Natural product

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 https://en.wikipedia.org/wiki/Natural_product

 

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

 

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 sourcees may lead to basic research on potential bioactive components for commercial development as lead compounds in drug discovery. Although natural products have inspired numerous U.S. Food and Drug Administration-approved 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.

Classes

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. One estimate of the number of natural product molecules is about 326,000.

Function

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

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 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.

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

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 metabolites

Representative examples of each of the major classes of secondary metabolites

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

Secondary metabolites have a broad range of functions. These include pheromones that act as social signaling molecules with other individuals of the same species, communication molecules that attract and activate symbiotic organisms, agents that solubilize and transport nutrients (siderophores etc.), and competitive weapons (repellants, venoms, toxins etc.) that are used against competitors, prey, and predators. For many 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.

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

Biosynthesis

Biosynthesis of primary and secondary metabolites.

The biosynthetic pathways leading to the major classes of natural products are described below.

• 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. 

Carbohydrate are the products of plant photosynthesis and animal gluconeogenesis. Photosynthesis produces initially 3-phosphoglyceraldehyde, a three carbon atom containing sugar (a triose). This triose in turn may be converted into glucose (a six carbon atom containing sugar) or a variety of pentoses (five carbon atom containing sugars) through the Calvin cycle. In animals, the three carbon precursors lactate or glycerol can be converted into pyruvate which in turn can be converted into carbohydrates in the liver.

Fatty acids and polyketides

Through the process of glycolysis sugars are broken down into acetyl-CoA. In an ATP dependent enzymatically catalyzed reaction, acetyl-CoA is carboxylated to form malonyl-CoA. Acetyl-CoA and malonyl-CoA undergo a Claisen condensation with lose of carbon dioxide to form acetoacetyl-CoA. Additional condensation reactions produce successively higher molecular weight poly-β-keto chains which are then converted into other polyketides. The polyketide class of natural products have diverse structures and functions and include prostaglandins and macrolide antibiotics.

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. Fatty acid are essential components of lipid bilayers that form cell membranes as well as fat energy stores in animals.

Sources

Natural products may be extracted from the cells, tissues, and 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.

Prokaryotic

Bacteria

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

The serendipitous discovery and subsequent clinical success of 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.

Archaea

Because many Archaea have adapted to life in extreme environments such as polar regions, hot springs, acidic springs, alkaline springs, salt lakes, and the high pressure of deep ocean water, they possess enzymes that are functional under quite unusual conditions. These enzymes are of potential use in the food, chemical, and pharmaceutical industries, where biotechnological processes frequently involve high temperatures, extremes of pH, high salt concentrations, and / or high pressure. Examples of enzymes identified to date include amylases, pullulanases, cyclodextrin glycosyltransferases, cellulases, xylanases, chitinases, proteases, alcohol dehydrogenase, and esterases. Archaea represent a source of novel chemical compounds also, for example isoprenyl glycerol ethers 1 and 2 from Thermococcus S557 and Methanocaldococcus jannaschii, respectively.

Eukaryotic

Fungi

The antibiotic penicillin is a natural product derived from the fungus Penicillium chrysogenum

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. 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

The opioid analgesic drug morphine is a natural product derived from the plant Papaver somniferum

 

Plants are a major source of complex and highly structurally diverse chemical compounds (phytochemicals), this structural diversity attributed in part to the natural selection of organisms producing potent compounds to deter herbivory (feeding deterrents). 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.

Animals

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

 

Animals also represent a source of bioactive natural products. In particular, venomous animals such as snakes, spiders, scorpions, caterpillars, bees, wasps, centipedes, ants, toads, and frogs have attracted much attention. This is because venom constituents (peptides, enzymes, nucleotides, lipids, biogenic amines etc.) often have very specific interactions with a 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).

Medical uses

Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases. As such, natural products are the active components of many traditional medicines. Moreover, synthetic analogs of natural products with improved potency and safety can be prepared and therefore natural products are often used as starting points for drug discovery. Natural product constituents have inspired numerous drug discovery efforts that eventually gained approval as new drugs by the U.S. Food and Drug Administration

Traditional medicine

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 in isolated cases, traditional healers or shamans found some sources to provide therapeutic effect, representing knowledge of a crude drug that was passed down through generations in such practices as traditional Chinese medicine and Ayurveda. Extracts of some natural products led to modern discovery of their active ingredients and eventually to the development of new 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 inhibitor captopril. Captopril is based on the peptidic bradykinin potentiating factor isolated from venom of the Brazilian arrowhead viper (Bothrops jararaca).

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 high-throughput screening of pure synthetic compounds with shorter timelines to refinement. Natural product sources are often unreliable to access and supply, have a high probability of duplication, inherently create intellectual property concerns about patent protection, vary in composition due to sourcing season or environment, and are susceptible to rising extinction rates.

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

Isolation and purification

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 scientists sharing the 1945 Nobel Prize in Medicine for the work. Fleming recognized the antibacterial activity and clinical potential of "pen G", but was unable to purify or stabilize it. Developments in chromatographic separations and freeze drying helped move progress forward in the production of commercial quantities of penicillin and other natural products.

