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Technical Terms

A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discoverydrug design
Drug design
Drug design, also sometimes referred to as rational drug design, is the inventive process of finding new medications based on the knowledge of the biological target. The drug is most commonly an organic small molecule which activates or inhibits the function of a biomolecule such as a protein which...

A natural product can be considered as such even if it can be prepared by total synthesis.

These small molecules provide the source or inspiration for the majority of FDA-approved agents and continue to be one of the major sources of inspiration for drug discovery. In particular, these compounds are important in the treatment of life-threatening conditions.

Natural sources


Natural products may be extracted from tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. Hence, a tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function...

s of terrestrial plants, marine
Marine (ocean)
Marine is an umbrella term. As an adjective it is usually applicable to things relating to the sea or ocean, such as marine biology, marine ecology and marine geology...

 organisms or microorganism
Microorganism
A microorganism or microbe is an organism that is microscopic...

 fermentation broths. A crude (untreated) extract from any one of these sources typically contains novel, structurally diverse chemical compounds, which the natural environment is a rich source of.

Chemical diversity in nature is based on biological and geographical 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.

Screening of natural products


Pharmacognosy
Pharmacognosy
Pharmacognosy is the study of medicines derived from natural sources. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical and biological properties of drugs, drug substances or potential drugs or drug substances of natural origin as well...

 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 act as a lead compound
Lead compound
A lead compound in drug discovery is a chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.Lead compounds are often found in...

 (not to be confused with compounds containing the element lead
Lead
Lead is a main-group element with symbol Pb and atomic number 82. Lead is a soft, malleable poor metal, also considered to be one of the heavy metals. Lead has a bluish-white color when freshly cut, but tarnishes to a dull grayish color when exposed to air...

). Many of today's medicines are obtained directly from a natural source.

On the other hand, some medicines are developed from a lead compound
Lead compound
A lead compound in drug discovery is a chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.Lead compounds are often found in...

 originally obtained from a natural source. This means the lead compound:
  • can be produced by total synthesis, or
  • can be a starting point (precursor) for a semisynthetic compound, or
  • can act as a template for a structurally different total synthetic compound.

This is because most biologically active natural product compounds are secondary metabolites with very complex structures. This has an advantage in that they are extremely novel compounds but this complexity also makes many lead compounds' synthesis difficult and the compound usually has to be extracted from its natural source - a slow, expensive and inefficient process. As a result, there is usually an advantage in designing simpler analogue
Analog (chemistry)
In chemistry, structural analogs , also known as chemical analogs or simply analogs, are compounds in which one or more atoms, functional groups, or substructures have been replaced with different atoms, groups, or substructures...

s.

The plant kingdom


Plants have always been a rich source of lead compounds (e.g. morphine
Morphine
Morphine is a potent opiate analgesic psychoactive drug and is considered to be the prototypical opioid. In clinical medicine, morphine is regarded as the gold standard, or benchmark, of analgesics used to relieve severe or agonizing pain and suffering. Like other opioids, e.g...

, cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system and an appetite suppressant...

, digitalis
Digitalis
Digitalis is a genus of about 20 species of herbaceous perennials, shrubs, and biennials that are commonly called foxgloves. This genus was traditionally placed in the figwort family Scrophulariaceae, but upon recent reviews of phylogenetic research, it has now been placed in the much enlarged...

, quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , and anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic.Though it has been synthesized in the lab, the bark of the cinchona...

, tubocurarine
Tubocurarine
Tubocurarine is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation...

, nicotine
Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...

, and muscarine
Muscarine
Muscarine, L--muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. It was first isolated from Amanita muscaria in 1869...

). Many of these lead compounds are useful drugs in themselves (e.g. morphine and quinine), and others have been the basis for synthetic drugs (e.g. local anaesthetics developed from cocaine). Clinically useful drugs which have been recently isolated from plants include the anticancer agent paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific Yew tree, Taxus brevifolia and named it taxol...

