Natural product
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
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]
Classes
The broadest definition of natural product is anything that is produced by life,
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[14][15] and 400,000.[16]
Function
Following Albrecht Kossel's original proposal in 1891,[17] natural products are often divided into two major classes, the primary and secondary metabolites.[18][19] 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.[20]
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.[13]
Primary metabolites
Primary metabolites as defined by Kossel are components of basic metabolic pathways that are required for life. They are associated with essential cellular functions such as nutrient assimilation, energy production, and growth/development. They have a wide species distribution that span many phyla and frequently more than one kingdom. Primary metabolites include the basic building blocks of life: carbohydrates, lipids, amino acids, and nucleic acids.[21]
Primary metabolites that are involved with energy production include
Primary metabolite enzymatic cofactors include members of the
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.[26]
Secondary metabolites have a broad range of functions. These include
General structural classes of secondary metabolites include alkaloids, phenylpropanoids, polyketides, and terpenoids.[7]
Biosynthesis
The biosynthetic pathways leading to the major classes of natural products are described below.[13][24]: Ch. 2
- Photosynthesis or gluconeogenesis → monosaccharides → polysaccharides (cellulose, chitin, glycogen etc.)
- Acetate pathway → fatty acids and polyketides
- Shikimate pathway → aromatic amino acids and phenylpropanoids
- Mevalonate pathway and methyletrythritol phosphate pathway → terpenoids and steroids
- Amino acids → alkaloids
Carbohydrates
Carbohydrates 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 cell walls of bacteria and plants.[citation needed]
Carbohydrate are the products of plant
Fatty acids and polyketides
Through the process of
One molecule of acetyl-CoA (the "starter unit") and several molecules malonyl-CoA (the "extender units") are condensed by fatty acid synthase to produce fatty acids.[24]: Ch. 3 Fatty acid are essential components of lipid bilayers that form cell membranes as well as fat energy stores in animals.[citation needed]
Sources
Natural products may be extracted from the
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.[32][33] In this and related ways, modern medicines can be developed directly from natural sources.[citation needed]
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.
Prokaryotic
Bacteria
The serendipitous discovery and subsequent clinical success of
Although most of the drugs derived from bacteria are employed as anti-infectives, some have found use in other fields of medicine.
Archaea
Because many
Eukaryotic
Fungi
Several anti-infective medications have been derived from fungi including penicillin and the
Plants
Plants are a major source of complex and highly structurally diverse chemical compounds (
: Ch. 6Animals
Animals also represent a source of bioactive natural products. In particular,
Because of these specific chemical-target interactions, venom constituents have proved important tools for studying
In addition to the
Medical uses
Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases.[65][66][67] 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[68][69]
Modern natural product-derived drugs
A large number of currently prescribed drugs have been either directly derived from or inspired by natural products.[1][70]
Some of the oldest natural product based drugs are analgesics. The bark of the
A significant number of
Several natural product drugs target
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.[77] 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).[78]
Limiting and enabling factors
Numerous challenges limit the use of natural products for drug discovery, resulting in 21st century preference by pharmaceutical companies to dedicate discovery efforts toward
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.[79][80] As of 2008, the field of metagenomics was proposed to examine genes and their function in soil microbes,[80][81] 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
All natural products begin as mixtures with other compounds from the natural source, often very complex mixtures, from which the product of interest must be isolated and purified. The isolation of a natural product refers, depending on context, either to the isolation of sufficient quantities of pure chemical matter for chemical structure elucidation, derivitzation/degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but historically, often more),[citation needed] 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).[83][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 natural product.[citation needed]
Structure determination refers to methods applied to determine the
Synthesis
Many natural products have very complex structures. The perceived complexity of a natural product is a qualitative matter, consisting of consideration of its molecular mass, the particular arrangements of substructures (
Some natural products, especially those less complex, are easily and cost-effectively prepared via complete chemical synthesis from readily available, simpler chemical ingredients, a process referred to as total synthesis (especially when the process involves no steps mediated by biological agents). Not all natural products are amenable to total synthesis, cost-effective or otherwise. In particular, those most complex often are not. Many are accessible, but the required routes are simply too expensive to allow synthesis on any practical or industrial scale. However, to be available for further study, all natural products must yield to isolation and purification. This may suffice if isolation provides appropriate quantities of the natural product for the intended purpose (e.g. as a drug to alleviate disease). Drugs such as penicillin, morphine, and paclitaxel proved to be affordably acquired at needed commercial scales solely via isolation procedures (without any significant synthetic chemistry contributing).[citation needed] However, in other cases, needed agents are not available without synthetic chemistry manipulations.[citation needed]
