Natural product

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). Natural products may be classified according to their biological function, biosynthetic pathway, or source. Depending on the sources, the number of known natural product molecules ranges between 300,000 and 400,000. == 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. For instance, alkaloids like morphine and nicotine act as defense chemicals against herbivores, while flavonoids attract pollinators, and terpenes such as menthol serve to repel insects. 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. Primary metabolites involved in energy production include enzymes essential for respiratory and photosynthetic processes. These enzymes are composed of amino acids and often require non-peptidic cofactors for proper function. The basic structures of cells and organisms are also built from primary metabolites, including components such as cell membranes (e.g., phospholipids), cell walls (e.g., peptidoglycan, chitin), and cytoskeletons (proteins). Enzymatic cofactors that are primary metabolites include several members of the vitamin B family. For instance, vitamin B1 (thiamine diphosphate), synthesized from 1-deoxy-D-xylulose 5-phosphate, serves as a coenzyme for enzymes such as pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, and transketolase—all involved in carbohydrate metabolism. Vitamin B2 (riboflavin), derived from ribulose 5-phosphate and guanosine triphosphate, is a precursor to FMN and FAD, which are crucial for various redox reactions. Vitamin B3 (nicotinic acid or niacin), synthesized from tryptophan, is an essential part of the coenzymes NAD and NADP, necessary for electron transport in the Krebs cycle, oxidative phosphorylation, and other redox processes. Vitamin B5 (pantothenic acid), derived from α,β-dihydroxyisovalerate (a precursor to valine) and aspartic acid, is a component of coenzyme A, which plays a vital role in carbohydrate and amino acid metabolism, as well as fatty acid biosynthesis. Vitamin B6 (pyridoxol, pyridoxal, and pyridoxamine, originating from erythrose 4-phosphate), functions as pyridoxal 5′-phosphate and acts as a cofactor for enzymes, particularly transaminases, involved in amino acid metabolism. Vitamin B12 (cobalamins) contains a corrin ring structure, similar to porphyrin, and serves as a coenzyme in fatty acid catabolism and methionine synthesis. 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. == Biosynthesis ==

s are organic molecules essential for energy storage, structural support, and various biological processes in living organisms. They are produced through photosynthesis in plants or gluconeogenesis in animals and can be converted into larger polysaccharides: and plants. During photosynthesis, plants initially produce , a three-carbon triose. Fatty acids and polyketides Enzyme abbreviations: ACC: acetyl-CoA carboxylase; ACS: acyl-CoA synthase; AT: acyltransferase; ER: enoyl reductase; HD: hydroxyacyl dehydratase; KR: ketoacyl reductase; KS: ketoacyl synthase; TE: thioesterase. Fatty acids and polyketides are synthesized via the acetate pathway, which starts from basic building blocks derived from sugars: and serve as energy storage in the form of fat in animals. The plant-derived fatty acid linoleic acid is converted in animals through elongation and desaturation into arachidonic acid, which is then transformed into various eicosanoids, including leukotrienes, prostaglandins, and thromboxanes. These eicosanoids act as signaling molecules, playing key roles in inflammation and immune responses. and includes important compounds such as macrolide antibiotics. Aromatic amino acids and phenylpropanoids The shikimate pathway is a key metabolic route responsible for the production of aromatic amino acids and their derivatives in plants, fungi, bacteria, and some protozoans: This pathway is vital as it connects primary metabolism to specialized metabolic processes, directing an estimated 20-50% of all fixed carbon through its reactions. It begins with the condensation of phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P), leading through several enzymatic steps to form chorismate, the precursor for all three AAAs. Phenylalanine serves as the starting point for the phenylpropanoid pathway, which leads to a diverse array of secondary metabolites. The MVA pathway, discovered in the 1950s, functions in eukaryotes, some bacteria, and plants. It converts acetyl-CoA to IPP via HMG-CoA and mevalonate, and is essential for steroid biosynthesis. Statins, which lower cholesterol, work by inhibiting HMG-CoA reductase in this pathway. Both pathways converge at IPP and DMAPP, which combine to form longer prenyl diphosphates like geranyl (C10), farnesyl (C15), and geranylgeranyl (C20). Steroids, primarily synthesized via the MVA pathway, are derived from farnesyl diphosphate through intermediates like squalene and lanosterol, which are precursors to cholesterol and other steroid molecules. Alkaloids are nitrogen-containing organic compounds produced by plants through complex biosynthetic pathways, starting from amino acids. The biosynthesis of alkaloids from amino acids is essential for producing many biologically active compounds in plants. These compounds range from simple cycloaliphatic amines to complex polycyclic nitrogen heterocycles. The biosynthesis of the tropane alkaloid cocaine follows this general pathway. Oxidoreductases, including cytochrome P450s and flavin-containing monooxygenases, play a vital role in modifying the core alkaloid structures through oxidation, contributing to their structural diversity and bioactivity. For instance, in the biosynthesis of morphine, oxidative coupling is essential for forming the complex polycyclic structures typical of these alkaloids. Modified peptides include antibiotics like penicillins and cephalosporins, characterized by their β-lactam ring structure, which is essential for their antibacterial activity. These compounds undergo complex enzymatic modifications during biosynthesis. Cyanogenic glycosides are amino acid derivatives in plants that can release hydrogen cyanide when tissues are damaged, serving as a defense mechanism. Their biosynthesis involves converting amino acids into cyanohydrins, which are then glycosylated. Glucosinolates are sulfur-containing compounds in cruciferous vegetables like broccoli and mustard. Their biosynthesis starts with amino acids such as methionine or tryptophan and involves adding sulfur and glucose groups. When tissues are damaged, glucosinolates break down into isothiocyanates, which contribute to the pungent flavors of these vegetables and offer potential health benefits. == Sources ==

Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases. 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. Modern natural product-derived drugs Many prescribed drugs have been either directly derived from or inspired by natural products. Approximately 35% of the annual global market of medicine is either from natural products or related drugs. This breaks down as 25% from plants, 13% from microorganisms, and 3% from animal sources. Some of the oldest natural product based drugs are analgesics. The bark of the willow tree has been known since antiquity to have pain-relieving properties due to 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 extracted from the latex of Papaver somniferous (a flowering poppy plant). The most potent narcotic component of opium is the alkaloid morphine, which acts as an opioid receptor agonist. The N-type calcium channel blocker ziconotide is an analgesic based on a cyclic peptide cone snail toxin (ω-conotoxin MVIIA) from the species Conus magus. Numerous 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 the 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. 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 ==

, 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, 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. Structure determination refers to methods applied to determine the chemical structure of an isolated, pure natural product. 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). Modern structure determination often involves a combination of advanced analytical techniques. Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography are commonly used as primary tools for structure elucidation. High-resolution tandem mass spectrometry (MS/MS) also plays a crucial role, providing information on molecular formula and fragmentation patterns. For complex structures, computational methods are increasingly employed to assist in structure determination. This may include computer-assisted structure elucidation (CASE) platforms and in silico fragmentation prediction tools. Determination of the absolute configuration often relies on a combination of NMR data (coupling constants and nuclear Overhauser effect (NOE), chemical derivatization methods (e.g., Mosher's ester analysis), and spectroscopic techniques like vibrational circular dichroism (VCD), and optical rotatory dispersion (ORD). In cases where traditional methods are insufficient, especially for novel compounds with unprecedented molecular skeletons, advanced computational chemistry approaches are used to predict and compare spectral data, helping to elucidate the complete structure including stereochemistry. == Synthesis ==

Many natural products have complex structures. The complexity is determined by factors like molecular mass, arrangement of substructures (e.g., functional groups, rings), number and density of these groups, their stability, stereochemical elements, and physical properties, as well as the novelty of the structure and prior synthetic efforts. Less complex natural products can often be cost-effectively synthesized from simpler chemical ingredients through total synthesis. However, not all natural products are suitable for total synthesis. The most complex ones are often impractical to synthesize on a large scale due to high costs. In these cases, isolation from natural sources may be sufficient if it provides adequate quantities, as seen with drugs like penicillin, morphine, and paclitaxel, which were obtained at commercial scales without significant synthetic chemistry. Additionally, the number of structural analogues available for structure–activity analysis (SAR) is limited by the biology of the organism, and thus beyond experimental control. When the desired product is difficult to obtain or modify to create analogs, a middle-to-late stage biosynthetic precursor or analog can sometimes be used to produce the final target. This approach, called semisynthesis or partial synthesis, involves extracting a biosynthetic intermediate and converting it into the final product using conventional chemical synthesis techniques. Second, the semisynthetic process allows for the creation of analogues of the final product, as seen in the development of newer generation semisynthetic penicillins. Total synthesis , a 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 Robert Burns Woodward and Albert 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. Biomimetic synthetic strategies have emerged due to their ability to simplify the synthesis of complex structures, especially those containing unusual moieties like spiro-ring systems or quaternary carbon atoms. These approaches mainly involve reactions such as Diels-Alder dimerizations, photocycloadditions, cyclizations, oxidative and radical reactions and these reactions can be used to efficiently construct complex molecular frameworks. Thus, mimicking the biosynthetic processes, chemists have been able to design more effective and economical processes for the synthesis of natural products that are of interest in drug discovery and chemical biology. == Research and teaching ==

Research and teaching activities related to natural products fall into a number of diverse academic areas, including organic chemistry, medicinal chemistry, pharmacognosy, 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 development and history of chemistry. Isolating and identifying natural products has been important to source substances for early preclinical drug discovery research, to understand traditional medicine and ethnopharmacology, and to find pharmacologically useful areas of chemical space. To achieve this, many technological advances have been made, such as the evolution of technology associated with chemical separations, and the development of modern methods in chemical structure determination such as NMR. Early attempts to understand the biosynthesis of natural products, saw chemists employ first radiolabelling and more recently stable isotope labeling combined with NMR experiments. In addition, natural products are prepared by organic synthesis, to provide confirmation of their structure, or to give access to larger quantities of natural products of interest. In this process, the structure of some natural products have been revised, and the challenge of synthesising natural products has led to the development of new synthetic methodology, 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). == History ==