 

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). 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).

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 (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.

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. 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.

Total synthesis

Structural representation of cobalamin, an early natural product isolated and structurally characterized. 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 and A. Eschenmoser.

 

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. 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"). Early efforts in natural products synthesis targeted complex substances such as cobalamin (vitamin B₁₂), an essential cofactor in cellular metabolism.

Symmetry

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, C_s, or C_2v 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

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, systems biology, molecular modeling, chemometrics, and chemoinformatics.

Chemistry

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 a 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 principal motivation in the development of new variants of old chemical reactions (e.g., the Evans aldol reaction), as well as the discovery of completely new chemical reactions (e.g., the Woodward cis-hydroxylation, Sharpless epoxidation, and Suzuki–Miyaura cross-coupling reactions).

Biochemistry

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.

History

Antoine Lavoisier (1743-1794)

 

Friedrich Wöhler (1800-1882)

 

Hermann Emil Fischer (1852-1919)

 

Richard Willstätter (1872-1942)

 

Robert Robinson (1886-1975)

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.

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 glycosides. It was long been known that opium, a sticky mixture of alkaloids (including codeine, morphine, noscapine, thebaine, and papaverine) from the opium poppy (Papaver somniferum), possessed a narcotic and at the same time mind-altering properties. By 1805, morphine had already been isolated by the German chemist Friedrich Sertürner and in the 1870s it was discovered that boiling morphine with acetic anhydride produced a substance with a strong pain suppressive effect: heroin. In 1815, Eugène Chevreul isolated cholesterol, a crystalline substance, from animal tissue that belongs to the class of steroids, and in 1820 strychnine, an alkaloid was isolated.

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 Jöns Jacob Berzelius held that an indispensable force of nature for the synthesis of organic compounds, called vital force or life force, was needed. This philosophical idea, vitalism, well into the 19th century had many supporters, even after the introduction of the atomic theory. The idea of vitalism especially fitted in with beliefs in medicine; the most traditional healing practices believed that disease was the result of some imbalance in the vital energies that distinguishes life from nonlife. A first attempt to break the vitalism idea in science was made in 1828, when the German chemist Friedrich Wöhler succeeded in synthesizing urea, a natural product found in urine, by heating ammonium cyanate, an inorganic substance:

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

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

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 Justus von Liebig, who both studied a silver salt of the same composition but had different properties. Wöhler studied silver cyanate, a harmless substance, while von Liebig investigated silver fulminate, a salt with explosive properties. The elemental analysis shows that both salts contain equal quantities of silver, carbon, oxygen and nitrogen. According to the then prevailing ideas, both substances should possess the same properties, but this was not the case. This apparent contradiction was later solved by Berzelius's theory of isomers, whereby not only the number and type of elements are of importance to the properties and chemical reactivity, but also the position of atoms in within a compound. This was a direct cause for the development of structure theories, such as the radical theory of Jean-Baptiste Dumas and the substitution theory of Auguste Laurent. However, it took until 1858 before by August Kekulé formulated a definite structure theory. He posited that carbon is tetravalent and can bind to itself to form carbon chains as they occur in natural products.

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 Justus von Liebig. Hermann Emil Fischer in 1884, turned his attention to the study of carbohydrates and purines, work for which he was awarded the Nobel Prize in 1902. He also succeeded to make synthetically in the laboratory in a variety of carbohydrates, including glucose and mannose. After the discovery of penicillin by Alexander Fleming in 1928, fungi and other micro-organisms were added to the arsenal of sources of natural products.

Milestones

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

• Terpenes, first systematically studied by Otto Wallach (Nobel Prize 1910) and later by Leopold Ružička (Nobel Prize 1939)
• Dyes based on porphins (including chlorophyll and heme), studied by Richard Willstätter (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 anthocyanins, studied by, among others, Robert Robinson (Nobel Prize 1947)

Ergoline

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Ergoline 

 

Ergoline

Clinical data
ATC code	none
Identifiers
IUPAC name[show]
CAS Number	478-88-6
PubChem CID	6857537
ChemSpider	5256873
ChEBI	CHEBI:38484
CompTox Dashboard (EPA)	DTXSID00963944
Chemical and physical data
Formula	C14H16N2
Molar mass	212.29g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES[show]
InChI[show]

Ergoline derivatives comprise a diverse group of chemical compounds whose structural skeleton is the alkaloid ergoline. Ergoline derivatives are used clinically for the purpose of vasoconstriction (5-HT₁ receptor agonists—ergotamine) and in the treatment and alleviation of migraines (used with caffeine) and Parkinson's disease. Some ergoline alkaloids found in ergot fungi are implicated in the condition ergotism, which causes convulsive and gangrenous symptoms. Others are psychedelic substances, including LSD and some alkaloids in Argyreia nervosa, Ipomoea tricolor and related species.