 (Taxol) from the yew tree, and the antimalarial agent artemisinin
Artemisinin
Artemisinin and its derivatives are a group of drugs that possess the most rapid action of all currently drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...

 from Artemisia annua
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...

.

Plants provide a large bank of rich, complex and highly varied structures which are unlikely to be synthesized in laboratories. Furthermore, evolution
Evolution
Evolution is the change in the relative frequencies of inherited traits within a population of organisms through successive generations. After a population splits into smaller groups, these groups evolve independently and may eventually diversify into new species...

 has already carried out a screening process itself whereby plants are more likely to survive if they contain potent
Potency
Potency may refer to:* Potency , a measure of the activity of a drug in a biological system* Virility* Potency is a measure of the differentiation potential of stem cells...

 compounds which deter animals or insects from eating them. Even today, the number of plants that have been extensively studied is relatively very few and the vast majority have not been studied at all.

The microbial world


Microorganisms such as bacteria and fungi have been invaluable for discovering drugs and lead compounds. These microorganisms produce a large variety of antimicrobial agents which have evolved to give their hosts an advantage over their competitors in the microbiological world.

The screening of microorganisms became highly popular after the discovery of penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases such as syphilis and Staphylococcus infections...

. Soil
Soil
Soil is a natural body consisting of layers of mineral constituents of variable thicknesses, which differ from the parent materials in their morphological, physical, chemical, and mineralogical characteristics....

 and water samples were collected from all over the world in order to study new bacterial or fungal strains
Strain (biology)
In biology, a strain is a low-level taxonomic rank used in three related ways.-Microbiology and virology:A strain is a genetic variant or subtype of a microorganism . For example, a "flu strain" is a certain biological form of the influenza or "flu" virus...

, leading to an impressive arsenal of antibacterial agents such as the cephalosporins, tetracyclines, aminoglycosides, rifamycins, and chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriocidal antimicrobial. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines....

.

Although most of the drugs derived from microorganisms are used in antibacterial therapy, some microbial metabolites have provided lead compounds in other fields of medicine
Medicine
Medicine is the science and art of healing. It encompasses a range of health care practices evolved to maintain and restore health by the prevention and treatment of illness. Before scientific medicine, healing arts were practiced in accordance with alchemist treatments in accordance with ritual...

. For example, asperlicin
Asperlicin
Asperlicin is a mycotoxin, derived from the fungus Aspergillus alliaceus. It acts as a selective antagonist for the cholecystokinin receptor CCKA, and has been used as a lead compound for the development of a number of novel CCKA antagonists with potential clinical applications....

 - isolated from Aspergillus alliaceus - is a novel antagonist of a peptide hormone
Peptide hormone
Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals. Peptide hormones are increasingly being identified in plants with important roles in cell-to-cell communication and plant defense...

 called cholecystokinin
Cholecystokinin
Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein...

 (CCK) which is involved in the control of appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...

. CCK also acts as a neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals which transmit signals from a neuron to a target cell across the synapse. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...

 in the brain
Brain
The brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...

 and is thought to be involved in panic attacks. Analogues of asperlicin may therefore have potential in treating anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by cognitive, somatic, emotional, and behavioral components. These components combine to create an unpleasant feeling that is typically associated with uneasiness, apprehension, fear, or worry. Anxiety is a generalized mood condition...

. Other examples include the fungal metabolite lovastatin
Lovastatin
Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...

, which was the lead compound for a series of drugs that lower cholesterol
Cholesterol
Cholesterol is a waxy steroid metabolite found in the cell membranes and transported in the blood plasma of all animals. It is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity...

 levels, and another fungal metabolite called ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin or cyclosporin A, is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system, and therefore the risk of organ rejection...

 which is used to suppress the immune response after transplantation operations.

