A natural product is a chemical compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. 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.
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. Within the field of medicinal chemistry, the definition is often further restricted to secondary metabolites. Secondary metabolites are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage. Many secondary metabolites are cytotoxic and have been selected and optimized through evolution for use as "chemical warfare" agents against prey, predators, and competing organisms.
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 not only of most traditional medicines but also many modern medicines. Furthermore, because the structural diversity of natural products exceeds that readily achievable by chemical synthesis, and synthetic analogs can be prepared with improved potency and safety, 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.
- 1 Classes
- 2 Function
- 3 Biosynthesis
- 4 Sources
- 5 Medical uses
- 6 Isolation and purification
- 7 Synthesis
- 8 Research and teaching
- 9 See also
- 10 References
- 11 Further reading
- 12 Journals
- 13 External links
The broadest definition of natural product is anything that is produced by life, and includes the likes of biotic materials (e.g. wood, silk), bio-based materials (e.g. bioplastics, cornstarch), bodily fluids (e.g. milk, plant exudates), and other natural materials (e.g. soil, coal). A more restrictive definition of a natural product is an organic compound that is synthesized by a living organism. The remainder of this article restricts itself to this more narrow definition.
Natural products may be classified according to their biological function, biosynthetic pathway, or source as described below.
Following Albrecht Kossel's original proposal in 1891, natural products are often divided into two major classes, the primary and secondary metabolites. Primary metabolites have an intrinsic function that is essential to the survival of the organism that produces them. Secondary metabolites in contrast have an extrinsic function that mainly affects other organisms. Secondary metabolites are not essential to survival but do increase the competitiveness of the organism within its environment. Because of their ability to modulate biochemical and signal transduction 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.
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 which are the basic building blocks of life.
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. The basic structure of cells and of organisms are also composed of primary metabolites. These include cell membranes (e.g. phospholipids), cell walls (e.g. peptidoglycan, chitin), and cytoskeletons (proteins).
Primary metabolite enzymatic cofactors include members of the vitamin B family. Vitamin B1 as thiamine diphosphate is a coenzyme for pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, and transketolase which are all involved in carbohydrate metabolism. Vitamin B2 (riboflavin) is a constituent of FMN and FAD which are necessary for many redox reactions. Vitamin B3 (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.:Chapter 2
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.
Secondary in contrast to primary metabolites are dispensable and not absolutely required for survival. Furthermore secondary metabolites typically have a narrow species distribution.
Secondary metabolites have a broad range of functions. These include pheromones that act as social signaling molecules with other individuals of the same species, 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. For other secondary metabolites, the function is unknown. One hypothesis is that they confer a competitive advantage to the organism that produces them. An alternative view is that, in analogy to the immune system, 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.
- 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
Natural products may be extracted from the cells, tissues, and secretions of microorganisms, plants and animals. A crude (unfractionated) extract from any one of these sources will contain a range of structurally diverse and often novel chemical compounds. Chemical diversity in nature is based on biological diversity, so researchers 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.
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. 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.), the polymyxins (from Paenibacillus polymyxa), and the rifamycins (from Amycolatopsis rifamycinica).
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. Also, the glycopeptide bleomycin is used for the treatment of several cancers including Hodgkin's lymphoma, head and neck cancer, and testicular cancer. 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, subterranean bacteria found deep underground via mining/drilling, and marine bacteria.
Several anti-infective medications have been derived from fungi including penicillin and the cephalosporins (antibacterial drugs from Penicillium chrysogenum and Cephalosporium acremonium, respectively) and griseofulvin (an antifungal drug from Penicillium griseofulvum). 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.:Chapter 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.
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). Major classes of phytochemical include phenols, polyphenols, tannins, terpenes, and alkaloids. 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), the antimalarial agent artemisinin (from Artemisia annua), and the acetylcholinesterase inhibitor galantamine (from Galanthus spp.), used to treat Alzheimer's disease. Other plant-derived drugs, used medicinally and/or recreationally include morphine, cocaine, quinine, tubocurarine, muscarine, and nicotine.:Chapter 6
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). As with plant feeding deterrents, this biological activity is attributed to natural selection, organisms capable of killing or paralyzing their prey and/or defending themselves against predators being more likely to survive and reproduce.
Because of these specific chemical-target interactions, venom constituents have proved important tools for studying receptors, ion 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. 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.
