Anatural product is a naturalcompound orsubstance produced by a living organism—that is, found innature.[2][3] In the broadest sense, natural products include any substance produced by life.[4][5] Natural products can also be prepared bychemical synthesis (bothsemisynthesis andtotal synthesis and have played a central role in the development of the field oforganic chemistry by providing challenging synthetic targets). The termnatural product has also been extended for commercial purposes to refer tocosmetics,dietary supplements, and foods produced from natural sources without added artificial ingredients.[6]
Within the field of organic chemistry, the definition of natural products is usually restricted toorganic compounds isolated from natural sources that are produced by the pathways ofprimary orsecondary metabolism.[7] Within the field ofmedicinal chemistry, the definition is often further restricted to secondary metabolites.[8][9] Secondary metabolites (or specialized metabolites) are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage.[10] Many secondary metabolites arecytotoxic and have been selected and optimized through evolution for use as "chemical warfare" agents against prey, predators, and competing organisms.[11] Secondary or specialized metabolites are often unique to specific species, whereas primary metabolites are commonly found across multiple kingdoms. Secondary metabolites are marked by chemical complexity which is why they are of such interest to chemists.
Natural sources may lead tobasic research on potential bioactive components for commercial development aslead compounds indrug discovery.[12] Although natural products have inspired numerous drugs,drug development from natural sources has received declining attention in the 21st century by pharmaceutical companies, partly due to unreliable access and supply, intellectual property, cost, andprofit concerns, seasonal or environmental variability of composition, and loss of sources due to risingextinction rates.[12] Despite this, natural products and their derivatives still accounted for about 10% of new drug approvals between 2017 and 2019.[13]
The broadest definition of natural product is anything that is produced by life,[4][14] and includes the likes ofbiotic materials (e.g. wood, silk),bio-based materials (e.g.bioplastics, cornstarch),bodily fluids (e.g. milk, plant exudates), and othernatural 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[15][16] and 400,000.[17]
FollowingAlbrecht Kossel's original proposal in 1891,[18] natural products are often divided into two major classes, the primary and secondary metabolites.[19][20] 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 likemorphine andnicotine act as defense chemicals against herbivores, whileflavonoids attract pollinators, andterpenes such asmenthol serve to repel insects. Because of their ability to modulate biochemical andsignal transduction pathways, some secondary metabolites have useful medicinal properties.[21]
Natural products especially within the field oforganic chemistry are often defined as primary and secondary metabolites.[8][9] A more restrictive definition limiting natural products to secondary metabolites is commonly used within the fields ofmedicinal chemistry andpharmacognosy.[14]
Primary metabolites, as defined byKossel, are essential components of basic metabolic pathways required for life. They are associated with fundamental cellular functions such as nutrient assimilation, energy production, and growth and development. These metabolites have a wide distribution across manyphyla and often span more than onekingdom. Primary metabolites include the basic building blocks of life:carbohydrates,lipids,amino acids, andnucleic acids.[22]
Primary metabolites involved in energy production include enzymes essential forrespiratory andphotosynthetic processes. These enzymes are composed ofamino acids and often require non-peptidiccofactors for proper function.[23] 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), andcytoskeletons (proteins).[24]
Enzymatic cofactors that are primary metabolites include several members of thevitamin B family. For instance,Vitamin B1 (thiamine diphosphate), synthesized from1-deoxy-D-xylulose 5-phosphate, serves as a coenzyme for enzymes such aspyruvate dehydrogenase,2-oxoglutarate dehydrogenase, andtransketolase—all involved in carbohydrate metabolism.Vitamin B2 (riboflavin), derived fromribulose 5-phosphate andguanosine triphosphate, is a precursor toFMN andFAD, which are crucial for various redox reactions.Vitamin B3 (nicotinic acid or niacin), synthesized from tryptophan, is an essential part of the coenzymesNAD+ andNADP+, necessary for electron transport in theKrebs cycle,oxidative phosphorylation, and other redox processes.Vitamin B5 (pantothenic acid), derived fromα,β-dihydroxyisovalerate (a precursor tovaline) and aspartic acid, is a component ofcoenzyme 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 fromerythrose 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 acorrin ring structure, similar toporphyrin, and serves as a coenzyme in fatty acid catabolism andmethionine synthesis.[25]: Ch. 2
Other primary metabolite vitamins includeretinol (vitamin A),[25]: 304–305 synthesized in animals from plant-derivedcarotenoids via themevalonate pathway, andascorbic acid (vitamin C),[25]: 492–493 which is synthesized fromglucose in the liver of animals, though not in humans.
