STK31003 Terrestrial Natural Product Chemistry Alkaloids PDF

STK31003 – Terrestrial Natural Product Chemistry ALKALOIDS  ALKALOIDS  Alkaloids are naturally occurring amine produced by plants, animals and fungi.  Many alkaloids have pharmacological effects on humans and other animals.  The name derives from the word alkaline; origin...

STK31003 – Terrestrial Natural Product Chemistry ALKALOIDS  ALKALOIDS  Alkaloids are naturally occurring amine produced by plants, animals and fungi.  Many alkaloids have pharmacological effects on humans and other animals.  The name derives from the word alkaline; originally, the term was used to describe any nitrogen- containing base.  ALKALOID  Alkaloids areusually derivatives of amino acids, and many have a bitter taste. They are found as secondary metabolites in plants (e.g. potatoes and tomatoes), animals (e.g. salamander, frogs) and fungi. Many alkaloids can be purified from crude extracts by acid-base extraction.  While many alkaloids are poisonous, some are used medicinally as analgesics (pain relievers) or anaesthetics, particularly morphine and codeine, and for other uses.  Catharanthus roseus Papaver somniferum Atropa belladonna Galanthus nivalis Indolizidine alkaloids  Indolizidine Alkaloids  Indolizidine alkaloids are chemical constituents isolated from various marine and terrestrial plants and animals, including but not limited to trees, fungi, ants, and frogs, with a myriad of important biological activities.  Two examples of indolizidine alkaloids that are well known for their potent biological activities are swainsonine, isolated from the fungus Rhizoctonia leguminicola, which has recently been selected for clinical testing as an anti-cancer drug and pumilotoxin B, isolated from Dendrobatid Amazonian frogs, which is a potent cardiovascular agent. ALKALOIDS - Characteristics Plants and animal as sources for alkaloids – ~15 % plants contain alkaloids; Examples- Morphine from Papaver somniferum; vinblastine from Catharanthus roseus; lisergic acid from Claviceps purpurea; saxitoxin from Gonyaulax tamarensis; tetradotoxin (from Spheroides rubripes, frogs, toads and symbiotic bacteria such as Pseudomonas spp. and Vibrio spp.)  Papaver somniferum Catharanthus roseus Claviceps purpurea Dendrobates tinctorius  ALKALOIDS - Characteristics  Nitrogen in alkaloid molecules – Alkaloids can contain one or more nitrogen especially in the cyclic forms.  Amino acid as a biosynthesis precursor – Various amino acid can be involved in the synthesis of alkaloids such as phenylalanine, tyrosine, lysine, ornithine, tryptophan, etc. Nitrogen in the molecules  Phenylalanine Tryptophan Tyrosine Lysine Ornitine  ALKALOIDS - Characteristics  Alkalinity – Alkaloids possess basic characteristic because of the nitrogen in the molecules. Alkaloids can react with acid to give alkaloids salts.  Solubility – Alkaloids have good solubility in organic solvents such as chloroform but will not dissolve in water. Alkaloids salts on the other hand will dissolve easily in aqueous solutions.  ALKALOIDS - Characteristics  Colour reaction – Alkaloids can give colours in the presence of suitable reagents. For examples ergot alkaloids gives blue colour with Ehrlich reagent; orange colour with Dragendorff reagent.  Precipitation – Most alkaloids in small quantities (10 mg) can give precipitation with reagents such as Mayer (white), Wagner (Brown), Dragendorff (orange) and Hager (Yellow)  ALKALOIDS - Characteristics  Stability to heat – Most alkaloids are not stable above 70 oC and degradation occurs at high temperature.  Pharmacological avtivities – All alkaloids shows significant pharmacological activities although being used in minute quantities  Alkaloids Alkaloids are a class of "secondary" plant metabolites that traditionally have been classified as basic compounds derived from amino acids that contain one or more heterocyclic nitrogen atoms.  Alkaloids  Humans have been using alkaloids in the form of plant extracts for poisons, narcotics, stimulants and medicines for at least the past several thousand years.  Morphine was isolated from poppy seeds in 1806 although its structure wasn't known until 1952.  Alkaloid  The antimalarial properties of quinine, an alkaloid extracted from the bark of Cinchona spp. trees indigenous to the high eastern slopes of the Andes Mountains have long been known.  More than 10,000 alkaloids of widely differing structures are now known from the small fraction of the planet's plants that have so far been examined  Alkaloids  Like many secondary metabolites, plants apparently synthesize alkaloids for defensive purposes.  