Uses

In addition to the naturally occurring ergonovine (used as an oxytocic) and ergotamine (a vasoconstrictor used to control migraine), synthetic derivatives of importance are the oxytocic methergine, the anti-migraine drugs dihydroergotamine and methysergide, hydergine (a mixture of dihydroergotoxine mesylates, INN: ergoline mesylates), and bromocriptine, used for numerous purposes including treatment of Parkinson's disease. Newer synthetic ergolines used for Parkinson's disease include pergolide and lisuride. 

Perhaps the most famous ergoline derivative is the psychedelic drug LSD. Ergometrine and ergotamine are included as schedule I precursors in the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.

Ergolines can pass into breast milk and should not be used during breastfeeding. They are uterine contractors that can increase the risk of miscarriage during pregnancy.

Natural occurrence

Ergoline alkaloids are found in lower fungi and some species of flowering plants: the Mexican species Turbina corymbosa and Ipomoea tricolor of the Convolvulaceae (morning glory) family, the seeds of which were identified as the psychedelic plant drugs known as "ololiuhqui" and "tlitliltzin", respectively. The principal alkaloids in the seeds are ergine and its optical isomer isoergine, with several other lysergic acid derivatives and clavines present in lesser amounts. The Hawaiian species Argyreia nervosa includes similar alkaloids. It is possible, though not proven, that ergine or isoergine are responsible for the psychedelic effects. There may be a fungal origin of the ergoline alkaloids also in the Convolvulaceae. Like the ergot alkaloids in some monocot plants, the ergoline alkaloids found in the plant Ipomoea asarifolia (Convolvulaceae) are produced by a seed-transmitted endophytic clavicipitaceous fungus.

History

Ergoline alkaloids were first isolated from ergot, a fungus that infects grain and causes the disease ergotism. Ergot also has a long history of medicinal use, which led to attempts to characterize its activity chemically. This began in 1906 with the isolation by G. Barger and F. H. Carr of ergotoxine, so-named since it appeared to exhibit more of the toxicity of ergot than its therapeutic qualities. The isolation of ergotamine in 1918 by Arthur Stoll made possible the first therapeutic use of isolated ergoline alkaloids.

With the determination of the basic chemical structure of the ergot alkaloids in the early 1930s, an era of intensive exploration of synthetic derivatives began.

Ergoline derivatives

There are 3 main classes of ergoline derivatives, the water-soluble amides of lysergic acid, the water-insoluble ergopeptines (i.e., ergopeptides), and the clavine group.

Lysergic acid amides

• Ergine (LSA, D-lysergic acid amide, LAA, LA-111)
  • IUPAC name: 9,10-didehydro-6-methylergoline-8beta-carboxamide
  • CAS number: 478-94-4
• Ergonovine (ergobasine)
  • INN: ergometrine
  • IUPAC name: (8beta(S))-9,10-didehydro-N-(2-hydroxy-1-methylethyl)-6-methyl-ergoline-8-carboxamide
  • CAS number: 60-79-7
• Methergine (ME-277)
  • INN: methylergometrine
  • IUPAC name: (8beta(S))-9,10-didehydro-N-(1-(hydroxymethyl)propyl)-6-methyl-ergoline-8-carboxamide
  • CAS number: 113-42-8
• Methysergide (UML-491)
  • INN: methysergide
  • IUPAC name: (8beta)-9,10-didehydro-N-(1-(hydroxymethyl)propyl)-1,6-dimethyl-ergoline-8-carboxamide
  • CAS number: 361-37-5
• LSD (D-lysergic acid diethylamide, LSD-25)
  • INN: lysergide
  • IUPAC name: (8beta)-9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8-carboxamide
  • CAS number: 50-37-3
• LSH (D-lysergic acid α-hydroxyethylamide)
  • IUPAC name: 9,10-didehydro-N-(1-hydroxyethyl)-6-methylergoline-8-carboxamide
  • CAS number: 3343-15-5

The relationship between these compounds is summarized in the following structural formula and table of substitutions. 

Name	R1	R2	R3
Ergine	H	H	H
Ergonovine	H	CH(CH3)CH2OH	H
Methergine	H	CH(CH2CH3)CH2OH	H
Methysergide	CH3	CH(CH2CH3)CH2OH	H
LSD	H	CH2CH3	CH2CH3

Peptide alkaloids

Peptide ergot alkaloids or ergopeptines (also known as ergopeptides) are ergoline derivatives that contain a tripeptide structure attached to the basic ergoline ring in the same location as the amide group of the lysergic acid derivatives. This structure consists of proline and two other α-amino acids, linked in an unusual cyclol formation >N-C(OH)< with the carboxyl carbon of proline, at the juncture between the two lactam rings. Some of the important ergopeptines are summarized below. In addition to the following ergopeptines, a commonly encountered term is ergotoxine, which refers to a mixture of equal proportions of ergocristine, ergocornine and ergocryptine, the latter being a 2:1 mixture of alpha- and beta-ergocryptine.

