# Produit naturel

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Le paclitaxel (Taxol) est un produit naturel dérivé de l'if.[1]

Un produit naturel est un composé chimique ou une substance produite par un organisme vivant, c'est-à-dire qui se trouve dans la nature[2],[3]. Au sens le plus large, un produit naturel est toute substance produite par la vie[4],[5]. Les produits naturels peuvent également être préparés par synthèse chimique (semi-synthèse et synthèse totale) et ont joué un rôle central dans le développement du domaine de la chimie organique en fournissant des cibles synthétiques difficiles. Le terme « produit naturel » a également été étendu à des fins commerciales pour désigner les cosmétiques, les compléments alimentaires et les aliments produits à partir de sources naturelles sans ingrédients artificiels ajoutés[6][réf. insuffisante].

Dans le domaine de la chimie organique, la définition des produits naturels se limite d'habitude aux composés organiques purifiés isolés de sources naturelles qui sont produits par les voies du métabolisme primaire ou secondaire[7]. Dans le domaine de la chimie médicale, la définition se limite souvent aux métabolites secondaires[8],[9].  Les métabolites secondaires ne sont pas essentiels à la survie, mais procurent néanmoins aux organismes qui les produisent un avantage évolutif[10]. De nombreux métabolites secondaires sont cytotoxiques et ont été sélectionnés et optimisés au cours de l'évolution pour être utilisés comme agents de « guerre chimique » contre les proies, les prédateurs et les organismes concurrents[11].

Les produits naturels ont parfois un effet thérapeutique bénéfique en tant que médicaments traditionnels pour le traitement des maladies, ce qui permet d'obtenir des connaissances pour en tirer des composants actifs en tant que composés tête de série (en) pour la découverte de médicaments (en)[12]. Bien que les produits naturels aient inspiré beaucoup des médicaments approuvés par l'Agence américaine des produits alimentaires et médicamenteux, leur mise au point (en) à partir de sources naturelles a fait l'objet d'une attention décroissante de la part des entreprises pharmaceutiques, en partie en raison d'un accès et d'un approvisionnement peu fiables, de problèmes de propriété intellectuelle, de la variabilité saisonnière ou environnementale de la composition et de la perte des sources causées par le rythme croissant d'extinction des espèces[12].

## Classes

La définition la plus large d'un produit naturel est qu'il s'agit de tout ce qui est produit par la vie[4],[13], y compris les matériaux biotiques (en) (p. ex. bois, soie), les matériaux d'origine biologique (p. ex. bioplastiques, amidon de maïs), les fluides corporels (p. ex. lait, exsudats végétaux) et d'autres matériaux naturels (en) (p. ex. sol, charbon). Une définition plus restrictive d'un produit naturel affirme qu'il s'agit un composé organique qui est synthétisé par un organisme vivant[7]. Le reste du présent article se limite à cette définition plus étroite.

Les produits naturels peuvent être classés selon leur fonction biologique, leur voie de biosynthèse ou leur source, tels que décrit ci-dessous.

## Fonction

Suite à la proposition originale d'Albrecht Kossel en 1891[14], les produits naturels sont souvent divisés en deux grandes classes : les métabolites primaires et secondaires[15],[16]. Les métabolites primaires ont une fonction intrinsèque (propre) qui est essentielle à la survie de l'organisme qui les produit. En revanche, les métabolites secondaires ont une fonction extrinsèque (externe) qui affecte principalement d'autres organismes. Les métabolites secondaires ne sont pas essentiels à sa survie, mais ils augmentent la compétitivité de l'organisme dans son environnement. En raison de leur capacité à moduler les voies biochimiques et les voies de transduction du signal, certains métabolites secondaires ont des propriétés médicinales utiles.

Les produits naturels, en particulier dans le domaine de la chimie organique, sont souvent définis comme des métabolites primaires et secondaires. Une définition plus restrictive limitant les produits naturels aux métabolites secondaires est couramment utilisée dans les domaines de la chimie médicinale et de la pharmacognosie[13].