Nicotine and derivatives are among the earliest known and most potent insecticides.  Alkaloid  Like most natural product chemistry, the accumulation of alkaloids tends to run in families.  The plant families with the highest alkaloid levels are the Papaveraceae, Berberidaceae, Leguminosae, Boraginaceae, Apocynaceae, Asclepiadaceae, Liliaceae, Gnetaceae, Ranunculaceae, Rubiaceae, Solanaceae and Rutaceae.  Alkaloids Classification  Alkaloids with exocyclic nitrogen and aliphatic amine: Epedrine  Putresine, spermidine and spermine alkaloids: Pausine, cadonocarpine  Peptide alkaloids: Integerine  Steroids and terpenoids alkaloids: akonitine; salonidine  Heterocyclic alkaloids: Various types of skleton Epedrine Spermidine alkaloids Peptide Alkaloids Steroids Alkaloids Solanidine Amphibine E  Heterocyclic Alkaloids  Pyridine group: piperine, coniine, trigonelline, arecaidine, guvacine, pilocarpine, cytisine, nicotine, sparteine, pelletierine.  Pyrrolidine group: hygrine, cuscohygrine, nicotine  Tropane group: atropine, cocaine, ecgonine, scopolamine  Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine, brucine, veratrine, cevadine  Isoquinoline group: The opium alkaloids (morphine, codeine, thebaine, papaverine, narcotine, sanguinarine, narceine, hydrastine, berberine)  Heterocyclic Alkaloids  Phenethylamine group: mescaline, ephedrine, dopamine, amphetamine  Indole group: Tryptamines: DMT, N-methyltryptamine, psilocybin, serotonin Ergolines: the ergot alkaloids (ergine, ergotamine, lysergic acid, etc.) Beta-carbolines: harmine, harmaline, yohimbine, reserpine, emetine Rauwolfia alkaloids: Reserpine  Heterocyclic Alkaloids  Purine group: Xanthines: caffeine, theobromine, theophylline  Terpenoid group: Aconite alkaloids: aconitine Steroids: solanine, samandaris (quaternary ammonium compounds): muscarine, choline, neurine  Vinca alkaloids: vinblastine, vincristine. They are antineoplastic and binds free tubulin dimers thereby disrupting balance between microtuble polymerization and delpolymerization resulting in arrest of cells in metaphase.  Phenylalkylamines: e.g. Ephedrine CH2 CH CH3 NH2  Pyridine and piperidine e.g. lobeline, nicotine N N H  Tropane e.g. Atropine. NCH 3 OH  Quinoline e.g.quinine and quinidine N  Isoquinoline e.g. papaverine N  Indole e.g.ergometrine N H  Imidazole N e.g. pilocarpine N  Purine 6 H 7 e.g. caffeine 1 N 5 N 8 2 N 4 N 9 3 Purine  Steroidal e.g. Solanum and Veratrum alkaloids Conessine  Terpenoid e.g. Taxol Taxol  Pyridine Alkaloid  Pyridine alkaloids are a class of alkaloids, nitrogen-containing chemical compounds widely found in plants, that contain a pyridine ring.  Examples include nicotine and anabasine which are found in plants of the genus Nicotiana including tobacco  Pyridine Alkaloid  Plants that contain the alkaloid in various concentrations include those from several genera of the Faboideae subfamily, including Laburnum, Anagyris, Thermopsis, Cytisus, Genista and Sophora. Also present in Gymnocladus of the Caesalpinioideae subfamily.  Cytisine is a nicotinic acetylcholine receptor agonist, and as a pharmaceutical preparation it is available for the treatment of nicotinism.  Pyridine Alkaloid  Pyridine-containing compounds have been used in medicinal chemistry for antimicrobial, antitubercular, anticancer, antiviral, antimalarial, antidiabetic, antioxidant, analgesic, anti-inflammatory, and anti- infection applications.  Tropane Biosynthesis of tropane: The starting compound of this synthesis is ornithine, methylornithine is the first intermediate.  Tropane  Tropane is a nitrogenous bicyclic organic compound with chemical formula C8H15N.  It is mainly known for a group of alkaloids derived from it (called tropane alkaloids), which include, among others, atropine and cocaine.  Both alkaloids contain tropinone from which tropane is a derivate.  Tropane Tropane alkaloids occur in plants of the families Solanaceae (mandrake, henbane, deadly nightshade, Datura, Potato, Tomato species) and Erythroxylaceae (coca).  Tropane Atropine, the racemic form of hyoscyamine, comes from Atropa belladonna (deadly nightshade) and is used to dilate the pupils of the eye. Atropine is also a CNS stimulant and is used as a treatment for nerve gas poisoning. Atropine Scopolamine  Tropane  Scopolamine, another member of this class is used as a treatment for motion sickness.  