DNA andRNA, which store and transmitgenetic information, are synthesized from primary metabolites, specificallynucleic acids and carbohydrates.[23]
First messengers are signaling molecules that regulatemetabolism andcellular differentiation. These include hormones and growth factors composed of peptides,biogenic amines,steroid hormones,auxins, andgibberellins. These first messengers interact with cellular receptors, which are protein-based, and trigger the activation ofsecond messengers to relay the extracellular signal to intracellular targets. Second messengers often include primary metabolites such ascyclic nucleotides anddiacyl glycerol.[26]
Secondary in contrast to primary metabolites are dispensable and not absolutely required for survival. Furthermore, secondary metabolites typically have a narrow species distribution.[27]
Secondary metabolites have a broad range of functions. These includepheromones that act as social signaling molecules with other individuals of the same species, communication molecules that attract and activatesymbiotic organisms, agents that solubilize and transport nutrients (siderophores etc.), and competitive weapons (repellants,venoms,toxins etc.) that are used against competitors, prey, and predators.[28] For many other secondary metabolites, the function is unknown. One hypothesis is that they confer a competitive advantage to the organism that produces them.[29] An alternative view is that, in analogy to theimmune 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.[30]
General structural classes of secondary metabolites includealkaloids,phenylpropanoids,polyketides, andterpenoids.[7]
The biosynthetic pathways leading to the major classes of natural products are described below.[14][25]: Ch. 2
Carbohydrates are organic molecules essential for energy storage, structural support, and various biological processes in living organisms. They are produced throughphotosynthesis in plants orgluconeogenesis in animals and can be converted into largerpolysaccharides:[25]: Ch. 8
Carbohydrates serve as a primary energy source for most life forms. Additionally,polysaccharides derived from simpler sugars are vital structural components, forming thecell walls of bacteria[31] and plants.[32][33]
During photosynthesis, plants initially produce3-phosphoglyceraldehyde, a three-carbontriose.[25]: Ch. 8 This can be converted intoglucose (a six-carbon sugar) or variouspentoses (five-carbon sugars) through theCalvin cycle. In animals, three-carbon precursors likelactate orglycerol are converted intopyruvate, which can then be synthesized into carbohydrates in the liver.[34]
Fatty acids andpolyketides are synthesized via theacetate pathway, which starts from basic building blocks derived from sugars:[25]: Ch. 3
Duringglycolysis, sugars are broken down intoacetyl-CoA. In an ATP-dependent enzymatic reaction, acetyl-CoA is carboxylated to formmalonyl-CoA. Acetyl-CoA and malonyl-CoA then undergo aClaisen condensation, releasing carbon dioxide to formacetoacetyl-CoA which is used by themevalonate pathway to produce steroids. Infatty acid synthesis, one molecule of acetyl-CoA (the "starter unit") and several molecules of malonyl-CoA (the "extender units") are condensed byfatty acid synthase.[25]: Ch. 3 After each round of elongation, theketo group is reduced, the intermediatealcohol dehydrated, and resulting enoyl-CoAs are reduced to acyl-CoAs. Fatty acids are essential components oflipid bilayers that formcell membranes[36] and serve as energy storage in the form of fat in animals.[37]
The plant-derived fatty acidlinoleic acid is converted in animals through elongation anddesaturation intoarachidonic acid, which is then transformed into variouseicosanoids, includingleukotrienes,prostaglandins, andthromboxanes. These eicosanoids act as signaling molecules, playing key roles ininflammation andimmune responses.[25]: Ch. 3
Alternatively the intermediates from additional condensation reactions are left unreduced to generate poly-β-keto chains, which are subsequently converted into various polyketides.[25]: Ch. 3 Thepolyketide class of natural products has diverse structures and functions[38] and includes important compounds such asmacrolide antibiotics.[39]
Theshikimate pathway is a key metabolic route responsible for the production ofaromatic amino acids and their derivatives in plants, fungi, bacteria, and some protozoans:[25]: Ch. 4
The shikimate pathway leads to the biosynthesis ofaromatic amino acids (AAAs) —phenylalanine,tyrosine, andtryptophan.[40][41] 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.[40][42] It begins with the condensation ofphosphoenolpyruvate (PEP) anderythrose-4-phosphate (E4P), leading through several enzymatic steps to formchorismate, the precursor for all three AAAs.[41][43]