The marine world


In recent years, there has been a great interest in finding lead compounds from marine
Marine (ocean)
Marine is an umbrella term. As an adjective it is usually applicable to things relating to the sea or ocean, such as marine biology, marine ecology and marine geology...

 sources. Coral
Coral
Corals are marine organisms in class Anthozoa of phylum Cnidaria typically living in compact colonies of many identical individual "polyps"...

, sponges
Sea sponge
Sponges are animals of the phylum Porifera . Their bodies consist of jelly-like mesohyl sandwiched between two thin layers of cells. While all animals have unspecialized cells that can transform into specialized cells, sponges are unique in having some specialized cells that can transform into...

, fish
Fish
A fish is any aquatic vertebrate animal that is covered with scales, and equipped with two sets of paired fins and several unpaired fins. Most fish are "cold-blooded", or ectothermic, allowing their body temperatures to vary as ambient temperatures change. Fish are abundant in most bodies of water...

, and marine microorganisms have a wealth of biologically potent chemicals with interesting inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. Inflammation is not a synonym...

, antiviral
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...

, and anticancer activity. For example, curacin A is obtained from a marine cyanobacterium and shows potent antitumor activity. Other antitumor agents derived from marine sources include eleutherobin, discodermolide
Discodermolide
-Discodermolide is a recently discovered polyketide natural product found to be a potent inhibitor of tumor cell growth. The molecule's carbon skeleton is made up of eight polypropionate and four acetate units with 13 stereocenters.-History:...

, bryostatins, dolostatins, and cephalostatins.

Animal sources


Animals can sometimes be a source of new lead compounds. For example, a series of antibiotic
Antibiotic
In common usage, an antibiotic is a substance or compound that kills bacteria or inhibits their growth...

 peptide
Peptide
Peptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....

s were extracted from the skin of the African clawed frog
African clawed frog
The African clawed frog is a species of South African aquatic frog of the genus Xenopus. Its name is derived from the three short claws on each hind foot, which it uses to tear apart its food...

 and a potent analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos...

 compound called epibatidine
Epibatidine
Epibatidine is an alkaloid that originally is found in the skin of a neotropical poisonous frog, Epipedobates tricolor, found in Ecuador....

 was obtained from the skin extracts of the Ecuadorian poison frog.

Venoms and toxins


Venoms and toxins from animals, plants, snakes, spider
Spider
Spiders are air-breathing chelicerate arthropods that have eight legs, and chelicerae modified into fangs that inject venom. They are the largest order of arachnids and rank seventh in total species diversity among all other groups of organisms...

s, scorpion
Scorpion
Scorpions are predatory arthropod animals of the order Scorpiones within the class Arachnida. They have eight legs and are easily recognised by the pair of grasping claws and the narrow, segmented tail, carried in a characteristic forward curve over the back, ending with a venomous stinger...

s, insect
Insect
Insects are a class within the arthropods that have a chitinous exoskeleton, a three-part body , three pairs of jointed legs, compound eyes, and two antennae...

s, and microorganism
Microorganism
A microorganism or microbe is an organism that is microscopic...

s are extremely potent because they often have very specific interactions with a macromolecular target in the body. As a result, they have proved important tools in studying receptors
Receptor (biochemistry)
In biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signaling molecules may attach...

, ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of all living cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...

s, and enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...

s. Many of these toxins are polypeptides (e.g. α-bungarotoxin from cobra
Cobra
A cobra is a venomous snake belonging to the family elapidae. The name is short for cobra de capelo, which is Portuguese for "snake with hood", or "hood-snake". When disturbed, most of these snakes can rear up and spread their neck in a characteristic threat display...

s). However, non-peptide toxins such as tetrodotoxin
Tetrodotoxin
Tetrodotoxin is a potent neurotoxin with no known antidote. There have been successful tests of a possible antidote in mice, but further tests must be carried out to determine efficacy in humans...

 from the puffer fish are also extremely potent.