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. Two examples developed for clinical use include ω-conotoxin (from the marine snail Conus magus) and ecteinascidin 743 (from the tunicate Ecteinascidia turbinata). The former, ω-conotoxin, is used to relieve severe and chronic pain, while the latter, ecteinascidin 743 is used to treat metastatic soft tissue sarcoma. Other natural products derived from marine animals and under investigation as possible therapies include the antitumour agents discodermolide (from the sponge Discodermia dissoluta), eleutherobin (from the coral Erythropodium caribaeorum), and the bryostatins (from the bryozoan Bugula neritina).
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.
Traditional medicine and ethnopharmacology
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. 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.
Modern natural product-derived drugs
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.
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. 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 agonist. A more recent example is the N-type calcium channel blocker ziconotide analgesic which is based on a cyclic peptide cone snail toxin (ω-conotoxin MVIIA) from the species Conus magus.
A significant number of anti-infectives are based on natural products. The first antibiotic to be discovered, penicillin, was isolated from the mold Penicillium. Penicillin and related beta lactams work by inhibiting DD-transpeptidase enzyme that is required by bacteria to cross link peptidoglycan to form the cell wall.
Several natural product drugs target tubulin, which is a component of the cytoskeleton. These include the tubulin polymerization inhibitor colchicine isolated from the Colchicum autumnale (autumn crocus flowering plant), which is used to treat gout. Colchicine is biosynthesized from the amino acids phenylalanine and tryptophan. Paclitaxel, in contrast, is a tubulin polymerization stabilizer and is used as a chemotherapeutic drug. Paclitaxel is based on the terpenoid natural product taxol, which is isolated from Taxus brevifolia (the pacific yew tree).
A class of drugs widely used to lower cholesterol are the HMG-CoA reductase inhibitors, for example atorvastatin. These were developed from mevastatin, a polyketide produced by the fungus Penicillium citrinum. Finally, a number natural product drugs are used to treat hypertension and congestive heart failure. These include the angiotensin-converting enzyme (ACE) inhbitior captopril. Captopril is based on the peptidic bradykinin potentiating factor (BPF) isolated from venom of the Brazilian arrowhead viper (Bothrops jararaca).
Isolation and purification
All natural products begin as mixtures with other compounds from the natural source, often very complex mixtures, from which the product of interest must be isolated and purified. The isolation of a natural product refers, depending on context, either to the isolation of sufficient quantities of pure chemical matter for chemical structure elucidation, derivitzation/degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but historically, often more), or to the isolation of "analytical quantities" of the substance of interest, where the focus is on identification and quantitation of the substance (e.g. in biological tissue or fluid), and where the quantity isolated depends on the analytical method applied (but is generally always sub-microgram in scale).[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.
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. In the modern era, methods focus on mass spectrometry and nuclear magnetic resonance methods, often multidimensional, and, when feasible, small molecule crystallography. 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).
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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 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). 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, 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 penicillin, morphine, and paclitaxel proved to be affordably acquired at needed commercial scales solely via isolation procedures (without any significant synthetic chemistry contributing). However, in other cases, needed agents are not available without synthetic chemistry manipulations.
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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. 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.
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.
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. Secondly, the route designed between semisynthetic starting material and ultimate product may permit analogues of the final product to be synthesized. The newer generation semisynthetic penicillins are an illustration of the benefit of this approach.
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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. Also, no natural product structure is considered fully affirmed by science until it has been produced by total synthesis (so-called proof-by-synthesis). Early efforts in natural products synthesis targeted complex substances such as cobalamin (vitamin B12), an essential cofactor in cellular metabolism.
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 steric hindrance at the core of the molecule, as most natural products dimerize and trimerize in a head-to-head fashion rather than head-to-tail.
Research and teaching
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Research and teaching activities related to natural products fall into a number of different academic areas, including organic chemistry, medicinal chemistry, pharmacognosy, ethnobotany, traditional medicine and ethnopharmacology. Other biological areas include chemical biology, chemical ecology, chemogenomics, and systems biology.
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. 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. 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).
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.
- Cutler S, Cutler HG (2000). Biologically active natural products: pharmaceuticals. CRC Press. p. 5. ISBN 978-0-8493-1887-0.
- 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.
- "All natural". Nature Chemical Biology 3 (7): 351. 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.
- Samuelson G (1999). Drugs of Natural Origin: A Textbook of Pharmacognosy. Taylor & Francis Ltd,. ISBN 9789186274818.
- National Center for Complementary and Alternative Medicine (2013-07-13). "Natural Products Research—Information for Researchers | NCCAM". U.S. Department of Health & Human Services.