• Ergotoxine group (valine as the amino acid attached to the ergoline moiety, at R² below)
  • Ergocristine
    • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)-5'-(phenylmethyl)-, (5'-alpha)-
    • CAS number: 511-08-0
  • Ergocornine
    • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2',5'-bis(1-methylethyl)-, (5'-alpha)-
    • CAS number: 564-36-3
  • alpha-Ergocryptine
    • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-, (5'alpha)-
    • CAS number: 511-09-1
  • beta-Ergocryptine
    • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)-5'-(1-methylpropyl)-, (5'alpha(S))-
    • CAS number: 20315-46-2
• Ergotamine group (alanine at R²)
  • Ergotamine
    • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenylmethyl)-, (5'-alpha)-
    • CAS number: 113-15-5
  • Ergovaline
    • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylethyl)-, (5'alpha)-
    • CAS number: 2873-38-3
  • alpha-Ergosine
    • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(2-methylpropyl)-, (5'-alpha)-
    • CAS number: 561-94-4
  • beta-Ergosine
    • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylpropyl)-, (5'-alpha(S))-
    • CAS number: 60192-59-8

Name	R1	R2	R3	Amino acid at R3
Ergocristine		CH(CH3)2	benzyl	Phenylalanine
Ergocornine		CH(CH3)2	CH(CH3)2	Valine
alpha-Ergocryptine		CH(CH3)2	CH2CH(CH3)2	Leucine
beta-Ergocryptine		CH(CH3)2	CH(CH3)CH2CH3 (S)	Isoleucine
Ergotamine		CH3	benzyl	Phenylalanine
Ergovaline		CH3	CH(CH3)2	Valine
alpha-Ergosine		CH3	CH2CH(CH3)2	Leucine
beta-Ergosine		CH3	CH(CH3)CH2CH3 (S)	Isoleucine
Bromocriptine (semisynthetic)	Br	CH(CH3)2	CH2CH(CH3)2	Leucine

Clavines

A variety of modifications to the basic ergoline are seen in nature, for example agroclavine, elymoclavine, lysergol. Those deriving from dimethylergoline are referred to as clavines. Examples of clavines, include festuclavine, fumigaclavine A, fumigaclavine B and fumigaclavine C.

Others

Some synthetic ergoline derivatives do not fall easily into any of the above groups. Some examples are:

• Cabergoline (INN)
  • IUPAC name: 1-[(6-Allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea
  • CAS number: 81409-90-7
• Pergolide (INN)
  • IUPAC name: (8β)-8-((methylthio)methyl)-6-propyl-ergoline
  • CAS number: 66104-22-1
• Lisuride (INN)
  • IUPAC name: 3-(9,10-didehydro-6-methylergolin-8α-yl)-1,1-diethylurea
  • CAS number: 18016-80-3

Ergot

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Ergot

Ergot
Claviceps purpurea
Scientific classification
Kingdom:	Fungi
Division:	Ascomycota
Class:	Sordariomycetes
Order:	Hypocreales
Family:	Clavicipitaceae
Genus:	Claviceps Tul., 1853
Species
About 50, including: Claviceps africana Claviceps fusiformis Claviceps paspali Claviceps purpurea Claviceps sorghi Claviceps zizaniae Claviceps lutea

Ergot (pron. /ˈɜːrɡət/ UR-gət) or ergot fungi refers to a group of fungi of the genus Claviceps.

The most prominent member of this group is Claviceps purpurea ("rye ergot fungus"). This fungus grows on rye and related plants, and produces alkaloids that can cause ergotism in humans and other mammals who consume grains contaminated with its fruiting structure (called ergot sclerotium).

Claviceps includes about 50 known species, mostly in the tropical regions. Economically significant species include C. purpurea (parasitic on grasses and cereals), C. fusiformis (on pearl millet, buffel grass), C. paspali (on dallis grass), C. africana (on sorghum), and C. lutea (on paspalum). C. purpurea most commonly affects outcrossing species such as rye (its most common host), as well as triticale, wheat, and barley. It affects oats only rarely.

C. purpurea has at least three races or varieties, which differ in their host specificity:

• G1 — land grasses of open meadows and fields;
• G2 — grasses from moist, forest, and mountain habitats;
• G3 (C. purpurea var. spartinae) — salt marsh grasses (Spartina, Distichlis).

Life cycle

An ergot kernel, called a sclerotium, develops when a spore of fungal species of the genus Claviceps infects a floret of flowering grass or cereal. The infection process mimics a pollen grain growing into an ovary during fertilization. Infection requires that the fungal spore have access to the stigma; consequently, plants infected by Claviceps are mainly outcrossing species with open flowers, such as rye (Secale cereale) and ryegrasses (genus Lolium). The proliferating fungal mycelium then destroys the plant ovary and connects with the vascular bundle originally intended for seed nutrition. The first stage of ergot infection manifests itself as a white soft tissue (known as sphacelia) producing sugary honeydew, which often drops out of the infected grass florets. This honeydew contains millions of asexual spores (conidia), which insects disperse to other florets. Later, the sphacelia convert into a hard dry sclerotium inside the husk of the floret. At this stage, alkaloids and lipids accumulate in the sclerotium. 