From chorismate, biosynthesis branches out to produce the individual AAAs. In plants, unlike in bacteria, the production of phenylalanine and tyrosine typically occurs via the intermediatearogenate.[43] Phenylalanine serves as the starting point for thephenylpropanoid pathway, which leads to a diverse array of secondary metabolites.[43]
Beyond protein synthesis, AAAs and their derivatives have crucial roles in plant physiology, including pigment production, hormone synthesis, cell wall formation, and defense against various stresses.[40][41] Because animals cannot synthesize these amino acids, the shikimate pathway has also become a target for herbicides, most notably glyphosate, which inhibits one of the key enzymes in this pathway.[40][42]
The biosynthesis ofterpenoids andsteroids involves two primary pathways, which produce essential building blocks for these compounds:[25]: Ch. 5
Themevalonate (MVA) andmethylerythritol phosphate (MEP) pathways produce the five-carbon unitsisopentenyl diphosphate (IPP) anddimethylallyl diphosphate (DMAPP), which are the building blocks for all terpenoids.[44][45]
The MVA pathway, discovered in the 1950s, functions in eukaryotes, some bacteria, and plants. It converts acetyl-CoA to IPP viaHMG-CoA and mevalonate, and is essential for steroid biosynthesis.Statins, which lower cholesterol, work by inhibiting HMG-CoA reductase in this pathway.[44][45] The MEP pathway, found in bacteria, some parasites, and plant chloroplasts, starts withpyruvate andglyceraldehyde 3-phosphate to produce IPP and DMAPP. This pathway is crucial for the synthesis ofplastid terpenoids likecarotenoids andchlorophylls.[46][47] Both pathways converge at IPP and DMAPP, which combine to form longer prenyl diphosphates likegeranyl (C10),farnesyl (C15), andgeranylgeranyl (C20).[44] These compounds serve as precursors for a wide range of terpenoids, includingmonoterpenes,sesquiterpenes, andtriterpenes.[45]
The diversity of terpenoids arises from modifications such ascyclization,oxidation, andglycosylation, enabling them to play roles in plant defense, pollinator attraction, and signaling.[48] Steroids, primarily synthesized via the MVA pathway, are derived fromfarnesyl diphosphate through intermediates likesqualene andlanosterol, which are precursors to cholesterol and other steroid molecules.[45]
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 simplecycloaliphaticamines to complex polycyclic nitrogenheterocycles.[50][25]: Ch. 6
Alkaloid biosynthesis generally follows four key steps: (i) synthesis of anamine precursor, (ii) synthesis of analdehyde precursor, (iii) formation of animinium cation, and (iv) aMannich-like reaction. These steps form the core structure of many alkaloids and represent the initial committed steps in their production.[51] Amino acids such astryptophan,tyrosine,lysine,arginine, andornithine serve as essential precursors. Their accumulation is facilitated by mechanisms like increased gene expression, gene duplication, or the evolution of enzymes with broader substrate specificities.[51] The biosynthesis of the tropane alkaloidcocaine follows this general pathway.[49]
A key reaction in alkaloid biosynthesis is thePictet-Spengler reaction, which is crucial for forming theβ-carboline structure found in many alkaloids. This reaction involves the condensation of an aldehyde with an amine, as seen in the biosynthesis ofstrictosidine, a precursor to numerous monoterpene indole alkaloids.[52]
Oxidoreductases, including cytochrome P450s and flavin-containingmonooxygenases, play a vital role in modifying the core alkaloid structures through oxidation, contributing to their structural diversity and bioactivity. For instance, in the biosynthesis ofmorphine, oxidative coupling is essential for forming the complex polycyclic structures typical of these alkaloids.[50] The biosynthetic pathways of alkaloids involve numerous enzymatic steps. For example,tropane alkaloids, derived from ornithine, undergo processes such asdecarboxylation, oxidation, and cyclization. Similarly, the biosynthesis of isoquinoline alkaloids from tyrosine involves complex transformations, including the formation of (S)-reticuline, a key intermediate in the pathway.[50]
Biosynthesis of peptides, proteins, and other amino acid derivatives assembles amino acids into biologically active molecules, producing compounds like peptide hormones, modified peptides, and plant-derived substances.[25]: Ch. 8
Peptides and proteins are synthesized throughprotein synthesis or translation, a process involvingtranscription of DNA intomessenger RNA (mRNA). The mRNA serves as a template for protein assembly onribosomes. During translation,transfer RNA (tRNA) carries specific amino acids to match with mRNA codons, forming peptide bonds to create the protein chain.