### Métabolites primaires

Éléments constitutifs moléculaires de la vie

Primary metabolites as defined by Kossel are components of basic metabolic pathways that are required for life. They are associated with essential cellular functions such as nutrient assimilation, energy production, and growth/development. They have a wide species distribution that span many phyla and frequently more than one kingdom. Primary metabolites include carbohydrates, lipids, amino acids, and nucleic acids[15],[16] which are the basic building blocks of life[17].

Primary metabolites that are involved with energy production include appareil respiratoire and photosynthèse enzymes. Enzymes in turn are composed of acide aminés and often non-peptidic cofactors that are essential for enzyme function.[18] The basic structure of cells and of organisms are also composed of primary metabolites. These include cell membranes (e.g. phospholipides), cell walls (e.g. peptidoglycane, chitine), and cytosquelettes (proteins)[19].

Primary metabolite enzymatic cofactors include members of the vitamine B family. Vitamine B1 as thiamine diphosphate is a coenzyme for pyruvate déshydrogénase, Complexe alpha-cétoglutarate déshydrogénase, and transcétolase which are all involved in carbohydrate metabolism. Riboflavine (riboflavin) is a constituent of FMN and FAD which are necessary for many redox reactions. Vitamin B3 (nicotinic acid or niacin), synthesized from tryptophan is a component of the coenzymes NAD|width="5"| | align="left" style="width:auto;border:1px solid #aaaaaa;background:#F7F8FF" | and NADP|width="5"| | align="left" style="width:auto;border:1px solid #aaaaaa;background:#F7F8FF" | which in turn are required for electron transport in the Cycle de Krebs, phosphorylation oxydative, as well as many other redox reactions. Vitamine B5 (pantothenic acid) is a constituent of coenzyme A, a basic component of carbohydrate and amino acid metabolism as well as the biosynthesis of fatty acids and polyketides. Vitamine B6 (pyridoxol, pyridoxal, and pyridoxamine) as pyridoxal 5′-phosphate is a cofactor for many enzymes especially transaminases involve in amino acid metabolism. Vitamine B12 (cobalamins) contain a corrine ring similar in structure to porphyrine and is an essential coenzyme for the catabolism of fatty acids as well for the biosynthesis of méthionine.[20]:Chapter 2

Acide désoxyribonucléique and Acide ribonucléique which store and transmit séquence (acide nucléique) are composed of nucleic acid primary metabolites[18].

First messengers are signaling molecules that control métabolisme or différenciation cellulaire. These signaling molecules include hormones and growth factors in turn are composed of peptides, amine biogènes, hormone stéroïdiennes, auxines, gibbérellines etc. These first messengers interact with cellular receptors which are composed of proteins. Cellular receptors in turn activate second messengers are used to relay the extracellular message to intracellular targets. These signaling molecules include the primary metabolites cyclic nucleotides, diglycéride etc.[21]

### Métabolites secondaires

Article détaillé : secondary metabolite.
Exemples représentatifs de chacune des principales classes de métabolites secondaires

Secondary in contrast to primary metabolites are dispensable and not absolutely required for survival. Furthermore, secondary metabolites typically have a narrow species distribution.

Secondary metabolites have a broad range of functions. These include phéromones that act as social signaling molecules with other individuals of the same species, communication molecules that attract and activate symbiose organisms, agents that solubilize and transport nutrients (sidérophore etc.), and competitive weapons (repellants, venin, toxine etc.) that are used against competitors, prey, and predators.[22] For many other secondary metabolites, the function is unknown. One hypothesis is that they confer a competitive advantage to the organism that produces them.[23] An alternative view is that, in analogy to the système immunitaire, 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[24].

General structural classes of secondary metabolites include alcaloïdes, phénylpropanoïdes, polycétides, and terpénoïdes,[7] which are described in more detail in the biosynthesis section below.