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.
- "About Us". Natural Products Foundation. Retrieved 2013-12-07.
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.
- Hanson JR (2003). Natural products : the secondary metabolite. Cambridge: Royal Society of Chemistry. ISBN 0-85404-490-6.
Natural products are organic compounds that are formed by living systems.
- "Natural Products". Stedman's Medical Dictionary. Lippincott Williams & Wilkins.
Natural products: naturally occurring compounds that are end products of secondary metabolism; often, they are unique compounds for particular organisms or classes of organisms.
- 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).
- Maplestone RA, Stone MJ, Williams DH (June 1992). "The evolutionary role of secondary metabolites--a review". Gene 115 (1–2): 151–7. doi:10.1016/0378-1119(92)90553-2. PMID 1612430.
- Hunter P (September 2008). "Harnessing Nature's wisdom. Turning to Nature for inspiration and avoiding her follies". EMBO Rep. 9 (9): 838–40. doi:10.1038/embor.2008.160. PMC 2529361. PMID 18762775.
- Bhat SV, Nagasampagi BA, Sivakumar M (2005). Chemistry of Natural Products. Berlin ; New York: Springer. ISBN 81-7319-481-5.
- Kossel A (1891). "Ueber die chemische Zusammensetzung der Zelle" [The chemical composition of the cell]. Archiv für Physiologie (in German): 181–186. Vancouver style error (help)
- Kliebenstein DJ (2004). "Secondary metabolites and plant/environment interactions: a view through Arabidopsis thaliana tinged glasses". Plant, Cell and Environment 27 (6): 675–684. 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).
- Karlovsky P (2008). "Secondary metabolites in soil ecology". Soil Biology 14: 1–19. doi:10.1007/978-3-540-74543-3_1.
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.
- 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.
- Cox DL, Nelson MM (2013). Lehninger Principles of biochemistry (6th ed.). New York, N.Y.: W.H. Freeman. ISBN 978-1-4641-0962-1.
- Boal D (2006). Mechanics of the cell (4th printing ed.). Cambridge, UK: Cambridge University Press. ISBN 978-0-521-79681-1.
- Dewick PM (2009). Medicinal natural products: a biosynthetic approach (3rd ed.). Chichester: Wiley. ISBN 978-0-470-74167-2.
- Sitaramayya A (1999). Introduction to cellular signal transduction. Boston: Birkhäuser. ISBN 978-0-8176-3982-2.
- Demain AL, Fang A (2000). "The natural functions of secondary metabolites". Adv. Biochem. Eng. Biotechnol. 69: 1–39. doi:10.1007/3-540-44964-7_1. PMID 11036689.
- Williams DH, Stone MJ, Hauck PR, Rahman SK (1989). "Why are secondary metabolites (natural products) biosynthesized?". J. Nat. Prod. 52 (6): 1189–208. doi:10.1021/np50066a001. PMID 2693613.
- Firn RD, Jones CG (2000). "The evolution of secondary metabolism - a unifying model". Mol. Microbiol. 37 (5): 989–94. doi:10.1046/j.1365-2958.2000.02098.x. PMID 10972818.
- Strobel G, Daisy B (2003). "Bioprospecting for microbial endophytes and their natural products". Microbiol Mol Biol Rev 67 (4): 491–502. doi:10.1128/MMBR.67.4.491-502.2003. PMID 14665674.
- Zaffiri L, Gardner J, Toledo-Pereyra LH (2012). "History of antibiotics. From salvarsan to cephalosporins". J Invest Surg 25 (2): 66–67. doi:10.3109/08941939.2012.664099. PMID 22439833.
- Procópio RE, Silva IR, Martins MK, Azevedo JL, Araújo JM (2012). "Antibiotics produced by Streptomyces". Braz J Infect Dis 16 (5): 466–471. doi:10.1016/j.bjid.2012.08.014. PMID 22975171. Vancouver style error (help)
- Cochrane SA, Vederas JC (2015). "Lipopeptides from Bacillus and Paenibacillus spp.: a gold mine of antibiotic candidates (in press)". Med Res Rev. doi:10.1002/med.21321. PMID 24866700.
- Saxena A, Kumari R, Mukherjee U, Singh P, Lal R (2014). "Draft genome sequence of the rifamycin producer Amycolatopsis rifamycinica DSM 46095". Genome Announc 2 (4): e00662–14. doi:10.1128/genomeA.00662-14. PMID 24994803.