Venoms and toxins have been used as lead compounds in the development of novel drugs. For example, teprotide, a peptide isolated from the venom of the Brazilian viper, was the lead compound for the development of the antihypertensive
Antihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...

 agents cilazapril
Cilazapril
Cilazapril is a pyridazine angiotensin-converting enzyme inhibitor used for the treatment of hypertension and congestive heart failure. It is branded as Inhibace in Canada and New Zealand and Vascace and Dynorm in Europe...

 and captopril
Captopril
Captopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the...

.

The neurotoxins from Clostridium botulinum
Clostridium botulinum
Clostridium botulinum is a Gram-positive, rod shaped bacterium that produces neurotoxins known as botulinum neurotoxins types A-G, which causes flaccid muscular paralysis seen in botulism, and is also the main paralytic agent in botox...

are responsible for serious food poisoning (botulism
Botulism
Botulism also known as botulinus intoxication is a rare but serious paralytic illness caused by botulinum toxin, which is produced by the bacterium Clostridium botulinum under anaerobic conditions....

), but they have a clinical use as well. They can be injected into specific muscle
Muscle
Muscle is the contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

s (such as those controlling the eyelid
Eyelid
An eyelid is a thin fold of skin that covers and protects an eye. With the exception of the prepuce and the labia minora, it has the thinnest skin of the whole body. The levator palpebrae superioris muscle retracts the eyelid to "open" the eye. This can be either voluntarily or involuntarily...

) to prevent muscle spasm. These toxins prevent cholinergic
Cholinergic
Cholinergic means related to the neurotransmitter acetylcholine, and is typically used in a neurological perspective. The parasympathetic nervous system is entirely cholinergic. Neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem...

 transmission and could well prove a lead for the development of novel anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicyclomine, and the classic example is atropine....

 drugs.

Traditional Medicine


In the past, traditional peoples or ancient civilizations depended greatly on local flora
Flora
In botany, flora has two meanings: a flora refers to the plant life occurring in a particular region, generally the naturally occurring or indigenous plant life, while a Flora refers to a book or other work describing a flora and including aids for the identification of the plants it contains...

 and fauna
Fauna
Fauna or faunæ is all of the animal life of any particular region or time. The corresponding term for plants is flora.Zoologists and paleontologists use fauna to refer to a typical collection of animals found in a specific time or place, e.g...

 for their survival. They would experiment with various berries, leaves
Leaves
Leaves are an Icelandic five-piece alternative rock band who formed in 2001. Late in 2001 they played with Emiliana Torrini and drew early praise from the New York Times. They came to prominence in 2002 with their debut album, Breathe, drawing comparisons to groups such as The Verve and Doves...

, root
Root
In vascular plants, the root is the organ of a plant that typically lies below the surface of the soil. This is not always the case, however, since a root can also be aerial or aerating . Furthermore, a stem normally occurring below ground is not exceptional either...

s, animal parts or minerals to find out what effects they had. As a result, many crude drugs were observed by the local healer or shaman to have some medical use. Although some preparations may have been dangerous, or worked by a ceremonial or placebo effect
Placebo effect
Placebo effect may refer to:* Placebo effect, the tendency of any medication or treatment, even an inert or ineffective one, to exhibit results simply because the recipient believes that it will work...

, traditional healing systems usually had a substantial active pharmacopoeia, and in fact most western medicines up until the 1920s were developed this way. Some systems, like traditional Chinese medicine
Traditional Chinese medicine
Traditional Chinese Medicine, also known as TCM, includes a range of traditional medicine practices originating in China. Although well accepted in the mainstream of medical care throughout East Asia, it is considered an alternative medical system in much of the Western world.TCM practices include...

 or Ayurveda
Ayurveda
Ayurveda Ayurvedic medicine is a system of traditional medicine native to the Indian subcontinent and practiced in other parts of the world as a form of alternative medicine. In Sanskrit, the word ayurveda consists of the words , meaning "longevity", and , meaning "related to knowledge" or...