## Biosynthèse

Biosynthèse de métabolites primaires et secondaires[20]:Chapter 2.

Les voies de biosynthèse menant aux principales classes de produits naturels sont décrits ci-dessous[13],[20]:Chapter 2.

### Glucides

Glucides are an essential energy source for most life forms. In addition, polysaccharides formed from simpler carbohydrates are important structural components of many organisms such the paroi cellulaires of bacteria and plants.

Carbohydrate are the products of plant photosynthèse and animal néoglucogenèse. Photosynthesis produces initially Glycéraldéhyde-3-phosphate, a three carbon atom containing sugar (a triose).[20]:Chapter 8 This triose in turn may be converted into glucose (a six carbon atom containing sugar) or a variety of pentoses (five carbon atom containing sugars) through the Calvin cycle. In animals, the three carbon precursors lactate or glycérol can be converted into acide pyruvique which in turn can be converted into carbohydrates in the liver.

### Acides gras et polykétides

Through the process of glycolyse sugars are broken down into acétyl-coenzyme A. In an ATP dependent enzymatically catalyzed reaction, acetyl-CoA is carboxylated to form malonyl-coenzyme A. Acetyl-CoA and malonyl-CoA undergo a Condensation de Claisen with lose of carbon dioxide to form acétoacétyl-coenzyme A. Additional condensation reactions produce successively higher molecular weight poly-β-keto chains which are then converted into other polycétides.[20]:Chapter 3 The polyketide class of natural products have diverse structures and functions and include prostaglandines and macrolides.

One molecule of acetyl-CoA (the "starter unit") and several molecules malonyl-CoA (the "extender units") are condensed by acide gras synthase to produce acide grass.[20]:Chapter 3 Fatty acid are essential components of lipid bilayers that form cell membranes as well as fat energy stores in animals.

## Sources

Natural products may be extracted from the cells, tissues, and sécrétions of micro-organismes, plantes and animals.[25] 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 travel around the world obtaining samples to analyze and evaluate in drug discovery screens or bioassays. This effort to search for natural products is known as bioprospection.

Pharmacognosie provides the tools to identify, select and process natural products destined for medicinal use. Usually, the natural product compound has some form of biological activity and that compound is known as the substance active (médicament) - such a structure can evolve to become a discovery "lead". In this and related ways, some current medicines are obtained directly from natural sources.

On the other hand, some medicines are developed from the natural product lead originally obtained from the natural source. This means the lead may be:

• produced by total synthesis, or
• a starting point (precursor) for a semisynthetic compound, or
• a framework that serves as the basis for a structurally different compound arrived at by total/semisynthesis.

This is because many biologically active natural products are métabolite secondaires often with complex structure chimiques. This has an advantage in that they are novel compounds but this complexity also makes difficult the synthesis of such compounds; instead the compound may need to be extracted from its natural source – a slow, expensive and inefficient process. As a result, there is usually an advantage in designing simpler analogues.

### Procaryote

#### Bactéries

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

The serendipitous discovery and subsequent clinical success of pénicilline prompted a large-scale search for other environmental micro-organisme that might produce anti-infective natural products. Soil and water samples were collected from all over the world, leading to the discovery of streptomycine (derived from Streptomyces griseus), and the realization that bactérie, not just fungi, represent an important source of pharmacologically active natural products.[26] This, in turn, led to the development of an impressive arsenal of antibacterial and antifungal agents including amphotéricine B, chloramphénicol, daptomycine and tétracycline (from Streptomyces spp.),[27] the polymyxines (from Paenibacillus polymyxa),[28] and the rifamycine (from Amycolatopsis rifamycinica)[29].