Cocaine, from Erythroxylum coca, is closely related in structure, is also a CNS stimulant, and has been used as a topical anesthetic in opthamology. It is also a drug of abuse. Cocaine Erythroxylum novogranatense Indole Alkaloids  Indole Alkaloids  One of the most amazing stories about naturally- occurring alkaloids in fungi concerns ergot (Claviceps purpurea), a fungus that infects grains of rye and related grasses. One of the psychoactive components of ergot fungus is the alkaloid ergine (d-lysergic acid amide), better known as natural LSD.  The more potent synthetic LSD, is one of the most powerful psychoactive drugs known.Synthetic LSD was originally synthesized from natural psychoactive alkaloids in ergot. It is 4,000 times more powerful than mescaline (3,4,5-trimethoxyphenylethylamine). Natural LSD (ergine) is also found in the seeds of two species of Mexican morning glory vines which are still ingested by native Indians in an important medicinal and religious ritual. Claviceps purpurea  Indole  Synthetic LSD has two additional ethyl groups (C2H5) and is about 100 times more potent. Before it was discovered in morning glories, ergine was only known from ergot (Claviceps purpurea), a rust fungus that infects grains.  Psychoactive alkaloids, such as ergine and psilocybin (from the mushrooms Psilocybe, Stropharia, Paneolus and Conocybe) contain the indole structure, a double carbon-nitrogen ring also found in the natural neurotransmitter serotonin.  These alkaloids may interfere or compete with the action of serotonin in the brain, causing psychedelic visions, delusions and hallucinations Lisergic acid Isolisergic acid Ergonovine Ergot alkaloids can be detected easily by using Ehrlich Reagents (0.125% p-dimetylaminobenzaldehyde in 65% sulphuric acid and 0.2 ml 5% FeCl3 for every 100 ml reagent). Positive Results indicated by the formation of dark blue colour d-lysergic d-lysergic acid acid amide diethylamide (LSD) Synthetic LSD has two additional ethyl groups (C2H5) and is about 100 times more potent. Before it was discovered in morning glories, ergine was only known from ergot (Claviceps purpurea), a rust fungus that infects grains. Psychoactive alkaloids, such as ergine and psilocybin (from the mushrooms Psilocybe, Stropharia, Paneolus and Conocybe) contain the indole structure, a double carbon-nitrogen ring also found in the natural neurotransmitter serotonin. These alkaloids may interfere or compete with the action of serotonin in the brain, causing psychedelic visions, delusions and hallucinations  Ipomoea tricolor The beautiful morning glory (Ipomoea tricolor) is highly- prized by native Indians of Mexico for their medicinal and religious rituals. The black, angular seeds are called "tlitliltzin" and they contain the alkaloid ergine (d-lysergic acid amide), better known as natural LSD.  Vinca Alkaloids Periwinkles Catharanthus roseus Researchers finally noticed the plant in the 1950's when they learned of a tea Jamaicans were drinking to treat diabetes. They discovered the plant contains a motherlode of useful alkaloids (70 in all at last count). Some, such as catharanthine, leurosine sulphate, lochnerine, tetrahydroalstonine, vindoline and vindolinine lower blood sugar levels (thus easing the symptoms of diabetes). Others lower blood pressure, others act as hemostatics (arrest bleeding) and two others, vincristine and vinblastine, have anticancer properties. Periwinkles also contain the alkaloids reserpine and serpentine, which are powerful tranquilizers.  Vinca Alkaloids Vincristine, one of the most potent antileukemic drugs in use today, was isolated in a search for diabetes treatments from Vinca rosea (now Catharanthus roseus) in the 1950's along with vinblastine. This is such a complex structure that it is still isolated from the plant today rather than prepared by synthesis. The small change in structure, however, causes a significant change in pharmoacological efficacy. Vincristine (leurocristine, VCR) is most effective in treating childhood leukemias and non-Hodgkin’s lymphomas, where vinblastine (vincaleukoblastine, VLB) is used to treat Hodgkin’s disease  Non-Hodgkin's lymphoma & Hodgkin lymphoma  Non-Hodgkin's lymphoma is a type of cancer that begins in lymphatic system, which is part of the body's germ-fighting immune system. In non-Hodgkin's lymphoma, white blood cells called lymphocytes grow abnormally and can form growths (tumors) throughout the body.  Hodgkin lymphoma, also called Hodgkin disease, is a type of cancer that develops in the lymph system. Lymph system is part of our immune system. It helps protect our body from infection and disease. The lymph system is made up of tissues and organs that produce, store, and carry white blood cells.  