 were fully as sophisticated and as documented systems as western medicine, although they might use different paradigms. Many of these aqueous, ethanolic, distilled, condensed or dried extracts do indeed have a real and beneficial effect, and a study of ethnobotany
Ethnobotany
Ethnobotany is the scientific study of the relationships that exist between people and plants....

 can give clues as to which plants might be worth studying in more detail. Rhubarb
Rhubarb
Rhubarb is a group of plants that belong to the genus Rheum in the family Polygonaceae.They are herbaceous perennial plants growing from short, thick rhizomes. They have large leaves that are somewhat triangular shaped with long fleshy petioles...

 root has been used as a purgative for many centuries. In China
China
China is seen variously as an ancient civilization extending over a large area in East Asia, a nation and/or a multinational entity.China is one of the world's oldest civilizations and is regarded as the oldest continuous civilization...

, it was called "The General" because of its "galloping charge" and was only used for one or two doses unless processed to reduce its purgative qualities. (Bulk laxatives would follow or be used on weaker patients according to the complex laxative protocols of the medical system.) The most significant chemicals in rhubarb root are anthraquinones, which were used as the lead compounds in the design of the laxative
Laxative
Laxatives are foods, compounds, or drugs taken to induce bowel movements or to loosen the stool, most often taken to treat constipation. Certain stimulant, lubricant, and saline laxatives are used to evacuate the colon for rectal and bowel examinations, and may be supplemented by enemas in that...

 dantron
Dantron
1,8-Dihydroxyanthraquinone is an organic substance with formula , formally derived from anthraquinone by the replacement of two hydrogen atoms by hydroxyl groups...

.

The extensive records of Chinese medicine about response to Artemisia preparations for malaria also provided the clue to the novel antimalarial drug artemisinin
Artemisinin
Artemisinin and its derivatives are a group of drugs that possess the most rapid action of all currently drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...

. The therapeutic properties of the opium poppy
Opium poppy
Opium poppy, Papaver somniferum, is the species of plant from which opium and poppy seeds are extracted. Opium is the source of many opiates, including morphine, thebaine, codeine, papaverine, and noscapine...

 (active principle morphine
Morphine
Morphine is a potent opiate analgesic psychoactive drug and is considered to be the prototypical opioid. In clinical medicine, morphine is regarded as the gold standard, or benchmark, of analgesics used to relieve severe or agonizing pain and suffering. Like other opioids, e.g...

) were known in Ancient Egypt
Ancient Egypt
Ancient Egypt was an ancient civilization of eastern North Africa, concentrated along the lower reaches of the Nile River in what is now the modern country of Egypt. The civilization coalesced around 3150 BC with the political unification of Upper and Lower Egypt under the first pharaoh, and...

, were those of the Solanaceae
Solanaceae
Solanaceae is a family of flowering plants that contains a number of important agricultural crops as well as many toxic plants. The name of the family comes from the Latin Solanum "the nightshade plant", but the further etymology of that word is unclear...

plants in ancient Greece
Ancient Greece
Ancient Greece is the civilization belonging to the period of Greek history lasting from the Archaic period of the 8th to 6th centuries BC to 146 BC and the Roman conquest of Greece after the Battle of Corinth...

 (active principles atropine
Atropine
Atropine is a tropane alkaloid extracted from deadly nightshade , jimsonweed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects. It is a competitive antagonist for the muscarinic acetylcholine...

 and hyoscine). The snakeroot
Snakeroot (disambiguation)
Snakeroot may refer to different plant taxa that have been used as a folk remedy against snakebites* Ageratina, a genus with species native to the warm and temperate Americas* Certain plants in the temperate Northern Hemisphere genus Eupatorium...

 plant was well regarded in India
India
India, officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with 1.18 billion people, and the most populous democracy in the world...