Although most of the drugs derived from bacteria are employed as anti-infectives, some have found use in other fields of médecine. Toxine botulique (from Clostridium botulinum) and bléomycine (from Streptomyces verticillus) are two examples. Botulinum, the neurotoxine responsible for botulisme, can be injected into specific muscles (such as those controlling the eyelid) to prevent spasme.[30] Also, the glycopeptide bleomycin is used for the treatment of several cancers including Lymphome de Hodgkin, cancer des voies aérodigestives supérieures, and cancer du testicule.[31] Newer trends in the field include the metabolic profiling and isolation of natural products from novel bacterial species present in underexplored environments. Examples include symbiose or endophyte from tropical environments,[32] subterranean bacteria found deep underground via mining/drilling,[33],[34] and marine bacteria[35].

#### Archées

Because many Archaea have adapted to life in extreme environments such as région polaires, source chaude, acidic springs, alkaline springs, lac salé, 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, peptidases, alcool déshydrogénase, and eC 3.1s.[36] Archaea represent a source of novel composé chimique also, for example isoprenyl glycerol ethers 1 and 2 from Thermococcus S557 and Methanocaldococcus jannaschii, respectively[37].

### Eucaryotes

#### Fungi

The antibiotic pénicilline is a natural product derived from the fungus Penicillium notatum

Several anti-infective medications have been derived from fungi including pénicilline and the céphalosporine (antibacterial drugs from Penicillium notatum and Cephalosporium acremonium, respectively)[26] and griséofulvine (an antifungal drug from Penicillium griseofulvum).[38] Other medicinally useful fungal métabolites include lovastatine (from Pleurotus ostreatus), which became a lead for a series of drugs that lower cholestérol levels, ciclosporine (from Tolypocladium inflatum), which is used to suppress the immune response after organ transplant operations, and ergométrine (from Claviceps spp.), which acts as a vasoconstrictor, and is used to prevent bleeding after childbirth.[20]:Chapter 6 Asperlicin (from Aspergillus alliaceus) is another example. Asperlicin is a novel antagonist of cholécystokinine, a neurotransmetteur thought to be involved in attaque de panique, and could potentially be used to treat anxiété.

#### Plantes

The opioid analgesic drug morphine is a natural product derived from the plant Pavot somnifère

Plante are a major source of complex and highly structurally diverse chemical compounds (composé phytochimique), this structural diversity attributed in part to the sélection naturelle of organisms producing potent compounds to deter herbivory (feeding deterrents).[39] Major classes of phytochemical include phenols, polyphénols, tanins, terpènes, and alcaloïdes.[40] 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 If de l'Ouest and Cephalotaxus harringtonii, respectively),[41] the antimalarial agent artémisinine (from Armoise annuelle),[42] and the anticholinestérase galantamine (from Galanthus spp.), used to treat Maladie d'Alzheimer.[43] Other plant-derived drugs, used medicinally and/or recreationally include morphine, cocaïne, quinine, tubocurarine, muscarine, and nicotine.[20]:Chapter 6

#### Animaux

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

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 macromolécule target in the body (e.g. α-bungarotoxin from cobras).[44],[45] 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[45].

Because of these specific chemical-target interactions, venom constituents have proved important tools for studying receptors, canal ioniques, 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 antihypertenseur agents cilazapril and captopril. Also, echistatin, a disintegrin from the venom of the saw-scaled viper Echis carinatus was a lead in the development of the antiagrégant tirofiban[45].

In addition to the terrestrial animals and amphibias described above, many marine animals have been examined for pharmacologically active natural products, with corails, sponges, tunicatas, bigorneaus, and ectoproctans yielding chemicals with interesting antalgique, antiviral, and anticancer activities.[46] Two examples developed for clinical use include ω-conotoxine (from the marine snail Conus magus)[47],[48] and ecteinascidin 743 (from the tunicate Ecteinascidia turbinata).[49] The former, ω-conotoxin, is used to relieve severe and chronic pain,[48],[47] while the latter, ecteinascidin 743 is used to treat metastatic sarcome des tissus mous.[50] Other natural products derived from marine animals and under investigation as possible therapies include the chimiothérapie agents discodermolide (from the sponge Discodermia dissoluta),[51] eleutherobin (from the coral Erythropodium caribaeorum), and the bryostatins (from the bryozoan Bugula neritina)[51].