Semisynthesis
The process of isolating a natural product from its source can be costly in terms of committed time and material expense, and it may challenge the availability of the relied upon natural resource (or have ecological consequences for the resource). For instance, it has been estimated that the bark of an entire yew tree (Taxus brevifolia) would have to be harvested to extract enough paclitaxel for just a single dose of therapy.[85] Furthermore, the number of structural analogues 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.[citation needed]
In such cases where the ultimate target is harder to come by, or limits SAR, it is sometimes possible to source a middle-to-late stage biosynthetic precursor or analogue from which the ultimate target can be prepared. This is termed semisynthesis or partial synthesis. With this approach, the related biosynthetic intermediate is harvested and then converted to the final product by conventional procedures of chemical synthesis.[citation needed]
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
Total synthesis
In general, the total synthesis of natural products is a non-commercial research activity, aimed at deeper understanding of the synthesis of particular natural product frameworks, and the development of fundamental new synthetic methods. Even so, it is of tremendous commercial and societal importance. By providing challenging synthetic targets, for example, it has played a central role in the development of the field of organic chemistry.[89][90] 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").[91] Early efforts in natural products synthesis targeted complex substances such as cobalamin (vitamin B12), an essential cofactor in cellular metabolism.[87][88]
Symmetry
Examination of
Research and teaching
Research and teaching activities related to natural products fall into a number of diverse academic areas, including organic chemistry, medicinal chemistry, pharmacognosy,
Chemistry
Natural products chemistry is a distinct area of chemical research which was important in the development and
History
Foundations of organic and natural product chemistry
The concept of natural products dates back to the early 19th century, when the foundations of organic chemistry were laid. Organic chemistry was regarded at that time as the chemistry of substances that plants and animals are composed of. It was a relatively complex form of chemistry and stood in stark contrast to inorganic chemistry, the principles of which had been established in 1789 by the Frenchman Antoine Lavoisier in his work Traité Élémentaire de Chimie.[101]
Isolation
Lavoisier showed at the end of the 18th century that organic substances consisted of a limited number of elements: primarily carbon and hydrogen and supplemented by oxygen and nitrogen. He quickly focused on the isolation of these substances, often because they had an interesting pharmacological activity. Plants were the main source of such compounds, especially alkaloids and
Synthesis
A second important step was the synthesis of organic compounds. Whereas the synthesis of inorganic substances had been known for a long time, the synthesis of organic substances was a difficult hurdle. In 1827 the Swedish chemist
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
Structural theories
A third step was the structure elucidation of organic substances: although the elemental composition of pure organic substances (irrespective of whether they were of natural or synthetic origin) could be determined fairly accurately, the molecular structure was still a problem. The urge to do structural elucidation resulted from a dispute between Friedrich Wöhler and
Expanding the concept
The concept of natural product, which initially based on organic compounds that could be isolated from plants, was extended to include animal material in the middle of the 19th century by the German
Milestones
By the 1930s, several large classes of natural products were known. Important milestones included:[according to whom?]
- Terpenes, first systematically studied by Otto Wallach (Nobel Prize 1910) and later by Leopold Ružička (Nobel Prize 1939)
- Dyes based on (Nobel Prize 1915) and Hans Fischer (Nobel Prize 1930)
- Steroids, studied by Heinrich Otto Wieland (Nobel Prize 1927) and Adolf Windaus (Nobel Prize 1928)
- Carotenoids, studied by Paul Karrer (Nobel Prize 1937)
- Vitamins, studied among others by Paul Karrer, Adolf Windaus, Robert R. Williams, Norman Haworth (Nobel Prize 1937), Richard Kuhn (Nobel Prize 1938) and Albert Szent-Györgyi
- Hormones studied by Adolf Butenandt (Nobel Prize 1939) and Edward Calvin Kendall (Nobel Prize 1950)
- Alkaloids and Robert Robinson(Nobel Prize 1947)
See also
- Biogenic substance
- Pharmacognosy
- Phytotherapy
Journals
- Chemistry of Natural Compounds
- Journal of Natural Products
- Natural Product Reports
- Natural Product Research
References
Footnotes
- Nobel Prize in Medicinefor the work.
Citations
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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.
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Natural products: naturally occurring compounds that are end products of secondary metabolism; often, they are unique compounds for particular organisms or classes of organisms.
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Further reading
- Bhat SV, Nagasampagi BA, Sivakumar M (2005). Chemistry of Natural Products (2 ed.). Berlin: Springer. ISBN 3-540-40669-7.
- Hanson JR (2003). Natural Products: The Secondary Metabolites. Royal Society of Chemistry. ISBN 0-85404-490-6.
- Kaufman PB (1999). Natural Products from Plants. CRC Press. ISBN 0-8493-3134-X.
- Liang XT, Fang WS, eds. (2006). Medicinal Chemistry of Bioactive Natural Products. Wiley-Interscience. ISBN 0-471-73933-2.
- V. K. Ahluwalia; Lalita S. Kumar; Sanjiv Kumar (2022). Chemistry of natural products: amino acids, peptides, proteins and enzymes. Springer. ISBN 978-3-030-86697-6.
- Mayuri Napagoda, Lalith Jayasinghe, ed. (2022). Chemistry of natural products: phytochemistry and pharmacognosy of medicinal plants. De Gruyter. ISBN 978-3-11-059589-5.
External links
- 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.
- "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.