Peptide hormones, such asoxytocin andvasopressin, are short amino acid chains that regulate physiological processes, including social bonding and water retention.[53] Modified peptides includeantibiotics likepenicillins andcephalosporins, characterized by their β-lactam ring structure, which is essential for their antibacterial activity.[54] These compounds undergo complex enzymatic modifications during biosynthesis.[55]
Cyanogenic glycosides are amino acid derivatives in plants that can release hydrogen cyanide when tissues are damaged, serving as a defense mechanism.[56] Their biosynthesis involves converting amino acids into cyanohydrins, which are then glycosylated.[57]Glucosinolates aresulfur-containing compounds incruciferous vegetables likebroccoli andmustard. Their biosynthesis starts with amino acids such as methionine or tryptophan and involves adding sulfur and glucose groups.[58] When tissues are damaged, glucosinolates break down into isothiocyanates, which contribute to the pungent flavors of these vegetables and offer potential health benefits.[58]
Natural products may be extracted from thecells,tissues, andsecretions ofmicroorganisms, plants and animals.[59][60] 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 collect samples from around the world to analyze and evaluate indrug discovery screens orbioassays. This effort to search for biologically active natural products is known asbioprospecting.[59][60]
Pharmacognosy provides the tools to detect, isolate and identify bioactive natural products that could be developed for medicinal use. When an"active principle" is isolated from a traditional medicine or other biological material, this is known as a "hit". Subsequent scientific and legal work is then performed to validate the hit (e.g. elucidation ofmechanism of action, confirmation that there is no intellectual property conflict). This is followed by thehit to lead stage of drug discovery, where derivatives of the active compound are produced in an attempt to improve itspotency andsafety.[61][62] In this and related ways, modern medicines can be developed directly from natural sources.[63]
Although traditional medicines and other biological material are considered an excellent source of novel compounds, the extraction and isolation of these compounds can be a slow, expensive and inefficient process. For large scale manufacture therefore, attempts may be made to produce the new compound by total synthesis or semisynthesis.[64] Because natural products are generallysecondary metabolites with complexchemical structures, their total/semisynthesis is not always commercially viable. In these cases, efforts can be made to design simpleranalogues with comparable potency and safety that are amenable to total/semisynthesis.[65]
The serendipitous discovery and subsequent clinical success ofpenicillin prompted a large-scale search for other environmentalmicroorganisms that might produce anti-infective natural products. Soil and water samples were collected from all over the world, leading to the discovery ofstreptomycin (derived fromStreptomyces griseus), and the realization that bacteria, not just fungi, represent an important source of pharmacologically active natural products.[67] This, in turn, led to the development of an impressive arsenal of antibacterial and antifungal agents includingamphotericin B,chloramphenicol,daptomycin andtetracycline (fromStreptomycesspp.),[68] thepolymyxins (fromPaenibacillus polymyxa),[69] and therifamycins (fromAmycolatopsis rifamycinica).[70] Antiparasitic and antiviral drugs have similarly been derived from bacterial metabolites.[71]
Although most of the drugs derived from bacteria are employed as anti-infectives, some have found use in other fields of medicine.Botulinum toxin (fromClostridium botulinum) andbleomycin (fromStreptomyces verticillus) are two examples. Botulinum, theneurotoxin responsible forbotulism, can be injected into specific muscles (such as those controlling the eyelid) to preventmuscle spasm.[66] Also, theglycopeptide bleomycin is used for the treatment of several cancers includingHodgkin's lymphoma,head and neck cancer, andtesticular cancer.[72] Newer trends in the field include the metabolic profiling and isolation of natural products from novel bacterial species present in underexplored environments. Examples includesymbionts orendophytes from tropical environments,[73] subterranean bacteria found deep underground via mining/drilling,[74][75] andmarine bacteria.[76]
Because manyArchaea have adapted to life in extreme environments such aspolar regions,hot springs, acidic springs, alkaline springs,salt lakes, and thehigh pressure ofdeep ocean water, they possess enzymes that are functional under quite unusual conditions. These enzymes are of potential use in thefood,chemical, andpharmaceutical industries, where biotechnological processes frequently involve high temperatures, extremes of pH, high salt concentrations, and / or high pressure. Examples of enzymes identified to date includeamylases,pullulanases,cyclodextrin glycosyltransferases,cellulases,xylanases,chitinases,proteases,alcohol dehydrogenase, andesterases.[77] Archaea represent a source of novelchemical compounds also, for example isoprenyl glycerol ethers 1 and 2 fromThermococcus S557 andMethanocaldococcus jannaschii, respectively.[78]