## Utilisations médicale

Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases. As such, natural products are the active components of many médecine traditionnelles.[12],[11],[52],[53],[54] 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 by the U.S. Food and Drug Administration[55],[56]

Representative examples of drugs based on natural products

Peuple autochtone and civilisation experimented with various plant and animal parts to determine what effect they might have. Through méthode essai-erreur in isolated cases, guérisseurs or chamanisme found some sources to provide therapeutic effect, representing knowledge of a crude drug that was passed down through generations in such practices as médecine traditionnelle chinoise and Ayurveda.[57] Extracts of some natural products led to modern discovery of their active ingredients and eventually to the development of new drugs[58].

### Médicaments modernes dérivés de produits naturels

A large number of currently prescribed drugs have been either directly derived from or inspired by natural products.[1],[59] A few representative examples are listed below.

Some of the oldest natural product based drugs are antalgiques. The bark of the saule tree has been known from antiquity to have pain relieving properties. This is due to presence of the natural product salicyline which in turn may be hydrolyzed into acide salicylique. A synthetic derivative acide acétylsalicylique better known as aspirin is a widely used pain reliever. Its mechanism of action is inhibition of the cyclo-oxygénase (COX) enzyme.[60] Another notable example is opium is extracted from the latex from Papaver somniferous (a flowering poppy plant). The most potent narcotic component of opium is the alkaloid morphine which acts as an récepteur opiacé agonist.[61] A more recent example is the N-type calcium channel blocker ziconotide analgesic which is based on a cyclic peptide cone snail toxin (ω-conotoxine MVIIA) from the species Conus magus[62].

A significant number of anti-infectives are based on natural products. The first antibiotic to be discovered, pénicilline, was isolated from the mold Penicillium. Penicillin and related bêta-Lactames work by inhibiting Transpeptidase enzyme that is required by bacteria to cross link peptidoglycane to form the cell wall[63].

Several natural product drugs target tubuline, which is a component of the cytosquelette. These include the tubulin polymerization inhibitor colchicine isolated from the Colchique d'automne (autumn crocus flowering plant), which is used to treat goutte (maladie).[64] Colchicine is biosynthesized from the amino acids phénylalanine and tryptophane. Paclitaxel, in contrast, is a tubulin polymerization stabilizer and is used as a chimiothérapie drug. Paclitaxel is based on the terpenoid natural product paclitaxel, which is isolated from If de l'Ouest (the pacific yew tree)[65].

A class of drugs widely used to lower cholesterol are the Hydroxyméthylglutaryl-CoA réductase inhibitors, for example atorvastatine. These were developed from mevastatin, a polyketide produced by the fungus Penicillium citrinum.[66] Finally, a number natural product drugs are used to treat hypertension and congestive heart failure. These include the enzyme de conversion de l'angiotensine inhibitor captopril. Captopril is based on the peptidic bradykinin potentiating factor isolated from venom of the Brazilian arrowhead viper (Bothrops jararaca)[67].

### Facteurs limitants et favorables

Numerous challenges limit the use of natural products for drug discovery, resulting in 21st century preference by pharmaceutical companies to dedicate discovery efforts toward criblage à haut débit of pure synthetic compounds with shorter timelines to refinement.[12] Natural product sources are often unreliable to access and supply, have a high probability of duplication, inherently create propriété intellectuelle concerns about brevet, vary in composition due to sourcing season or environment, and are susceptible to rising extinction des espèces rates[12].