Non-Hodgkin lymphoma may arise in lymph nodes anywhere in the body, whereas Hodgkin lymphoma typically begins in the upper body, such as the neck, chest or armpits  Vinca Alkaloids Vinblastine is typically administered at a dose of 6 milligrams per square meter of body surface. It's marketed as Velban by Eli Lilly and has a half-life in the bloodstream of 24 hours. Vinblastine is mainly useful for treating Hodgkin's disease, lymphocytic lymphoma, histiocytic lymphoma, advanced testicular cancer, advanced breast cancer, Kaposi's sarcoma, and Letterer-Siwe disease. It also seems to fight cancer by interfering with glutamic acid metabolism (specifically, the pathways leading from glutamic acid to the Krebs cycle and to urea formation).  Vinca Alkaloids -Vinblastine  People with bacterial infections should not be given this drug, nor should pregnant women, since it caused severe birth defects in animal studies.  Side effects include hair loss, nausea, lowered blood cell counts, headache, stomach pain, numbness, constipation and mouth sores. Bone marrow damage is the typical dose-limiting factor Vincristine Vinblastine Quinoline Alkaloids  Quinoline Alkaloids Consist of alkaloids and alkaloid salts obtained from the bark of certain Cinchona species (Quinine, Quinidine, Cinchonine, Cinchonidine). The amount of alkaloids present depend on the species, environment of the tree, age, and method of bark collection. Quinine: Anti-malarial Synthetic alkaloids are now used as substitutes for quinine for malaria.  Cinchona - History Historically played an important role in the treatment of malaria. This has now lessened with the introduction of synthetic drugs.  Cinchona - Constituents Quinoline Alkaloids Mainly Quinine Quinidine Also Quinicine Cinchonicine Cinchotannic acid Anthraquinones Leaves contain Indole Alkaloids  Chloroquine is an aminoquinolone derivative first developed in the 1940s for the treatment of malaria. It was the drug of choice to treat malaria until the development of newer antimalarials such as pyrimethamine, artemisinin, and mefloquine. Chloroquine and its Chloroquine derivative hydroxychloroquine have since been repurposed for the treatment of a number of other conditions including HIV, and rheumatoid arthritis Mefloquine Isoquinoline Alkaloids  Isoquinoline Tyrosine is the starting product of a large family of alkaloids. The first important intermediate is dopamine which is the starting product of the biosyntheses of berberine, papaverine and morphine.  Isoquinoline Tyrosine derivates: Synthesis of Benzylisoquinolines, Starting with Two Mol Tyrosine  The Opium Poppy (Papaver somniferum) The milky latex sap of opium poppies contains isoquinoline alkaloids. This class of alkaloid contains a double carbon ring with one nitrogen atom (N). It is classified as a narcotic and is commonly found in certain members of the poppy family (Papaveraceae), such as the opium poppy (Papaver somniferum). Narcotic refers to the pain-relieving and sleep- inducing properties of these highly-addictive alkaloids, including morphine, codeine and thebaine.  Opium Alkaloids  The raw opium sap drips from fresh cuts into the pericarp of the capsules, and upon oxidation and solidification in the air it turns black.  Morphine is acetylated to produce diacetylmorphine, better known as heroin.  The poppy seeds used on bagels and rolls also come from opium poppies, and although they don't cause any narcotic effects on hungry people after their coffee breaks, they can trigger a positive reaction in very sensitive urine tests for drugs.  Opium Alkaloids  In addition to Papaver, naturally-occurring opiate alkaloids also occur in the related genera Argemone and Dicentra.  The opium poppy has undoubtedly caused untold suffering by people addicted to its alkaloids, but has also brought immeasurable relief from pain for countless people throughout the ages.  Natural morphine is still one of the world's best pain relievers.  Papaver somniferum Flower of opium poppy (Papaver somniferum) grown from commercial poppy seed. Left: Opium poppy (Papaver somniferum), Right: Raw opium latex is dripping from the incised seed capsule.  Papaver somniferum Opium poppy seed capsules (Papaver somniferum). Numerous minute seeds are released through pores below the stigmatic disk. This type of capsule is called poricidal. Biosynthesis of Codeine & Morphine  Opium Alkaloids  Morphine, the principal active agent in opium, is a powerful opioid analgesic drug. According to recent research, it may also be produced naturally by the human brain. Like other opiates, morphine acts directly on the central nervous system (CNS) to relieve pain.  