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Several anti-infective medications have been derived from fungi including penicillin and thecephalosporins (antibacterial drugs fromPenicillium rubens andCephalosporium acremonium, respectively)[79][67] andgriseofulvin (an antifungal drug fromPenicillium griseofulvum).[80] Other medicinally useful fungalmetabolites includelovastatin (fromPleurotus ostreatus), which became a lead for a series of drugs that lowercholesterol levels,cyclosporin (fromTolypocladium inflatum), which is used to suppress theimmune response afterorgan transplant operations, andergometrine (fromClaviceps spp.), which acts as avasoconstrictor, and is used to prevent bleeding after childbirth.[25]: Ch. 6 Asperlicin (fromAspergillus alliaceus) is another example. Asperlicin is a novel antagonist ofcholecystokinin, aneurotransmitter thought to be involved inpanic attacks, and could potentially be used to treatanxiety.[81]
Plants are a major source of complex and highly structurally diverse chemical compounds (phytochemicals), this structural diversity attributed in part to thenatural selection of organisms producingpotent compounds to deterherbivory (feeding deterrents).[82] Major classes of phytochemical includephenols,polyphenols,tannins,terpenes, and alkaloids.[83] 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 theanticancer agentspaclitaxel andomacetaxine mepesuccinate (fromTaxus brevifolia andCephalotaxus harringtonii, respectively),[84] theantimalarial agentartemisinin (fromArtemisia annua),[85] and theacetylcholinesterase inhibitorgalantamine (fromGalanthus spp.), used to treatAlzheimer's disease.[86] Other plant-derived drugs, used medicinally and/orrecreationally includemorphine,cocaine,quinine,tubocurarine,muscarine, andnicotine.[25]: Ch. 6
Animals also represent a source of bioactive natural products. In particular,venomous animals such as snakes, spiders, scorpions, caterpillars, bees, wasps, centipedes, ants, toads, and frogs have attracted much attention. This is because venom constituents (peptides, enzymes, nucleotides, lipids, biogenic amines etc.) often have very specific interactions with amacromolecular target in the body (e.g. α-bungarotoxin fromcobras).[88][89] 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.[89]
Because of these specific chemical-target interactions, venom constituents have proved important tools for studyingreceptors,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 viperBothrops jararaca, was a lead in the development of theantihypertensive agentscilazapril andcaptopril.[89] Also, echistatin, adisintegrin from the venom of the saw-scaled viperEchis carinatus was a lead in the development of theantiplatelet drugtirofiban.[90]
In addition to theterrestrial animals andamphibians described above, manymarine animals have been examined for pharmacologically active natural products, withcorals,sponges,tunicates,sea snails, andbryozoans yielding chemicals with interestinganalgesic,antiviral, andanticancer activities.[91] Two examples developed for clinical use include ω-conotoxin (from the marine snailConus magus)[92][87] andecteinascidin 743 (from the tunicateEcteinascidia turbinata).[93] The former, ω-conotoxin, is used to relieve severe and chronic pain,[87][92] while the latter, ecteinascidin 743 is used to treatmetastaticsoft tissue sarcoma.[94] Other natural products derived from marine animals and under investigation as possible therapies include theantitumour agentsdiscodermolide (from the spongeDiscodermia dissoluta),[95]eleutherobin (from the coralErythropodium caribaeorum), and thebryostatins (from the bryozoanBugula neritina).[95]
Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases.[96][97][98] Moreover, synthetic analogs of natural products with improved potency and safety can be prepared, and therefore, natural products are often used as starting points fordrug discovery. Natural product constituents have inspired numerous drug discovery efforts that eventually gained approval as new drugs.[99][100]
Many prescribed drugs have been either directly derived from or inspired by natural products.[1][101] Approximately 35% of the annual global market of medicine is either from natural products or related drugs.[102] This breaks down as 25% from plants, 13% from microorganisms, and 3% from animal sources.[102]
Between 1981 and 2019, the FDA approved 1,881new chemical entities, of which 65 (3.5%) were unaltered natural products, 99 (5.3%) were defined mixturebotanical drugs, 178 (9.5%) were natural product derivatives, and 164 (8.7%) were synthetic compounds containing natural productpharmacophores. Altogether, this accounts for 506 (26.9%) of all new approved drugs.[13] Additionally, natural products and their derivatives often show higher success rates in later clinical trial phases and may have lower toxicity profiles compared to synthetic compounds.[103]