Claviceps species from tropic and subtropic regions produce macro- and microconidia in their honeydew. Macroconidia differ in shape and size between the species, whereas microconidia are rather uniform, oval to globose (5x3μm). Macroconidia are able to produce secondary conidia. A germ tube emerges from a macroconidium through the surface of a honeydew drop and a secondary conidium of an oval to pearlike shape is formed, to which the contents of the original macroconidium migrates. Secondary conidia form a white, frost-like surface on honeydew drops and spread via the wind. No such process occurs in Claviceps purpurea, Claviceps grohii, Claviceps nigricans, and Claviceps zizaniae, all from northern temperate regions.

When a mature sclerotium drops to the ground, the fungus remains dormant until proper conditions (such as the onset of spring or a rain period) trigger its fruiting phase. It germinates, forming one or several fruiting bodies with heads and stipes, variously coloured (resembling a tiny mushroom). In the head, threadlike sexual spores form, which are ejected simultaneously when suitable grass hosts are flowering. Ergot infection causes a reduction in the yield and quality of grain and hay, and if livestock eat infected grain or hay it may cause a disease called ergotism.

Black and protruding sclerotia of C. purpurea are well known. However, many tropical ergots have brown or greyish sclerotia, mimicking the shape of the host seed. For this reason, the infection is often overlooked.

Insects, including flies and moths, carry conidia of Claviceps species, but it is unknown whether insects play a role in spreading the fungus from infected to healthy plants.

Evolution

The evolution of plant parasitism in the Clavicipitaceae dates back at least 100 million years, to the early-mid Cretaceous. An amber fossil discovered in 2014 preserves a grass spikelet and an ergot-like parasitic fungus. The fossil shows that the original hosts of the Clavicipitaceae could have been grasses. The discovery also establishes a minimum time for the conceivable presence of psychotropic compounds in fungi. Several evolutionary processes have acted to diversify the array of ergot alkaloids produced by fungi; these differences in enzyme activities are evident at the levels of substrate specificity (LpsA), product specification (EasA, CloA) or both (EasG and possibly CloA). The “old yellow enzyme,” EasA, presents an outstanding example. This enzyme catalyzes reduction of the C8=C9 double-bond in chanoclavine I, but EasA isoforms differ in whether they subsequently catalyze reoxidation of C8–C9 after rotation. This difference distinguishes most Clavicipitaceae from Trichocomaceae, but in Clavicipitaceae it is also the key difference dividing the branch of classical ergot alkaloids from dihydroergot alkaloids, the latter often being preferred for pharmaceuticals due to their relatively few side effects.

Effects on humans and other mammals

Ergot-derived drug to stop postpartum bleeding

The ergot sclerotium contains high concentrations (up to 2% of dry mass) of the alkaloid ergotamine, a complex molecule consisting of a tripeptide-derived cyclol-lactam ring connected via amide linkage to a lysergic acid (ergoline) moiety, and other alkaloids of the ergoline group that are biosynthesized by the fungus. Ergot alkaloids have a wide range of biological activities including effects on circulation and neurotransmission.

Ergot alkaloids are classified as:

1. derivatives of 6,8-dimethylergoline and
2. lysergic acid derivatives.

Ergotism is the name for sometimes severe pathological syndromes affecting humans or other animals that have ingested plant material containing ergot alkaloid, such as ergot-contaminated grains. The Hospital Brothers of St. Anthony, an order of monks established in 1095, specialized in treating ergotism victims with balms containing tranquilizing and circulation-stimulating plant extracts. The common name for ergotism is "St. Anthony's Fire", in reference to this order of monks and the severe burning sensations in the limbs which was one of the symptoms. There are two types of ergotism, the first is characterized by muscle spasms, fever and hallucinations and the victims may appear dazed, be unable to speak, become manic, or have other forms of paralysis or tremors, and suffer from hallucinations and other distorted perceptions. This is caused by serotonergic stimulation of the central nervous system by some of the alkaloids. The second type of ergotism is marked by violent burning, absent peripheral pulses and shooting pain of the poorly vascularized distal organs, such as the fingers and toes, and are caused by effects of ergot alkaloids on the vascular system due to vasoconstriction, sometimes leading to gangrene and loss of limbs due to severely restricted blood circulation. 

The neurotropic activities of the ergot alkaloids may also cause hallucinations and attendant irrational behaviour, convulsions, and even death. Other symptoms include strong uterine contractions, nausea, seizures, high fever, vomiting, loss of muscle strength and unconsciousness. Since the Middle Ages, controlled doses of ergot were used to induce abortions and to stop maternal bleeding after childbirth.^[17] Klotz offers a detailed overview of the toxicities in mammalian livestock, stating that the activities are attributable to antagonism or agonism of neurotransmitters, including dopamine, serotonin and norepinephrine. As well, he shares that the adrenergic blockage by ergopeptines (e.g., ergovaline or ergotamine) leads to potent and long-term vasoconstriction, and can result in reduced blood flow resulting in intense burning pain (St. Anthony’s fire), edema, cyanosis, dry gangrene and even loss of hooves in cattle or limbs in humans. Reduced prolactin due to ergot alkaloid activity on dopamine receptors in the pituitary is also common in livestock. Reduced serum prolactin is associated with various reproductive problems in cattle, and especially in horses, including agalactia and poor conception, and late-term losses of foals and sometimes mares due to dystocia and thickened placentas. Although both gangrenous and convulsive symptoms are seen in naturally occurring ergotism resulting from the ingestion of fungus infected rye, only gangrenous ergotism has been reported following the excessive ingestion of ergotamine tartrate. Ergot extract has been used in pharmaceutical preparations, including ergot alkaloids in products such as Cafergot (containing caffeine and ergotamine or ergoline) to treat migraine headaches, and ergometrine, used to induce uterine contractions and to control bleeding after childbirth. Clinical ergotism as seen today results almost exclusively from the excessive intake of ergotamine tartrate in the treatment of migraine headache.