Side effects include impairment of mental performance, drowsiness, lethargy, and blurred vision. It also decreases hunger, inhibits the cough reflex, and produces constipation. Morphine is usually highly addictive, and tolerance and physical and psychological dependence develop quickly. Patients on morphine often report insomnia and nightmares. Morphine  Opium Alkaloids  Morphine is used legally in the following :  the relief of acute, severe pain  pain after surgery  pain associated with trauma  the relief of moderate to severe chronic pain  cancer pain  tooth extraction  as an adjunct to general anesthesia  anesthesia  Opium Alkaloids A minor constituent of opium, thebaine or paramorphine (C19H21NO3) is chemically similar to both morphine and codeine. Thebaine is not used therapeutically, but is converted into a variety of compounds including codeine, hydrocodone, hydromorphone, oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine.  Hydrocodone Thebaine Oxycodone Codeine is an opioid pain reliever used to treat mild to moderately severe pain. It is also used, usually in combination with other medications, to reduce coughing. Codeine is available as a single-ingredient product, or in combination with acetaminophen or aspirin, and in some cough and cold medications Morphine Codeine Thebaine  Opium Alkaloids  Heroin or diacetylmorphine is a semi-synthetic opioid. It is the 3,6-diacetyl derivative of morphine (hence diacetylmorphine) and is synthesised from it by acetylation.  The white crystalline form is commonly the hydrochloride salt, diacetylmorphine hydrochloride.  It has a high addiction properties, and frequent repeated ingestion causes a fast development of tolerance to it when compared to other substances, although occasional use without symptoms of withdrawal is also possible.  Heroin Heroin Alkaloids from Animals Salamandra maculosa Samandarine, Samandarone Samandaradine Phyllobates spp. Batracotoxin, Homobatracotoxin Salamandra salamandra S. almanzoris  Alkaloids from Animal  Salamanders may actively defend themselves once they are grasped by a predator. Besides various antipredator postures, S. salamandra adults are able to extrude heavy toxic skin secretions, e.g. the neurotoxic alkaloid Samandarin.  This alkaloid causes strong muscle convulsions and high-blood pressure combined with hyperventilation in all vertebrates. Samandarin  Dendrobates tinctorius Dendrobates tinctorius, a strikingly beautiful poison dart frog native to tropical rain forests of the Guianas in the northeastern shoulder of South America. Dendrobates frogs produce a poison called pumiliotoxin, which is not as deadly as the batrachotoxin produced by Phyllobates frogs  Pumiliotoxins (PTXs), are one of several toxins found in the skin of poison dart frogs. Closely related, though more toxic, are allopumiliotoxins, (aPTXs).  Other toxins found in the skin of poison frogs are decahydroquinolines (DHQs), izidines, coccinellin es, and spiropyrrolizidines. Pumiliotoxins are very poisonous in high concentrations. Pumiliotoxins are much weaker than batrachotoxins, ranging between 100 and 1000 times less poisonous.  There are three different types of this toxin: A, B and C, of which toxins A and B are more toxic than C. Pumiliotoxins interfere with muscle contraction by affecting calcium channels, causing partial paralysis, difficulty moving, hyperactivity or death. Pumiliotoxin A: R = –H Pumiliotoxin B: R = –OH Allopumiliotoxin  Phyllobates spp. Batrachotoxin is a steroidal alkaloid secreted from skin glands and is deadly to other small animals. It blocks neuromuscular transmission, resulting in muscle and respiratory paralysis and death. Extrapolating from the lethal dosage (LD) in rats, approximately 136 micrograms of this alkaloid is the lethal dosage 68 kilogram person. This minute amount is roughly equivalent to the weight of two or three grains of ordinary table salt (NaCl). Bufotenin Dihydrobufotenin Bufotoxin Bufo vulgaris and others  Alkaloids from Animal Saxitoxin Tetradotoxin Dinaflogelate- Gonyaulax tamarensis etc. Spheroides rubripes, Fugu spp., Gobius criniger and frogs such as Atelopus spp. The chemicals produced in frog and toad skin protect them against predators. In the case of the genus, Atelopus, the majority of the toxins found in the skin are tetrodototoxins. TETRADOTOXIN - one of the most powerful neurotoxins known, it is about 1200 times more toxic to humans than cyanide and it has no known antidote