Some of the oldest natural product based drugs are analgesics. The bark of thewillow tree has been known since antiquity to have pain-relieving properties due to the natural productsalicin, which in turn may be hydrolyzed intosalicylic acid. A synthetic derivativeacetylsalicylic acid better known asaspirin is a widely used pain reliever. Its mechanism of action is inhibition of thecyclooxygenase (COX) enzyme.[104] Another notable example isopium extracted from the latex ofPapaver somniferous (a flowering poppy plant). The most potent narcotic component of opium is the alkaloid morphine, which acts as anopioid receptor agonist.[105] TheN-type calcium channel blockerziconotide is an analgesic based on a cyclic peptide cone snail toxin (ω-conotoxin MVIIA) from the speciesConus magus.[106]
Numerousanti-infectives are based on natural products.[60] The first antibiotic to be discovered, penicillin, was isolated from the moldPenicillium. Penicillin and relatedbeta lactams work by inhibiting theDD-transpeptidase enzyme that is required by bacteria to cross linkpeptidoglycan to form the cell wall.[107]
Several natural product drugs targettubulin, which is a component of thecytoskeleton. These include the tubulin polymerization inhibitorcolchicine isolated from theColchicum autumnale (autumn crocus flowering plant), which is used to treatgout.[108] Colchicine is biosynthesized from the amino acidsphenylalanine andtryptophan. Paclitaxel, in contrast, is a tubulin polymerization stabilizer and is used as achemotherapeutic drug. Paclitaxel is based on the terpenoid natural producttaxol, which is isolated fromTaxus brevifolia (the pacific yew tree).[109]
A class of drugs widely used to lower cholesterol are theHMG-CoA reductase inhibitors, for exampleatorvastatin. These were developed frommevastatin, a polyketide produced by the fungusPenicillium citrinum.[110] Finally, a number natural product drugs are used to treat hypertension and congestive heart failure. These include theangiotensin-converting enzyme inhibitorcaptopril. Captopril is based on the peptidic bradykinin potentiating factor isolated from venom of the Brazilian arrowhead viper (Bothrops jararaca).[111]
Numerous challenges limit the use of natural products for drug discovery, resulting in 21st century preference by pharmaceutical companies to dedicate discovery efforts towardhigh-throughput screening of pure synthetic compounds with shorter timelines to refinement.[12][112] Natural product sources are often unreliable to access and supply, have a high probability of duplication, inherently create intellectual property concerns aboutpatent protection, vary in composition due to sourcing season or environment, and are susceptible to risingextinction rates.[12][112]
The biological resource for drug discovery from natural products remains abundant, with small percentages of microorganisms, plant species, and insects assessed for bioactivity.[12] In enormous numbers, bacteria and marine microorganisms remain unexamined.[113][114] As of 2008, the field ofmetagenomics was proposed to examine genes and their function in soil microbes,[114][115] but most pharmaceutical firms have not exploited this resource fully, choosing instead to develop "diversity-oriented synthesis" from libraries of known drugs or natural sources for lead compounds with higher potential for bioactivity.[12]
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.[112] Theisolation 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,[118][119][120]
Structure determination refers to methods applied to determine thechemical structure of an isolated, pure natural product. For instance, the chemical structure of penicillin was determined byDorothy Crowfoot Hodgkin in 1945, work for which she later received a Nobel Prize in Chemistry (1964).[121]
Modern structure determination often involves a combination of advanced analytical techniques.Nuclear magnetic resonance (NMR) spectroscopy andX-ray crystallography are commonly used as primary tools for structure elucidation. High-resolutiontandem mass spectrometry (MS/MS) also plays a crucial role, providing information on molecular formula andfragmentation patterns. For complex structures, computational methods are increasingly employed to assist in structure determination. This may includecomputer-assisted structure elucidation (CASE) platforms and in silico fragmentation prediction tools. Determination of theabsolute configuration often relies on a combination of NMR data (coupling constants andnuclear Overhauser effect (NOE), chemical derivatization methods (e.g.,Mosher's ester analysis), and spectroscopic techniques likevibrational circular dichroism (VCD), andoptical 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 includingstereochemistry.[122]
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.[123]
Less complex natural products can often be cost-effectively synthesized from simpler chemical ingredients throughtotal 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.[123]
Isolating a natural product from its source can be costly in terms of time and materials, and may impact the availability of the natural resource or have ecological consequences. For example, it is estimated that harvesting enough paclitaxel for a single dose of therapy would require thebark of an entire yew tree (Taxus brevifolia).[124] Additionally, the number ofstructural analogues available forstructure–activity analysis (SAR) is limited by the biology of the organism, and thus beyond experimental control.[125]