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.[68],[69] As of 2008, the field of métagénomique was proposed to examine genes and their function in soil microbes,[69],[70] 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 et purification

Benzylpénicilline, 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 Walter Florey, and others, these three named scientists sharing the 1945 Nobel Prize in Medicine for the work. Fleming recognized the antibacterial activity and clinical potential of "pen G", but was unable to purify or stabilize it.[71] Developments in chromatographic separations and lyophilisation helped move progress forward in the production of commercial quantities of penicillin and other natural products.[réf. nécessaire]

All natural products begin as mixtures with other compounds from the natural source, often very complex mixtures, from which the product of interest must be isolated and purified. The isolation of a natural product refers, depending on context, either to the isolation of sufficient quantities of pure chemical matter for chemical structure elucidation, derivitzation/degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but historically, often more),[réf. nécessaire] or to the isolation of "analytical quantities" of the substance of interest, where the focus is on identification and quantitation of the substance (e.g. in biological tissue or fluid), and where the quantity isolated depends on the analytical method applied (but is generally always sub-microgram in scale).[72]Modèle:Page needed The ease with which the active agent can be isolated and purified depends on the structure, stability, and quantity of the natural product. The methods of isolation applied toward achieving these two distinct scales of product are likewise distinct, but generally involve extraction, precipitation, adsorptions, chromatographie, and sometimes cristallisation (chimie)s. In both cases, the isolated substance is purified to chemical homogeneity, i.e. specific combined separation and analytical methods such as LC-MS methods are chosen to be "orthogonal"—achieving their separations based on distinct modes of interaction between substance and isolating matrix—with the goal being repeated detection of only a single species present in the putative pure sample. Early isolation is almost inevitably followed by structure determination, especially if an important pharmacologic activity is associated with the purified natural product.

Structure determination refers to methods applied to determine the structure chimique of an isolated, pure natural product, a process that involves an array of chemical and physical methods that have changed markedly over the history of natural products research; in earliest days, these focused on chemical transformation of unknown substances into known substances, and measurement of physical properties such as melting point and boiling point, and related methods for determining molecular weight.[réf. nécessaire] In the modern era, methods focus on spectrométrie de masse and nuclear magnetic resonance methods, often multidimensional, and, when feasible, small molecule cristallographie.[réf. nécessaire] For instance, the structure chimique of penicillin was determined by Dorothy Crowfoot Hodgkin in 1945, work for which she later received a Nobel Prize in Chemistry (1964)[73].

## Synthèse

Many natural products have very complex structures. The perceived complexity of a natural product is a qualitative matter, consisting of consideration of its molecular mass, the particular arrangements of substructures (groupe fonctionnel, rings etc.) with respect to one another, the number and density of those functional groups, the stability of those groups and of the molecule as a whole, the number and type of stereochemical elements, the physical properties of the molecule and its intermediates (which bear on the ease of its handling and purification), all of these viewed in the context of the novelty of the structure and whether preceding related synthetic efforts have been successful (see below for details).[réf. nécessaire] Some natural products, especially those less complex, are easily and cost-effectively prepared via complete chemical synthesis from readily available, simpler chemical ingredients, a process referred to as synthèse totale (especially when the process involves no steps mediated by biological agents). Not all natural products are amenable to total synthesis, cost-effective or otherwise. In particular, those most complex often are not. Many are accessible, but the required routes are simply too expensive to allow synthesis on any practical or industrial scale. However, in order to be available for further study, all natural products must yield to isolation and purification. This may suffice if isolation provides appropriate quantities of the natural product for the intended purpose (e.g. as a drug to alleviate disease). Drugs such as pénicilline, morphine, and paclitaxel proved to be affordably acquired at needed commercial scales solely via isolation procedures (without any significant synthetic chemistry contributing).[réf. nécessaire] However, in other cases, needed agents are not available without synthetic chemistry manipulations.

### Hemisynthèse

Article détaillé : semi-synthesis.

The process of isolating a natural product from its source can be costly in terms of committed time and material expense, and it may challenge the availability of the relied upon natural resource (or have ecological consequences for the resource). For instance, it has been estimated that the bark of an entire yew tree (Taxus brevifolia) would have to be harvested to extract enough paclitaxel for just a single dose of therapy.[74] Furthermore, the number of analogue structurelues obtainable for structure-activity analysis (SAR) simply via harvest (if more than one structural analogue is even present) is limited by the biology at work in the organism, and so outside of the experimentalist's control.

