chemistry 1955". Nobelprize.org. Nobel Media AB. Retrieved 17 November 2016.
162. ^ Dewick PM (2009). Medicinal Natural Products: A Biosynthetic Approach. John Wiley & Sons. ISBN 978-0-470-74168-9.

## Further reading

[edit]

* Ahluwalia VK, Kumar LS, Kumar S (2022). Chemistry of natural products: amino acids, peptides, proteins and enzymes. Springer. ISBN 978-3-030-86697-6.
* Hanson JR (2003). Natural Products: The Secondary Metabolites. Royal Society of Chemistry. ISBN 978-0-85404-490-0.
* Kaufman PB (1999). Natural Products from Plants. CRC Press. ISBN 978-0-8493-3134-3.
* Liang XT, Fang WS, eds. (2006). Medicinal Chemistry of Bioactive Natural Products. Wiley-Interscience. ISBN 978-0-471-73933-3.
* Napagoda M, Jayasinghe L, eds. (2022). Chemistry of natural products: phytochemistry and pharmacognosy of medicinal plants. De Gruyter. ISBN 978-3-11-059589-5.
* Reusch W (2010). "Natural Products page". Virtual Textbook of Organic Chemistry. Ann Arbor, Mich.: Michigan State University, Department of Chemistry. Archived from the original on 3 February 2007.

## External links

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* "NAPROC-13 Base de datos de Carbono 13 de Productos Naturales y Relacionados (Carbon-13 Database of Natural Products and Related Substances)". Spanish language tools to facilitate structural identification of natural products.
* Porter N, ed. (1913). "Natural product". Webster's Dictionary. Springfield, Massachusetts: C. & G. Merriam Co.

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