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 orpartial synthesis, involves extracting a biosynthetic intermediate and converting it into the final product using conventionalchemical synthesis techniques.[125]
This strategy offers two advantages. First, the intermediate may be easier to extract and yield higher amounts than the final product. For instance, paclitaxel can be produced by extracting10-deacetylbaccatin III fromT. brevifolianeedles, followed by a four-step synthesis.[126] Second, the semisynthetic process allows for the creation of analogues of the final product, as seen in the development of newer generation semisyntheticpenicillins.[127]
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.[131][132] Prior to the development ofanalytical chemistry methods in the twentieth century, the structures of natural products were affirmed by total synthesis (so-called "structure proof by synthesis").[133] Early efforts in natural products synthesis targeted complex substances such as cobalamin (vitamin B12), an essentialcofactor in cellularmetabolism.[129][130]
Biomimetic synthesis is a branch of organic chemistry which aims at designing and preparing natural product compounds in the laboratory using thebiosynthetic pathways as a blueprint. This method is based on the mechanisms used by the living organisms for the synthesis of various compounds, which is usually done in astereoselective andregioselective manner.[134] Biomimetic synthetic strategies have emerged due to their ability to simplify the synthesis of complex structures, especially those containing unusual moieties likespiro-ring systems orquaternary carbon atoms.[135] 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 indrug discovery andchemical biology.[134][135]
Examination ofdimerized andtrimerized natural products has shown that an element ofbilateral symmetry is often present. Bilateral symmetry refers to a molecule or system that contains a C2, Cs, or C2vpoint 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 theory (DFT), theHartree–Fock method, andsemiempirical 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 tosteric 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.[136]
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, andethnopharmacology. Other biological areas includechemical biology,chemical ecology,chemogenomics,[137]systems biology,molecular modeling,chemometrics, andchemoinformatics.[138]
Natural products chemistry is a distinct area of chemical research which was important in the development andhistory 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 ofchemical space.[139] To achieve this, many technological advances have been made, such as the evolution of technology associated withchemical separations, and the development of modern methods inchemical structure determination such asNMR. 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 byorganic 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,[140][141][142] and the challenge of synthesising natural products has led to the development of new synthetic methodology, synthetic strategy, and tactics.[143] 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., theEvans aldol reaction), as well as the discovery of completely new chemical reactions (e.g., theWoodward cis-hydroxylation,Sharpless epoxidation, andSuzuki–Miyaura cross-coupling reactions).[144]
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 toinorganic chemistry, the principles of which had been established in 1789 by the FrenchmanAntoine Lavoisier in his workTraité Élémentaire de Chimie.[145]
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 andglycosides. It was long been known that opium, a sticky mixture of alkaloids (includingcodeine, morphine,noscapine,thebaine, andpapaverine) 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 chemistFriedrich Sertürner and in the 1870s it was discovered that boiling morphine withacetic anhydride produced a substance with a strong pain suppressive effect: heroin.[146] In 1815,Eugène Chevreul isolatedcholesterol, a crystalline substance, from animal tissue that belongs to the class of steroids,[147] and in 1819strychnine, an alkaloid was isolated.[148]
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 chemistJöns Jacob Berzelius argued that a vital force or life force was essential for synthesizing organic compounds. This idea, known asvitalism, had many supporters well into the 19th century, even after the introduction ofatomic 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 chemistFriedrich Wöhler synthesizedurea, a natural product found inurine, by heatingammonium cyanate, an inorganic substance:[149]
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 whenAdolph Wilhelm Hermann Kolbe synthesizedacetic acid fromcarbon disulfide.[150] Since then, organic chemistry has developed into a distinct field focused on studying carbon-containing compounds, which were found to be prevalent in nature.