In such cases where the ultimate target is harder to come by, or limits SAR, it is sometimes possible to source a middle-to-late stage biosynthetic precursor or analogue from which the ultimate target can be prepared. This is termed hémisynthèse or partial synthesis. With this approach, the related biosynthetic intermediate is harvested and then converted to the final product by conventional procedures of synthèse chimique.

This strategy can have two advantages. Firstly, the intermediate may be more easily extracted, and in higher yield, than the ultimate desired product. An example of this is paclitaxel, which can be manufactured by extracting 10-deacetylbaccatin III from T. brevifolia needles, then carrying out a four-step synthesis.[réf. nécessaire] Secondly, the route designed between semisynthetic starting material and ultimate product may permit analogues of the final product to be synthesized. The newer generation semisynthetic pénicilline are an illustration of the benefit of this approach.[réf. nécessaire]

### Synthèse totale

Article détaillé : total synthesis.
Structural representation of cobalamin, an early natural product isolated and structurally characterized.[75] The variable R group can be a méthyle 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[76] and A. Eschenmoser.[77]

In general, the synthèse totale 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 chimie organique.[78],[79] Prior to the development of chimie analytique methods in the twentieth century, the structures of natural products were affirmed by total synthesis (so-called "structure proof by synthesis").[80] Early efforts in natural products synthesis targeted complex substances such as cobalamin (vitamin B12), an essential cofactor in cellular métabolisme[76],[77].

### Symétrie

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 theoretical (DFT), Hartree Fock, 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 effet stérique at the core of the molecule, as most natural products dimerize and trimerize in a head-to-head fashion rather than head-to-tail[81].

## Recherche et enseignement

Research and teaching activities related to natural products fall into a number of different academic areas, including chimie organique, chimie pharmaceutique, pharmacognosie, ethnobotanique, médecine traditionnelle and ethnomédecine. Other biological areas include biologie chimique, Écologie chimique, chimiogénomique, and biologie des systèmes.

### Chimie

Natural products chemistry is a distinct area of chemical research which was important in the histoire de la chimie, the sourcing of substances in early preclinical drug discovery research, the understanding of médecine traditionnelle and ethnomédecine, the evolution of technology associated with chemical separations, the development of modern methods in structure chimique by Résonance magnétique nucléaire and other techniques, and in identification of pharmacologically useful areas of chemical diversity space.[réf. nécessaire] In addition, natural products are prepared by synthèse organique, and have played a central role to the development of the field of organic chemistry by providing tremendously challenging targets and problems for synthetic strategy and tactics.[78],[79] 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 Aldolisation reaction), as well as the discovery of completely new chemical reactions (e.g., the Woodward cis-hydroxylation, Époxydation de Sharpless, and Suzuki–Miyaura cross-coupling reactions).[réf. nécessaire]

### Biochimie

Research is being carried out to understand and manipulate the biochemical pathways involved in natural product synthesis in plants. It is hoped this knowledge will enable medicinally useful phytochemicals such as alkaloids to be produced more efficiently and economically[82].

## Histoire

Antoine Lavoisier (1743-1794)
Friedrich Wöhler (1800-1882)
Hermann Emil Fischer (1852-1919)
Richard Willstätter (1872-1942)
Robert Robinson (1886-1975)

### Fondements de la chimie des produits organiques et naturels

The concept of natural products dates back to the early 19th century, when the foundations of chimie organique 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 chimie minérale, the principles of which had been established in 1789 by the Frenchman Antoine Lavoisier in his work Traité élémentaire de chimie[83].

