Natural product

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Paclitaxel (Taxol) is a natural product derived from the yew tree.[1]

A natural product is a chemical compound or substance produced by a living organism – found in nature.[2][3] In the broadest sense, natural products include any substance produced by life.[4][5] 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 mean purified 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 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]

Natural products sometimes have pharmacological or biological activity that can be of therapeutic benefit in treating diseases. As such, natural products are the active components of many traditional medicines. Furthermore 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. In fact, natural products are the inspiration for approximately one half of U.S. Food and Drug Administration-approved drugs.

Natural products can also be prepared by total synthesis and have played a central role in the development of the field of organic chemistry by providing challenging synthetic targets.

Classes[edit]

The broadest definition of natural product is anything that is produced by life.[4][12] A more restrictive definition of a natural product is an organic compound that is synthesized by a living organism.[7] The remainder of this article restricts itself to this more narrow definition.

Natural products may be classified according to their biological function or the chemical structure/biosynthetic pathway as described below.

Biological function[edit]

Following Albrecht Kossel's original proposal in 1891,[13] natural products are often divided into two major classes, the primary and secondary metabolites.[14][15] Primary metabolites have an intrinsic function that is essential to the survival of the organism that produces them. Secondary metabolites in contrast have an extrinsic function that mainly affects other organisms. Secondary metabolites are not essential to survival but do increase the competitiveness of the organism within its environment. Because of their ability to modulate biochemical and signal transduction pathways, some secondary metabolites have useful medicinal properties.

Natural products especially within the field of organic chemistry are often defined as primary and secondary metabolites. A more restrictive definition limiting natural products to secondary metabolites is commonly used within the fields of medicinal chemistry and pharmacognosy.[12]

Primary metabolites[edit]

Molecular building blocks of life

Primary metabolites as defined by Kossel are components of basic metabolic pathways that are required for life. They are associated with essential cellular functions such as nutrient assimilation, energy production, and growth/development. They have a wide species distribution that span many phyla and frequently more than one kingdom. Primary metabolites include carbohydrates, lipids, amino acids, and nucleic acids[14][15] which are the basic building blocks of life.[16]

Primary metabolites that are involved with energy production include respiratory and photosynthetic enzymes. Enzymes in turn are composed of amino acids and often non-peptidic cofactors that are essential for enzyme function.[17] The basic structure of cells and of organisms are also composed of primary metabolites. These include cell membranes (phospholipids), cell walls (peptidoglycans), and cytoskeletons (proteins).[18]

Primary metabolite enzymatic cofactors include members of the vitamin B family. Vitamin B1 as thiamine diphosphate is a coenzyme for pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, and transketolase which are all involved in carbohydrate metabolism. Vitamin B2 (riboflavin) is a constituent of FMN and FAD which are necessary for many redox reactions. Vitamin B3 (nicotinic acid or niacin), synthesized from tryptophan is a component of the coenzymes NAD+ and NADP+ which in turn are required for electron transport in the Krebs cycle, oxidative phosphorylation, as well as many other redox reactions. Vitamin B5 (pantothenic acid) is a constituent of coenzyme A, a basic component of carbohydrate and amino acid metabolism as well as the biosynthesis of fatty acids and polyketides. Vitamin B6 (pyridoxol, pyridoxal, and pyridoxamine) as pyridoxal 5′-phosphate is a cofactor for many enzymes especially transaminases involve in amino acid metabolism. Vitamin B12 (cobalamins) contain a corrin ring similar in structure to porphyrin and is an essential coenzyme for the catabolism of fatty acids as well for the biosynthesis of methionine.[19]:Chapter 2

DNA and RNA which store and transmit genetic information are composed of nucleic acid primary metabolites.[17]

First messengers are signaling molecules that control metabolism or cellular differentiation. These signaling molecules include hormones and growth factors in turn are composed of peptides, biogenic amines, steroid hormones, auxins, gibberellins, etc. These first messengers interact with cellular receptors which are composed of proteins. Cellular receptors in turn activate second messengers are used to relay the extracellular message to intracellular targets. These signaling molecules include the primary metabolites cyclic nucleotides, diacyl glycerol, etc.[20]

Secondary metabolites[edit]

Main article: secondary metabolite
Representative examples of each of the major classes of secondary metabolites

Secondary in contrast to primary metabolites are dispensable and are not absolutely required for survival. Furthermore secondary metabolites typically have a narrow species distribution. Other than they are dispensable, the function of many secondary metabolites is otherwise unknown. It is assumed however that they confer a competitive advantage to the organism that produces them.[21] An alternative view is that in analogy to the immune system, a majority of individual secondary metabolites have no specific function, but having the machinery in place to produce these diverse chemical structures is important so that a few secondary metabolites that are useful are produced and selected for.[22]

Secondary metabolites are used for a broad range of purposes. These include pheromones that act as social signaling molecules with other individuals of the same species, signaling 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.[23]

General structural classes of secondary metabolites include alkaloids, phenylpropanoids, polyketides, and terpenoids[7] which are described in more detail in the biosynthesis section below.