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 andJustus von Liebig, who studied silver salts with identical compositions but different properties. Wöhler examinedsilver cyanate, a harmless compound, while von Liebig investigated the explosivesilver fulminate.[151] 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 byBerzelius's theory ofisomers, 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 theradical theory ofJean-Baptiste Dumas and the substitution theory ofAuguste Laurent.[152][153] A definitive structure theory was proposed in 1858 byAugust Kekulé, who suggested that carbon is tetravalent and can bond to itself, forming chains found in natural products.[154][153]
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 GermanJustus 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, includingglucose andmannose. After the discovery of penicillin byAlexander Fleming in 1928, fungi and other micro-organisms were added to the arsenal of sources of natural products.[146]
By the 1930s, several major classes of natural products had been identified and studied extensively. Key milestones in the field of natural product research include:[146]
These pioneering studies laid the foundation for our understanding of natural product chemistry and biochemistry,[162] 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.[30]
Footnotes
Citations
A chemical substance produced by a living organism; – a term used commonly in reference to chemical substances found in nature that have distinctive pharmacological effects. Such a substance is considered a natural product even if it can be prepared by total synthesis.
The simplest definition for a natural product is a small molecule that is produced by a biological source.
Natural products include a large and diverse group of substances from a variety of sources. They are produced by marine organisms, bacteria, fungi, and plants. The term encompasses complex extracts from these producers, but also the isolated compounds derived from those extracts. It also includes vitamins, minerals and probiotics.
Natural products are represented by a wide array of consumer goods that continue to grow in popularity each year. These products include natural and organic foods, dietary supplements, pet foods, health and beauty products, "green" cleaning supplies and more. Generally, natural products are considered those formulated without artificial ingredients and that are minimally processed.
Natural products are organic compounds that are formed by living systems.
Natural products: naturally occurring compounds that are end products of secondary metabolism; often, they are unique compounds for particular organisms or classes of organisms.
Natural product: A single chemical compound that occurs naturally. This term is typically used to refer to an organic compound of limited distribution in nature (often called secondary metabolites).
Figure 1. All new approved drugs 01JAN81 to 30SEP19; n = 1881. Figure 9. N/NB/ND & S* categories 01JAN81 to 30SEP19, n = 506.Natural products represent 100*(506/1881) = 27% of new drug approvals from 01JAN81 to 30SEP19. From Figure 9, the percentage was ~10% for 2017-2019.
In 1891, following Stahls work on plant biochemistry, Kossel suggested a distinction between basic and secondary metabolism (Stahl 1888).
The current, generally accepted concept in line with Kossel's view is that primary metabolites are chemical components of living organisms that are vital for their normal functioning, while secondary metabolites are compounds which are dispensable.
Secondary metabolites are distinguished more precisely by the following criteria: they have a restricted distribution being found mostly in plants and microorganisms, and are often characteristic of individual genera, species, or strains; they are formed along specialized pathwasys from primary metabolites. Primary metabolites, by contrast, have a broad distribution in all living things and are intimately involved in essential life processes.
Adipose tissue plays a critical role in mammalian life history strategies, serving as an organ for the storage of food and energy, as a source of heat and water, and as thermal insulation.
Drug Discovery – Is Mother Nature still the number one source for promising new drugs?