In addition to ergot alkaloids, Claviceps paspali also produces tremorgens (paspalitrem) causing "paspalum staggers" in cattle. The fungi of the genera Penicillium and Aspergillus also produce ergot alkaloids, notably some isolates of the human pathogen Aspergillus fumigatus, and have been isolated from plants in the family Convolvulaceae, of which morning glory is best known. The causative agents of most ergot poisonings are the ergot alkaloid class of fungal metabolites, though some ergot fungi produce distantly related indole-diterpene alkaloids that are tremorgenic.

Ergot does not contain lysergic acid diethylamide (LSD) but instead contains lysergic acid as well as its precursor, ergotamine. Lysergic acid is a precursor for the synthesis of LSD. Their realized and hypothesized medicinal uses have encouraged intensive research since the 1950s culminating on the one hand in development of drugs both legal (e.g., bromocriptine) and illegal (e.g., lysergic acid diethylamide= LSD), and on the other hand in extensive knowledge of the enzymes, genetics, and diversity of ergot alkaloid biosynthetic pathways.

The January 4, 2007 issue of the New England Journal of Medicine includes a paper that documents a British study of more than 11,000 Parkinson's disease patients. The study found that two ergot-derived drugs, pergolide and cabergoline, commonly used to treat Parkinson's Disease may increase the risk of leaky heart valves by up to 700%.

History

Ergot on wheat stalks

Ergotism is the earliest recorded example of mycotoxicosis, or poisoning caused by toxic molds. Early references to ergot poisoning (ergotism) date back as far as 600 BC, an Assyrian tablet referred to it as a 'noxious pustule in the ear of grain'. In 350 BC, the Parsees described 'noxious grasses that cause pregnant women to drop the womb and die in childbed'. In ancient Syria, ergot was called 'Daughter of Blood'. Radulf Glaber described an ailment he called 'hidden fire' or ignus ocultus, in which a burning of the limb is followed by its separation from the body, often consuming the victim in one night. In 1588, Johannes Thallius wrote that it is called 'Mother of Rye', or rockenmutter, and is used to halt bleeding.

Human poisoning due to the consumption of rye bread made from ergot-infected grain was common in Europe in the Middle Ages. The first mention of a plague of gangrenous ergotism in Europe comes from Germany in 857, following this France and Scandinavia experienced similar outbreaks; England is noticeably absent from the historical regions affected by ergotism as their main source of food was wheat, which is resistant to ergot fungi. In 944, a massive outbreak of ergotism caused 40,000 deaths in the regions of Aquitaine, Limousin, Perigord, and Angoumois in France. In Hesse in 1596, Wendelin Thelius was one of the first to attribute ergotism poisoning to grain. In 1778, S. Tessier, observing a huge epidemic in Sologne, France in which more than 8,000 people died, recommended drainage of fields, compulsory cleaning of grain, and the substitution of potatoes for affected grain.

Saint Anthony's fire and the Antonites

In 1722, the Russian Tzar Peter the Great was thwarted in his campaign against the Ottoman Empire as his army, traveling down the Terek steppe, were struck by ergotism and were forced to retreat in order to find edible grains. A diary entry from the time describes that as soon as people ate the poisoned bread they became dizzy, with such strong nerve contractions that those who did not die from the first day found their hands and feet falling off, akin to frostbite. The epidemic was known as Saint Anthony's fire, or ignis sacer, and some historical events, such as the Great Fear in France during the French Revolution have been linked to ergot poisoning. Saint Anthony was a 3rd Century Egyptian ascetic who lived by the Red Sea and was known for long fasting in which he confronted terrible visions and temptations sent from the Devil. He was credited by two noblemen for assisting them in recovery from the disease; they subsequently founded the Order of St. Anthony in honor of him. Anthony was a popular subject for art in the Middle Ages and his symbol is a large blue "T" sewn onto the shoulder of the order's monks, symbolizing the crutch used by the ill and injured.