Biosynthesis/chemical structure[edit]

Biosynthesis of primary and secondary metabolites.[19]:Chapter 2

The biosynthetic pathways leading to the major classes of natural products are described below.[12][19]:Chapter 2

Natural sources[edit]

Natural products may be extracted from tissues of terrestrial plants, marine organisms or microorganism fermentation broths. A crude (untreated) extract from any one of these sources typically contains novel, structurally diverse chemical compounds, which the natural environment is a rich source of.

Chemical diversity in nature is based on biological and geographical 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 bioprospecting.

Pharmacognosy 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 active principle - 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 secondary metabolites often with complex chemical structures. 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.

Plants[edit]

Plants have always been a rich source of pharmacologically active nature products (e.g. Alkaloids, morphine, cocaine, digitalis, quinine, tubocurarine, nicotine, and muscarine). Many of these compounds are useful drugs in themselves (e.g. Alkaloids, morphine and quinine), and others have been the basis for synthetic drugs (e.g. local anaesthetics developed from cocaine). Clinically useful drugs which have been recently isolated from plants include the anticancer agent paclitaxel (Taxol) from the yew tree, and the antimalarial agent artemisinin from Artemisia annua.

Plants provide a large bank of rich, complex and highly varied structures which are unlikely to be synthesized in laboratories. Furthermore, evolution has already carried out a screening process itself whereby plants are more likely to survive if they contain potent compounds which deter animals from eating them. Even today, the number of plants that have been extensively studied is relatively very few and the vast majority have not been studied at all.

Major classes of molecules include terpenoids, phytosterols, alkaloids, natural phenols and polyphenols.

Microbes[edit]

Microorganisms such as bacteria and fungi have been invaluable for discovering pharmacologically active nature products. These microorganisms produce a large variety of antimicrobial agents which have evolved to give their hosts an advantage over their competitors in the microbiological world.

The screening of microorganisms became highly popular after the discovery of penicillin. Soil and water samples were collected from all over the world in order to study new bacterial or fungal strains, leading to an impressive arsenal of antibacterial agents such as the cephalosporins, tetracyclines, aminoglycosides, rifamycins, and chloramphenicol.

Although most of the drugs derived from microorganisms are used in antibiotics, some microbial metabolites have provided pharmacologically active agents in other fields of medicine. For example, asperlicin - isolated from Aspergillus alliaceus - is a novel antagonist of a peptide hormone called cholecystokinin (CCK) which is involved in the control of appetite. CCK also acts as a neurotransmitter in the brain and is thought to be involved in panic attacks. Analogues of asperlicin may therefore have potential in treating anxiety. Other examples include the fungal metabolite lovastatin, which became a lead for a series of drugs that lower cholesterol levels, and another fungal metabolite called ciclosporin which is used to suppress the immune response after transplantation operations.

Marine world[edit]

In recent years, there has been a great interest in finding pharmacologically active nature products from marine sources. Coral, sponges, fish, and marine microorganisms have a wealth of biologically potent chemicals with interesting inflammatory, antiviral, and anticancer activity. For example, curacin A is obtained from a marine cyanobacterium and shows potent antitumor activity. Other antitumor agents derived from marine sources include eleutherobin, discodermolide, bryostatins, dolostatins, and cephalostatins.

Animals[edit]

Animals can sometimes be a source of new pharmacologically active nature products.[24] For example, a series of antibiotic peptides were extracted from the skin of the African clawed frog and a potent analgesic compound called epibatidine was obtained from the skin extracts of the Ecuadorian poison frog.

Venoms and toxins[edit]

Venoms and toxins from animals, plants, snakes, spiders, scorpions, insects,[24] and microorganisms are extremely potent because they often have very specific interactions with a macromolecular target in the body. As a result, they have proved important tools in studying receptors, ion channels, and enzymes. Many of these toxins are polypeptides (e.g. α-bungarotoxin from cobras). However, non-peptide toxins such as tetrodotoxin from the puffer fish are also extremely potent.

Venoms and toxins have been developed as leads in the development of novel drugs. For example, teprotide, a peptide isolated from the venom of the Brazilian viper, was a lead in the development of the antihypertensive agents cilazapril and captopril.