 (active principle reserpine
Reserpine
Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely...

), and herbalists in medieval England used extracts from the willow tree(salicin) and foxglove (active principle digitalis
Digitalis
Digitalis is a genus of about 20 species of herbaceous perennials, shrubs, and biennials that are commonly called foxgloves. This genus was traditionally placed in the figwort family Scrophulariaceae, but upon recent reviews of phylogenetic research, it has now been placed in the much enlarged...

 - a mixture of compounds such as digitoxin
Digitoxin
Digitoxin is a cardiac glycoside. It has similar structure and effects to digoxin . Unlike digoxin , it is eliminated via the liver, so could be used in patients with poor or erratic kidney function. However, it is now rarely used in current UK medical practice...

, digitonin
Digitonin
Digitonin is a glycoside obtained from Digitalis purpurea; the aglycone is digitogenin, a spirostan steroid. Used as a detergent, it effectively water-solubilizes lipids...

, digitalin). The Aztec
Aztec
The Aztec people were certain ethnic groups of central Mexico, particularly those groups who spoke the Nahuatl language and who dominated large parts of Mesoamerica in the 14th, 15th and 16th centuries, a period referred to as the late post-classic period in Mesoamerican chronology.Aztec is the...

 and Mayan
Maya civilization
The Maya is a Mesoamerican civilization, noted for the only known fully developed written language of the pre-Columbian Americas, as well as its art, architecture, and mathematical and astronomical systems. Initially established during the Pre-Classic period The Maya is a Mesoamerican civilization,...

 cultures of Mesoamerica
Mesoamerica
Mesoamerica or Meso-America is a region and culture area in the Americas, extending approximately from central Mexico to Honduras and Nicaragua, within which a number of pre-Columbian societies flourished before the Spanish colonization of the Americas in the 15th and 16th centuries.Prehistoric...

 used extracts from a variety of bushes and trees including the ipecacuanha
Ipecacuanha
Psychotria ipecacuanha is a synonym for Carapichea ipecacuanha, a species of flowering plant in the madder family, Rubiaceae, that is native to Brazil. Other synonyms are sometimes erroneously listed as different plants. These include: Callicocca ipecacuanha, Cephaelis acuminata and Cephaelis...

 root (active principle emetine), coca
Coca
Coca is a plant in the family Erythroxylaceae, native to north-western South America. The plant plays a significant role in traditional Andean culture. Coca is best known throughout the world because of its alkaloids, which include cocaine, a powerful stimulant.The plant resembles a blackthorn...

 bush (active principle cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system and an appetite suppressant...

), and cinchona
Cinchona
Cinchona is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink or red,...

 bark (active principle quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , and anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic.Though it has been synthesized in the lab, the bark of the cinchona...

).

It can be challenging to obtain information from practitioners of traditional medicine unless a genuine long term relationship is made. Ethnobotanist Richard Schultes approached the Amazonian shamans with respect, dealing with them on their terms. He became a "depswa" - medicine man
Medicine man
"Medicine man" or "Medicine woman" are English terms used to describe Native American healers and spiritual figures. Anthropologists tend to prefer the term "shaman."- Role in native society :...

 - sharing their rituals while gaining knowledge. They responded to his inquiries in kind, leading to new medicines. On the other hand Cherokee
Cherokee
The Cherokee are a Native American people historically settled in the Southeastern United States . Linguistically, they are part of the Iroquoian-language family...

 herbalist David Winston
David Winston
David Winston RH is an American herbalist and ethnobotanist. He has been in practice and teaching since 1977. He works in the Cherokee, Chinese and the western eclectic herbal traditions...

 recounts how his uncle, a medicine priest, would habitually give misinformation to the visiting ethnobotanists. The acupuncturists who investigated Mayan medicine recounted in Wind in the Blood had something to share with the native healers and thus were able to find information not available to anthropologists. The issue of rights to medicine derived from native plants used and frequently cultivated by native healers complicates this issue.