The Order of St. Anthony, who were also known as Antonites, grew quickly and hospitals spread through France, Germany, and Scandinavia and gained wealth and power as grateful patrons bestowed money and charitable goods to the hospitals. By the end of the Middle Ages, there were 396 settlements and 372 hospitals owned by the order and pilgrimages to such hospitals became popular as well as the donation of limbs lost to ergotism, which were displayed near shrines to the saint. These hagiotherapeutic centers were the first specialized European medical welfare systems and the friars of the order were knowledgeable about treatment of ergotism and the horrifying effects of the poison. The sufferers would receive ergot-free meals, wines containing vasodilating and analgesic herbs, and applications of Antonites-balsalm, which was the first transdermal therapeutic system (TTS) in medical history. Their medical recipes have been lost to time, though some recorded treatments still remain. After 1130 AD, the monks were no longer permitted to perform operations, and so barber surgeons were employed to remove gangrenous limbs and treat open sores. Three barbers founded a hospital in Memmingen in 1214 and accepted those who were afflicted with the gangrenous form of ergotism. Patients were fed and housed with the more able-bodied individuals acting as orderlies and assistants. Patients with the convulsive form of ergotism, or ergotismus convulsivus, were welcomed for only nine days before they were asked to leave as convulsive ergotism was seen as less detrimental. Though the sufferers often experienced irreversible effects, they most often returned to their families and resumed their livelihoods.

An important aspect to the Order of St. Anthony's treatment practices was the exclusion of rye bread and other ergot-containing edibles, which halted the progression of ergotism. There was no known cure for ergotism itself, however there was treatment of the symptoms, which often included blood constriction, nervous disorder, and/or hallucinations; if the sufferer survived the initial poisoning, his limbs would often fall off and he or she would continue to improve in health if they halted consumption of ergot. The trunk of the body remained relatively untouched by the disease until its final stages and the victims, not understanding the cause of their ailment, would continue to imbibe ergot-laden food for weeks until the condition reached their digestive system. It is believed that the peasantry and children were most susceptible to ergotism, though the wealthy were afflicted as well, as at times entire villages relied on tainted crops for sustenance and during times of famine, ergotism reached into every house. Ergot fungus is impervious to heat and water, thus it was most often baked into bread through rye flour; though other grasses can be infected, it was uncommon in Medieval Europe to consume grasses other than rye. The physiological effects of ergot depended upon the concentration and combinations of the ingested ergot metabolites, as well as the age and nutritional status of the afflicted individual. The Antonites began to decline after physicians discovered the genesis of ergotism and recommended methods for removing the sclerotium from the rye crops. In 1776, the cloisters of the Antonites were incorporated into the Maltese Knights Hospitaller, losing much of their medical histories in the process and losing the ergotism cures and recipes due to lack of use and lack of preservation.

Usage in gynaecology and obstetrics

Midwives and very few doctors in Europe have used extracts from ergot for centuries:

1. In a Nürnberg manuscript of 1474 powdered ergot was prescribed together with Laurel-fruits and rhizomes of Salomon’s seals to cure »permutter« or »heffmutter«, that means pain in the lower abdomen caused by the »uprising of the womb«
2. In a printed book of 1582 the German physician Adam Lonicer wrote, that three sclerotia of ergot, used several times a day, were used by midwives as a good remedy in case of the »uprising and pain of the womb« (»auffſteigen vnd wehethumb der mutter«)
3. Joachim Camerarius the Younger wrote in 1586, that sclerotia of ergot held under the tongue, would stop bleeding

To prove, that ergot is a harmless sort of grain, in 1774 the French pharmacist Antoine-Augustin Parmentier edited a letter, he had received from Madame Dupile, a midwife of Chaumont-en-Vexin. She had told him, that if uterine contractions were too weak in the expulsion stage of childbirth she and her mother gave peeled ergot in an amount of the filling of a thimble solved in water, wine or broth. The administration of ergot was followed by a mild childbirth within 15 minutes. The French physician Jean-Baptiste Desgranges (1751–1831) published in 1818, that in 1777 he had met midwives in Lyon, who successfully treated feeble uterine contractions by administering the powder of ergot. Desgranges joined this remedy into his therapeutic arsenal. From 1777 to 1804 he was successful in alleviating childbirth for more than twenty women by the administration of the powder of ergot. He never saw any side-effect of this treatment.

In 1807 Dr. John Stearns of Saratoga County wrote to a friend, that he had used over several years a »pulvis parturiens« with complete success in patients with »lingering parturitation«. This »pulvis parturiens« consisted of ergot, that he called a »spurious groth of rye«. He boiled »half a drachm« (ca. 2g) of that powder in half a pint of water and gave one third every twenty minutes, till the pains commenced. In 1813 Dr. Oliver Prescott (1762–1827) of Newburyport published a dissertation "on the natural history and medical effects of the secale cornutum,” in which he described and analysed the experience he had gathered over five years while using ergot in cases of poor uterine action in the second stage of labour in childbirth.

The 1836 Dispensatory of the United States recommended »to a woman in labour fifteen or twenty grains [ca. 1 to 1,3g] of ergot in powder to be repeated every twenty minutes, till its peculiar effects are experienced, or till the amount of a drachm [ca. 3,9g] has been taken«.

In 1837 the French Codex Pharmacopee Francaise required ergot to be kept in all pharmacies.

Low to very low evidence from clinical trials suggests that prophylactic use of ergot alkaloids, administered by intravenous (IV) or intramuscular (IM) in the third stage of labor, may reduce blood loss and may reduce the risk of moderate to severe hemorrhage following delivery, however this medication may also be associated with higher blood pressure and higher pain. It is not clear of oral ergo alkaloids are beneficial or harmful as they have not been well studied. A 2018 Cochrane Systematic Review concluded that other medications such as oxytocin, syntometrine and prostaglandins, may be preferred over ergot alkaloids.