(1743–1794) (1800–1882) (1852–1919) 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 1819 strychnine, an alkaloid was isolated. Synthesis A second important step was the synthesis of organic compounds. While the synthesis of inorganic substances had been known for a long time, creating organic substances was a major challenge. In 1827, the Swedish chemist Jöns Jacob Berzelius argued that a vital force or life force was essential for synthesizing organic compounds. This idea, known as vitalism, had many supporters well into the 19th century, even after the introduction of atomic theory. Vitalism also aligned with traditional medicine, which often viewed disease as a result of imbalances in vital energies that distinguish life from nonlife. The first significant challenge to vitalism came in 1828 when German chemist Friedrich Wöhler synthesized urea, a natural product found in urine, by heating ammonium cyanate, an inorganic substance: :\mathrm{NH_4OCN\ \xrightarrow {\ \ 60^{\circ}C \ \ }\ H_2NCONH_2} This reaction demonstrated that a life force was not needed to create organic substances. Initially, this idea faced skepticism, but it gained acceptance 20 years later when Adolph Wilhelm Hermann Kolbe synthesized acetic acid from carbon disulfide. Since then, organic chemistry has developed into a distinct field focused on studying carbon-containing compounds, which were found to be prevalent in nature. Structural theories The third key development was the structure elucidation of organic substances. While the elemental composition of pure organic compounds could be determined accurately, their molecular structures remained unclear. This issue became evident in a dispute between Friedrich Wöhler and Justus von Liebig, who studied silver salts with identical compositions but different properties. Wöhler examined silver cyanate, a harmless compound, while von Liebig investigated the explosive silver fulminate. Elemental analysis showed both salts had the same amounts of silver, carbon, oxygen, and nitrogen, yet their properties differed, contradicting the prevailing view that composition alone determined properties. This discrepancy was explained by Berzelius's theory of isomers, which proposed that not only the number and type of elements but also the arrangement of atoms affects a compound's properties. This insight led to the development of structural theories, such as the radical theory of Jean-Baptiste Dumas and the substitution theory of Auguste Laurent. A definitive structure theory was proposed in 1858 by August Kekulé, who suggested that carbon is tetravalent and can bond to itself, forming chains found in natural products. and later by Leopold Ružička (Nobel Prize 1939). • Porphyrin-based dyes: Including chlorophyll and heme, investigated by Richard Willstätter (Nobel Prize 1915) and Hans Fischer (Nobel Prize 1930). These tetrapyrrole compounds play essential roles in various biological processes (including photosynthesis, respiration, electron transfer, and catalysis) and have been the subject of extensive research. • Steroids: Researched by Heinrich Otto Wieland (Nobel Prize 1927) and Adolf Windaus (Nobel Prize 1928). Their work contributed significantly to our understanding of sterol biosynthesis and structure. • Carotenoids: Studied by Paul Karrer (Nobel Prize 1937). These pigments are important for their antioxidant properties and roles in photosynthesis and vision. • Vitamins: Investigated by numerous scientists, including Paul Karrer, Robert R. Williams, Adolf Windaus (Nobel Prize 1928), Norman Haworth (Nobel Prize 1937), Richard Kuhn (Nobel Prize 1938), and Albert Szent-Györgyi (Nobel Prize 1937). The discovery and characterization of vitamins revolutionized our understanding of nutrition and health. • Steroid hormones: Studied by Adolf Butenandt (Nobel Prize 1939) and Edward Calvin Kendall (Nobel Prize 1950). Their work on steroid hormones paved the way for modern endocrinology. • Alkaloids and anthocyanins: Researched by Robert Robinson (Nobel Prize 1947) and others. These compounds, particularly alkaloids, have been crucial in the development of many pharmaceuticals. • Polypeptide hormones: Investigated by Vincent du Vigneaud (Nobel Prize 1955) who completed the first total synthesis of the natural polypeptide oxytocin and vasopressin. • Total synthesis of natural products: Robert Burns Woodward was awarded a Nobel Prize in 1965 for synthesizing compounds including quinine, cholesterol, cortisone, strychnine, reserpine, chlorophyll, and vitamin B12. Elias James Corey received a Nobel Prize in 1990 for similar achievements, such as the synthesis of gibberellic acid, ginkgolide, and prostaglandins. These pioneering studies laid the foundation for our understanding of natural product chemistry and biochemistry, leading to numerous Nobel Prizes in Chemistry and Physiology or Medicine. The field of natural products has continued to evolve, with recent research focusing on the evolutionary and ecological roles of these compounds. == See also ==