- Hallett M, Albanese A, Dressler D, Segal KR, Simpson DM, Truong D et al. (2013). "Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders". Toxicon 67 (June): 94–114. doi:10.1016/j.toxicon.2012.12.004. PMID 23380701.
- "Bleomycin". US National Library of Medicine. Retrieved 28 January 2015.
- Alvin A, Miller KI, Neilan BA (2014). "Exploring the potential of endophytes from medicinal plants as sources of antimycobacterial compounds". Microbiol Res 169 (7-8): 483–495. doi:10.1016/j.micres.2013.12.009. PMID 24582778.
- Wang X, Elshahawi SI, Shaaban KA, Fang L, Ponomareva LV, Zhang Y et al. (2014). "Ruthmycin, a new tetracyclic polyketide from Streptomyces sp. RM-4-15". Org Lett 16 (2): 456–459. doi:10.1021/ol4033418. PMID 24341358.
- Wang X, Shaaban KA, Elshahawi SI, Ponomareva LV, Sunkara M, Copley GC et al. (2014). "Mullinamides A and B, new cyclopeptides produced by the Ruth Mullins coal mine fire isolate Streptomyces sp. RM-27-46". J Antibiot (Tokyo) 67 (8): 571–575. doi:10.1038/ja.2014.37. PMID 24713874.
- Akey DL, Gehret JJ, Khare D, Smith JL (2012). "Insights from the sea: structural biology of marine polyketide synthases". Nat Prod Rep 29 (10): 1038–49. doi:10.1039/c2np20016c. PMC 3709256. PMID 22498975.
- Beekman AM, Barrow RA (2014). "Fungal metabolites as pharmaceuticals". Aust J Chem 67 (6): 827–843.
- 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.
- Kittakoop P, Mahidol C, Ruchirawat S (2014). "Alkaloids as important scaffolds in therapeutic drugs for the treatments of cancer, tuberculosis, and smoking cessation". Curr Top Med Chem 14 (2): 239–252. doi:10.2174/1568026613666131216105049. PMID 24359196.
- Kano S (2014). "Artemisinin-based combination therapies and their introduction in Japan". Kansenshogaku Zasshi 88 (3 Suppl 9-10): 18–25. PMID 24979951.
- Russo P, Frustaci A, Del Bufalo A, Fini M, Cesario A (2013). "Multitarget drugs of plants origin acting on Alzheimer's disease". Curr Med Chem 20 (13): 1686–93. doi:10.2174/0929867311320130008. PMID 23410167.
- Dossey AT (January 2010). "Insects and their chemical weaponry: new potential for drug discovery". Nat Prod Rep 27 (12): 1737–57. doi:10.1039/C005319H. PMID 20957283.
- Fernandes-Pedrosa MF, Félix-Silva J, Menezes YAS (2013). An Integrated View of the Molecular Recognition and Toxinology: From Analytical Procedures to Biomedical Applications. InTechOpen. p. 23-72.
- Mayer AM, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD et al. (2010). "The odyssey of marine pharmaceuticals: a current pipeline perspective". Trends Pharmacol Sci 31 (6): 255–265. doi:10.1016/j.tips.2010.02.005. PMID 20363514.
- Bowersox SS, Luther R (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. doi:10.1016/S0041-0101(98)00158-5. PMID 9792182.
- Prommer E (2006). "Ziconotide: a new option for refractory pain". Drugs Today 25 (2): 66–67. doi:10.1358/dot.2006.42.6.973534. PMID 16845440.
- Rinehart KL (2000). "Antitumor compounds from tunicates". Med Res Rev 20 (1): 1–27. doi:10.1002/(SICI)1098-1128(200001)20:1<1::AID-MED1>3.0.CO;2-A. PMID 10608919.
- Petek BJ, Loggers ET, Pollack SM, Jones RL (2015). "Trabectedin in soft tissue sarcomas". Mar Drugs 13 (2): 947–983. doi:10.3390/md13020974. PMID 25686274.
- Singh R, Sharma M, Joshi P, Rawat DS (2008). "Clinical status of anti-cancer agents derived from marine sources". Anticancer Agents Med Chem 8 (6): 603–617. doi:10.2174/187152008785133074. PMID 18690825.
- Brahmachari G (2010). Handbook of Pharmaceutical Natural Products. Weinheim: Wiley-VCH. ISBN 978-3-52732148-3.