The neurotoxins from Clostridium botulinum are responsible for serious food poisoning (botulism), but they have a clinical use as well. They can be injected into specific muscles (such as those controlling the eyelid) to prevent muscle spasm. These toxins prevent cholinergic transmission and could well prove a lead for the development of novel anticholinergic drugs.[citation needed][editorializing]

Medical uses[edit]

Natural products sometimes have pharmacological or biological activity that can be of therapeutic benefit in treating diseases. As such, natural products are the active components of many traditional medicines.[25] Furthermore 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.[11][26][27] In fact, natural products are the inspiration for approximately one half of U.S. Food and Drug Administration-approved drugs.[28][29]

Traditional medicine and ethnopharmacology[edit]

Representative examples of drugs based on natural products

Indigenous peoples and ancient civilizations experimented with various plant and animal parts to determine what effect they might have. Through trial and error, traditional healers or shamans found that some had healing power. These represented the first crude drugs and this knowledge was past down through the generations and systematized for example in traditional Chinese medicine and Ayurveda.[30] Many of these traditional medicines have real, beneficial effects and extracts of these crude drugs lead to the discovery of their active ingredients and eventually to the development of modern chemically pure drugs.[31]

Modern natural product-derived drugs[edit]

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

Some of the oldest natural product based drugs are analgesics. The bark of the willow tree has been known from antiquity to have pain relieving properties. This is due to presence of the natural product salicin which in turn may be hydrolyzed into salicylic acid. A synthetic derivative acetylsalicylic acid better known as aspirin is a widely used pain reliever. Its mechanism of action is inhibition of the cyclooxygenase (COX) enzyme.[32] Another notable example is opium is extracted from the latex from Papaver somniferous (a flowering poppy plant). The most potent narcotic component of opium is the alkaloid morphine which acts as an opioid receptor antagonist.[33] A more recent example is the N-type calcium channel blocker ziconotide analgesic which is based on a cyclic peptide cone snail toxin (ω-conotoxin MVIIA) from the species Conus magus.[34]

A significant number of antiinfectives are based on natural products. The first and still most widely used antibacterial drug is penicillin which is isolated from the mold Penicillium. Penicillin and related beta lactams work by inhibiting DD-transpeptidase enzyme that is required by bacteria to cross link peptidoglycan to form the cell wall.[35]

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.[36] 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).[37]

A widely prescribed class of drugs that is used to lower cholesterol are the HMG-CoA reductase inhibitors that include atorvastatin. These were developed from the mevastatin, a polyketide produced by the fungus Penicillium citrinum.[38] Finally, a number natural product drugs are used to treat hypertension and congestive heart failure. These include the angiotensin-converting enzyme (ACE) inhbitiors such as captopril. Captopril in turn is based on the peptidic bradykinin potentiating factor (BPF) isolated from snake venom from the Brazilian arrowhead viper (Bothrops jararaca).[39]

Isolation and purification[edit]

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, and others, these three named sharing the 1945 Nobel Prize in Medicine for the work. Fleming recognized the antibiotic properties and remarkable lack of toxicity of "pen G" in humans, but was unable to capture its clinical utility because he could only prepare aqueous extracts; his removal of water led to decomposition of the drug.[citation needed] Developments in chromatographic separations and freeze drying helped move progress forward in the production of commercial quantities of penicillin and other natural products.[citation needed]

All natural products of interest begin as mixtures with other compounds from the natural source, often very complex mixtures, from which the particular product of interest must be isolated and purified. The isolation of a natural product refers, depending on context, either to the isolation of the considerable quantities of pure chemical matter required for chemical structure elucidation, derivitzation/degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but historically, often more),[citation needed] 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 amount isolated depends on the analytical method applied (but is generally always sub-microgram in scale).[40][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, chromatography, and sometimes crystallizations. In both cases, the isolated substance is purified to chemical homogeneity, i.e., specific combined separation and analytical methods such as 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 activity.

Structure determination refers to methods applied to determine the chemical structure of an isolated, pure natural product, a process that involves an array of chemical and physical methods that have changed markedly over the history of natural products research; in earliest days, these focused on chemical transformation of unknown substances into known substances, and measurement of physical properties such as melting point and boiling point, and related methods for determining molecular weight.[citation needed] In the modern era, methods focus on mass spectrometry and nuclear magnetic resonance methods, often multidimensional, and, when feasible, small molecule crystallography.[citation needed] 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).[41]

Synthesis[edit]