### Isolation

Lavoisier showed at the end of the 18th century that organic substances consisted of a limited number of elements: primarily carbon and hydrogen and supplemented by oxygen and nitrogen. He quickly focused on the isolation of these substances, often because they had an interesting pharmacological activity. Plants were the main source of such compounds, especially alcaloïde and hétérosides. It was long been known that opium, a sticky mixture of alkaloids (including codéine, morphine, noscapine, thébaïne, and papavérine) from the opium poppy (Pavot somnifère), possessed a narcotic and at the same time mind-altering properties. By 1805, morphine had already been isolated by the German chemist Friedrich Wilhelm Adam Sertürner and in the 1870s it was discovered that boiling morphine with anhydride acétique produced a substance with a strong pain suppressive effect: héroïne.[84] In 1815, Michel-Eugène Chevreul isolated cholestérol, a crystalline substance, from animal tissue that belongs to the class of steroids, and in 1820 strychnine, an alkaloid was isolated.

### Synthèse

A second important step was the synthesis of organic compounds. Whereas the synthesis of inorganic substances had been known for a long time, the synthesis of organic substances was a difficult hurdle. In 1827 the Swedish chemist Jöns Jacob Berzelius held that an indispensable force of nature for the synthesis of organic compounds, called vital force or life force, was needed. This philosophical idea, vitalisme, well into the 19th century had many supporters, even after the introduction of the théorie atomique. The idea of vitalism especially fitted in with beliefs in medicine; the most traditional healing practices believed that disease was the result of some imbalance in the vital energies that distinguishes life from nonlife. A first attempt to break the vitalism idea in science was made in 1828, when the German chemist Friedrich Wöhler succeeded in synthesizing urée, a natural product found in urine, by heating cyanate d'ammonium, an inorganic substance:[85]

${\displaystyle \mathrm {NH_{4}OCN\ {\xrightarrow {\ \ 60^{\circ }C\ \ }}\ H_{2}NCONH_{2}} }$

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

### Théories structurelles

A third step was the structure elucidation of organic substances: although the elemental composition of pure organic substances (irrespective of whether they were of natural or synthetic origin) could be determined fairly accurately, the molecular structure was still a problem. The urge to do structural elucidation resulted from a dispute between Friedrich Wöhler and Justus von Liebig, who both studied a silver salt of the same composition but had different properties. Wöhler studied silver cyanate, a harmless substance, while von Liebig investigated fulminate d'argent, a salt with explosive properties.[86] The elemental analysis shows that both salts contain equal quantities of silver, carbon, oxygen and nitrogen. According to the then prevailing ideas, both substances should possess the same properties, but this was not the case. This apparent contradiction was later solved by Jöns Jacob Berzelius's theory of isoméries, whereby not only the number and type of elements are of importance to the properties and chemical reactivity, but also the position of atoms in within a compound. This was a direct cause for the development of structure theories, such as the radical theory of Jean-Baptiste Dumas (chimiste) and the substitution theory of Auguste Laurent.[87] However, it took until 1858 before by Friedrich Kekulé von Stradonitz formulated a definite structure theory. He posited that carbon tetravalent ad can bind itself to carbon chains as they occur in natural products[88].

### Élargissement du concept

The concept of natural product, which initially based on organic compounds that could be isolated from plants, was extended to include animal material in the middle of the 19th century by the German Justus von Liebig. 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 pénicilline by Alexander Fleming in 1928, fungi and other micro-organisms were added to the arsenal of sources of natural products[84].

### Étapes clés

By the 1930s, several large classes of natural products were known. Important milestones included:

## Notes et références

• (en) Cet article est partiellement ou en totalité issu de l’article de Wikipédia en anglais intitulé .
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« "The simplest definition for a natural product is a small molecule that is produced by a biological source." »

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## Bibliographie

• Chemistry of Natural Products, Berlin, Springer, (ISBN 3-540-40669-7)
• Hanson JR, Natural Products: The Secondary Metabolites, Royal Society of Chemistry, (ISBN 0-85404-490-6)
• Natural Products from Plants, CRC Press, (ISBN 0-8493-3134-X)
• Medicinal Chemistry of Bioactive Natural Products, Wiley-Interscience, (ISBN 0-471-73933-2)

## Liens externes

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