Isolation and purification


If the lead compound (or active principle) is present in a mixture of other compounds from a natural source, it has to be isolated and purified. The ease with which the active principle can be isolated and purified depends much on the structure, stability, and quantity of the compound. For example, Alexander Fleming
Alexander Fleming
Sir Alexander Fleming was a Scottish biologist and pharmacologist. Fleming published many articles on bacteriology, immunology and chemotherapy...

 recognized the antibiotic qualities of penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases such as syphilis and Staphylococcus infections...

 and its remarkable non-toxic nature to humans, but he disregarded it as a clinically useful drug because he was unable to purify it. He could isolate it in aqueous solution
Aqueous solution
An aqueous solution is a solution in which the solvent is water. It is usually shown in chemical equations by appending to the relevant formula. The word aqueous means pertaining to, related to, similar to, or dissolved in water...

, but whenever he tried to remove the water, the drug was destroyed. It was not until the development of new experimental procedures such as freeze drying
Freeze drying
Freeze-drying is a dehydration process typically used to preserve a perishable material or make the material more convenient for transport...

 and chromatography
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....

 that the successful isolation and purification
Purification
Purification is the process of rendering something pure, i.e. clean of foreign elements and/or pollution, and may refer to:* List of purification methods in chemistry* Organisms used in water purification...

 of penicillin and other natural products became feasible.

Synthesis


Not all natural products can be fully synthesized
Total synthesis
In principle a total synthesis is the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes . In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often petrochemical...

 and many natural products have very complex structures
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of a chemical compound. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together...

 that are too difficult and expensive to synthesize on an industrial scale. These include drugs such as penicillin, morphine
Morphine
Morphine is a potent opiate analgesic psychoactive drug and is considered to be the prototypical opioid. In clinical medicine, morphine is regarded as the gold standard, or benchmark, of analgesics used to relieve severe or agonizing pain and suffering. Like other opioids, e.g...

, and paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific Yew tree, Taxus brevifolia and named it taxol...

 (Taxol). Such compounds can only be harvested from their natural source - a process which can be tedious, time consuming, and expensive, as well as being wasteful on the natural resource. For example, one yew tree would have to be cut down to extract enough paclitaxel from its bark for a single dose. Furthermore, the number of structural analogues that can be obtained from harvesting is severely limited.

A further problem is that isolates often work differently than the original natural products which have synergies and may combine, say, antimicrobial compounds with compounds that stimulate various pathways of the immune system:
Many higher plants contain novel metabolites with antimicrobial and antiviral properties. However, in the developed world almost all clinically used chemotherapeutics have been produced by in vitro chemical synthesis. Exceptions, like taxol and vincristine, were structurally complex metabolites that were difficult to synthesize in vitro. Many non-natural, synthetic drugs cause severe side effects that were not acceptable except as treatments of last resort for terminal diseases such as cancer. The metabolites discovered in medicinal plants may avoid the side effect of synthetic drugs, because they must accumulate within living cells.


Semisynthetic procedures can sometimes get around these problems. This often involves harvesting a biosynthetic intermediate from the natural source, rather than the final (lead) compound itself. The intermediate could then be converted to the final product by conventional synthesis. This approach can have two advantages. First, the intermediate may be more easily extracted in higher yield than the final product itself. Second, it may allow the possibility of synthesizing analogues of the final product. The semisynthetic penicillins are an illustration of this approach. Another recent example is that of paclitaxel. It is manufactured by extracting 10-deacetylbaccatin III from the needles of the yew tree
Taxus brevifolia
Taxus brevifolia is a conifer native to the Pacific Northwest of North America. It ranges from southernmost Alaska south to central California, mostly in the Pacific Coast Ranges, but with an isolated disjunct population in southeast British Columbia, most notably occurring on Zuckerberg Island...

, then carrying out a four-stage synthesis.