Many natural products have very complex structures. The perceived complexity of a natural product is a qualitative matter, consisting of consideration of its molecular mass, the particular arrangements of substructures (functional groups, rings, etc.) with respect to one another, the number and density of those functional groups, the stability of those groups and of the molecule as a whole, the numbers and types of its 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,[citation needed] see details below. Some natural products, especially those less complex, are easily and cost-effectively prepared via a complete chemical synthesis from readily available, simpler chemical ingredients, a process referred to as total synthesis (especially when the process involves no steps mediated by biological agents). Not all natural products are amenable to total synthesis, cost-effective or otherwise; in particular, those most complex often are not. Many are accessible, but the required routes are simply too expensive to allow synthesis on any practical or industrial scale. However, in order to be available for further study, all natural products must yield to isolation and purification, as described above. In some cases, the isolation may suffice to fulfill all needed quantities at the point in time the natural product is put to use (e.g., as a drug to alleviate disease); drugs such as penicillin, morphine, and paclitaxel proved to be affordably acquired at needed commercial scales solely via isolation procedures (without any significant synthetic chemistry contributing).[citation needed] However, in other cases, needed agents are not available sans synthetic chemistry manipulations.

Semisynthesis[edit]

At times the process of isolating the ultimately desired natural product from its natural 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 entire yew tree would have to harvested to extract enough paclitaxel to provide a patient's single dose over the course of their therapy.[42] Furthermore, the number of structural analogues obtained that are useful for structure-activity analysis (SAR) simply via harvest (if any but a single one are) is defined by the biology at work in the organism, and so outside of the experimentalists control.

In such cases where the ultimate target is harder to come by, or limits SAR, it is sometimes possible to source an middle-to-late stage biosynthetic precursor or analog from which the ultimate target can be prepared. This approach is termed semisynthesis, or partial synthesis. In it, the harvested, related biosynthetic intermediate is then converted to the final product by conventional procedures of chemical synthesis.

This approach can have two advantages. First, the intermediate may be more easily extracted, and in higher yield, than the ultimate desired product. A recent example is paclitaxel, which has been manufactured in past by extracting 10-deacetylbaccatin III from T. brevifolia, needles, then carrying out a four step synthesis.[citation needed] Second, the route designed between semisynthetic starting material and ultimate product may allow for the possibility of synthesizing analogues of the final product. Inroads made into the newer generation semisynthetic penicillins are an illustration of this benefit of the approach.[citation needed]

Total synthesis[edit]

Structural representation of cobalamine, an early natural product isolated and structurally characterized.[43] 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 R.B. Woodward[44] and A. Eschenmoser.[45]

In general, the total synthesis of natural products is a largely 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 one of tremendous commercial and societal importance, and has played a central role in the development of the field of organic chemistry (by providing challenging synthetic targets).[46][47] As well, no natural product structure is considered fully affirmed by science, until the natural product has been synthesized (so-called proof by synthesis). Early efforts in natural products synthesis targeted complex substances as cobalamin (vitamin B12, at right), an essential cofactor in all of metabolism.[44][45]

Research and teaching[edit]

Research and teaching activities related to natural products fall into a number of different academic areas, including organic chemistry, medicinal chemistry, pharmacognosy, pharmacology, and traditional medicine (ethnobotany ethnopharmacology). Other biological areas include chemical biology, chemical ecology, chemogenomics, and systems biology.

Chemistry[edit]

Natural products chemistry is a distinct area of chemical research which was important in the history of chemistry, the sourcing of substances in early preclinical drug discovery research, the understanding of traditional medicine and ethnopharmacology, the evolution of technology associated with chemical separations, the development of modern methods in chemical structure determination by NMR and other techniques, and in identification of pharmacologically useful areas of chemical diversity space.[citation needed] In addition, natural products are prepared by organic synthesis, and have played an central role to the development of the field of organic chemistry by providing tremendously challenging targets and problems for synthetic strategy and tactics.[46][47] In this regard, natural products play a central role in the training of new synthetic organic chemists, and are a principle 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).[citation needed]

See also[edit]

References[edit]

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Further reading[edit]

  • Hanson JR (2003). Natural Products: The Secondary Metabolites. Royal Society of Chemistry. ISBN 0-85404-490-6. 
  • Liang X-T, Fang W-S, ed. (2006). Medicinal Chemistry of Bioactive Natural Products. Wiley-Interscience. ISBN 0-471-73933-2. 
  • Peter B, Kaufman PB (1999). Natural Products from Plants. CRC Press. ISBN 0-8493-3134-X. 
  • Bhat SV, Nagasampagi BA, Sivakumar M (2005). Chemistry of Natural Products (2 ed.). Berlin: Springer. ISBN 3-540-40669-7. 

Journals[edit]

External links[edit]

  • Natural Products page, William Reusch (2010) Virtual Textbook of Organic Chemistry, Ann Arbor, Mich.:Michigan State University, Department of Chemistry
  • 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 This article incorporates text from the public domain 1913 Webster's Dictionary.