Though ergot was known to cause abortions in cattle and humans, it was not a recognized use for it as abortion was illegal in most countries, thus evidence for its use in abortion is unknown. Most often, ergot was used to speed the process of parturition or delivery, and was not used for the purpose of halting postpartum bleeding, which is a concern of childbirth. However, until anesthesia became available, there was no antidote or way of controlling the effects of ergot. So if the fetus did not move as expected, the drug could cause the uterus to mold itself around the child, rupturing the uterus and killing the child. David Hosack, an American physician, noted the large number of stillbirths resulting from ergot use and stated that rather than pulvis ad partum, it should be called pulvis ad mortem. He began advocating for its use to halt postpartum bleeding. Eventually, doctors determined that the use of ergot in childbirth without an antidote was too dangerous. They ultimately restricted its use to expelling the placenta or stopping hemorrhage. Not only did it constrict the uterus, ergot had the ability to increase or decrease blood pressure, induce hypothermia and emesis, and influence pituitary hormone secretions. In 1926, Swiss psychiatrist Hans Maier suggested to use ergotamine for the treatment of vascular headaches of the migraine type.

In the 1930s, abortifacient drugs were marketed to women by various companies under various names such as Molex pills and Cote pills. Since birth control devices and abortifacients were illegal to market and sell at the time, they were offered to women who were "delayed". The recommended dosage was seven grains of ergotin a day. According to the United States Federal Trade Commission (FTC) these pills contained ergotin, aloes, Black Hellebore, and other substances. The efficacy and safety of these pills are unknown. The FTC deemed them unsafe and ineffective and demanded that they cease and desist selling the product. Currently, over a thousand compounds have been derived from ergot ingredients.

Speculated cause of hysterics and hallucinations

It has been posited that Kykeon, the beverage consumed by participants in the ancient Greek Eleusinian Mysteries cult, might have been based on hallucinogens from ergotamine, a precursor to the potent hallucinogen lysergic acid diethylamide (LSD), and ergonovine.

British author John Grigsby contends that the presence of ergot in the stomachs of some of the so-called 'bog-bodies' (Iron Age human remains from peat bogs Northeast Europe, such as the Tollund Man) is indicative of use of Claviceps purpurea in ritual drinks in a prehistoric fertility cult akin to the Greek Eleusinian Mysteries. In his 2005 book Beowulf and Grendel, he argues that the Anglo-Saxon poem Beowulf is based on a memory of the quelling of this fertility cult by followers of Odin. He writes that Beowulf, which he translates as barley-wolf, suggests a connection to ergot which in German was known as the 'tooth of the wolf'.

Linnda R. Caporael posited in 1976 that the hysterical symptoms of young women that had spurred the Salem witch trials had been the result of consuming ergot-tainted rye. However, Nicholas P. Spanos and Jack Gottlieb, after a review of the historical and medical evidence, later disputed her conclusions. Other authors have likewise cast doubt on ergotism as the cause of the Salem witch trials.

Claviceps purpurea

Mankind has known about Claviceps purpurea for a long time, and its appearance has been linked to extremely cold winters that were followed by rainy summers.

The sclerotial stage of C. purpurea conspicuous on the heads of ryes and other such grains is known as ergot. Favorable temperatures for growth are in the range of 18–30 °C. Temperatures above 37 °C cause rapid germination of conidia. Sunlight has a chromogenic effect on the mycelium, with intense coloration. Cereal mashes and sprouted rye are suitable substrates for growth of the fungus in the laboratory.

Claviceps africana

Claviceps africana infects sorghum. In sorghum and pearl millet, ergot became a problem when growers adopted hybrid technology, which increased host susceptibility. It only infects unfertilized ovaries, so self-pollination and fertilization can decrease the presence of the disease, but male-sterile lines are extremely vulnerable to infection. Symptoms of infection by C. africana include the secretion of honeydew (a fluid with high concentrates of sugar and conidia), which attracts insects like flies, beetles, and wasps that feed on it. This helps spread the fungus to uninfected plants. 

C. africana caused ergot disease that caused a famine in 1903-1906 in Northern Cameroon, West Africa, and also occurs in eastern and southern Africa, especially Zimbabwe and South Africa. Male sterile sorghums (also referred to as A-lines) are especially susceptible to infection, as first recognized in the 1960s, and massive losses in seed yield have been noted. Infection is associated with cold night temperatures that are below 12 °C occurring two to three weeks before flowering.

Sorghum ergot caused by Claviceps africana Frederickson, Mantle and De Milliano is widespread in all sorghum growing areas, whereas the species was formerly restricted to Africa and Asia where it was first recorded more than 90 years ago, it has been spreading rapidly and by the mid-1990s it reached Brazil, South Africa, and Australia. By 1997, the disease had spread to most South American countries and the Caribbean including Mexico, and by 1997 had reached Texas in the United States.