- Beghyn T, Deprez-Poulain R, Willand N, Folleas B, Deprez B (July 2008). "Natural compounds: leads or ideas? Bioinspired molecules for drug discovery". Chem Biol Drug Des 72 (1): 3–15. doi:10.1111/j.1747-0285.2008.00673.x. PMID 18554253.
- Koehn FE, Carter GT (March 2005). "The evolving role of natural products in drug discovery". Nat Rev Drug Discov 4 (3): 206–20. doi:10.1038/nrd1657. PMID 15729362.
- Newman DJ, Cragg GM (March 2007). "Natural products as sources of new drugs over the last 25 years". J. Nat. Prod. 70 (3): 461–77. doi:10.1021/np068054v. PMID 17309302.
- Gransalke K (February 2011). "Mother Nature’s Drug Cabinet". Lab Times 11 (1): 16–19.
Drug Discovery - Is Mother Nature still the number one source for promising new drugs?
- Patrick GL (2013). "12.4.2: Medical Folklore". An introduction to medicinal chemistry (Fifth ed.). Oxford: Oxford University Press. ISBN 978-0-19-969739-7.
- Sneader W (2005). "Part 1: Legacy of the Past". Drug discovery: a history (Rev. and updated ed. ed.). Chichester: Wiley. pp. 1–87. ISBN 978-0-471-89979-2.
- Schrör K (2008). "Chapter 1.1: History". Acetylsalicylic Acid. Weinheim: Wiley-VCH. pp. 5–24. ISBN 978-3-527-62600-7.
- 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.
- Lewis RJ, Dutertre S, Vetter I, Christie MJ (2012). "Conus venom peptide pharmacology". Pharmacol. Rev. 64 (2): 259–98. doi:10.1124/pr.111.005322. PMID 22407615.
- de la Bédoyère G (2005). The discovery of penicillin. London: Evans. ISBN 978-0-237-52739-6.
- Hartung EF (1954). "History of the use of colchicum and related medicaments in gout; with suggestions for further research". Ann. Rheum. Dis. 13 (3): 190–200. doi:10.1136/ard.13.3.190. PMC 1006735. PMID 13198053.
- Sneader W (2005). "Paclitaxel (taxol)". Drug discovery: a history (Rev. and updated ed. ed.). Chichester: Wiley. pp. 112–113. ISBN 978-0-471-89979-2.
- 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.
- Sneader W (2005). "ACE Inhibitors". Drug discovery: a history (Rev. and updated ed. ed.). Chichester: Wiley. pp. 280–283. ISBN 978-0-471-89979-2.
- Brown, Kevin (2009). "<’That’s funny!’: the discovery and development of penicillin>". Microbiology Today 36 (1): 12–15.
- For instance, see: HJL Makin & DB Gower (2010) Steroid analysis, Dordrecht/New York:Springerm pp. TBD, ISBN 9781402097744
- The Nobel Prize in Chemistry 1964, Perspectives. Retrieved July 14, 2012.
- "The Story of Taxol" (PDF). The American Society of Pharmacognosy.
- Hodgkin DC, Kamper J, Mackay M, Pickworth J, Trueblood KN, White JG (July 1956). "Structure of vitamin B12". Nature 178 (4524): 64–6. doi:10.1038/178064a0. PMID 13348621.
- Woodward RB (1973). "The total synthesis of vitamin B 12". Pure Appl. Chem. 33 (1): 145–77. doi:10.1351/pac197333010145. PMID 4684454.
- 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.
- 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 320. pp. 223–243. doi:10.1007/978-94-009-0255-8_9.
- 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". Angew. Chem. Int. Ed. Engl. 39 (1): 44–122. doi:10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L. PMID 10649349.
- Voloshchuk T, Farina NS, Wauchope OR, Kiprowska M, Haberfield P, Greer A (2004). "Molecular bilateral symmetry of natural products: prediction of selectivity of dimeric molecules by density functional theory and semiempirical calculations". J. Nat. Prod. 67 (7): 1141–6. doi:10.1021/np049899e. PMID 15270568.
- Glenn WS, Runguphan W, O'Connor SE (2013). "Recent progress in the metabolic engineering of alkaloids in plant systems". Curr Opin Biotechnol 24 (2): 354–65. doi:10.1016/j.copbio.2012.08.003. PMID 22954587.
- 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.
- Journal of Natural Products
- Natural Product Reports
- Natural Product Research
- Chemistry of Natural Compounds
- 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