Presentation on theme: "Some important classes of alkaloids"— Presentation transcript:
1Some important classes of alkaloids Class Precursors Examples _____________Piperidine alkaloids L-lysine (C5N) PiperinePyrrolidine/tropanealkaloids L-ornithine (C4N) Cocaine, scopolaminePyridine alkaloids L-Trp or L-Asp Niacin (Vit. B3), nicotineCatecholamines L-Tyr (C6C2N) Dopamine, adrenaline, mescalineand tetrahydroisoquinolines anhalamineOpiates 2 L-Tyr units Morphine, tubocurarinePhenylalanine-derived L-Phe (C6C3N) Capsaicin, ephedrineIndole alkaloids L-Trp Serotonin, ergotamine, LSD, vinblastineQuinoline alkaloids “ quinine, camptothecinPurine alkaloids L-Gly, L-Gln, L-Asp Caffeine, theobromineBuilding blocks from the acetate, shikimate, or deoxyxylulose phosphate pathways are also frequently incorporated into the alkaloid structures.Many alkaloids acquire their N via transamination reactions (catalyzed by Vitamin B6).Most alkaloids are quite toxic and produced by the plant as a defense against herbivores.
2Opiates: morphine and related compounds Focus:pieces/precursorskey assembly stepsstructure-activityphysiological interactionsFirst methylationPrecursor is formed by combining two C6C2 units, both originating from tyrosine
3Two stereoisomers lead to different classes of alkaloids From (S)-N-methylcoclaurineFurther methylationis commonBerberine is found in many members of the Berberidaceae, the Ranunculaceae, and other families used in traditional medicine. Berberine has antiamoebic, antibacterial, and anti-inflammatory properties.
4Curare (Chondrodendron tomentosum) Arrow poison prepared in the rain forests by native South American tribes from bark and stems may contain >30 different plants, C. tomentosum is the main one.Radical dimerization of the two coclaurine isomers produces a dimer.Tubocurarine is an ACh agonist, once it gets into the bloodstream, it relaxes voluntary muscles to paralysis by blocking nerve impulses at neuromuscular junction.Synthetic derivatives used during surgery as muscle relaxant.
5Oh oh…I think I just stuck myself… better get out my cholinesterase inhibitor pen!
6Making the morphine skeleton Key steps:oxidative coupling to make the 4th ring2) reduction and acetylation promotes formation of the furan ring3) Demethylation then reduction of the ketone
8Opium80% of the world’s illegal opium is grown in Afghanistan, supported by the Taliban.$ 4 billion/year industryNorthern alliance initiative to destroy poppy fields pits farmers and corrupt local officials against militaryU.S. troops are supporting efforts to provide farmers with crop alternatives like pomegranates or grapesHowever, many farmers told in 2007 that they will receive assistance in establishing legal crops are still waiting for helpR. Draper, “Opium Wars”, National Geographic, Feb
9Properties of opiatesBrain has opioid receptors (d, k and m) that mediate adenylcyclase, lower cAMP levels,increase K+ conductance, close Ca2+ channels, decrease transmission of pain signalsMorphine’s use as analgesic involves overall CNS depression so side effects include drowsiness, lethargy, constipation, unconsciousness
10Structural basis for bioactivity of opiates Enkephalins and endorphins areendogenous opioid peptide ligands producedduring labor, other times of stress or shock“Runner’s high”ACh inhibitors, rapidly degraded“Morphine rule”: structure must contain an aromatic ring attached to a quarternary C (Cq) with a 2-C linker to a tertiary (3o) amine
11Drugs derived from morphine semi-synthetically Similar activity, can beproduced from morphineby methylationHeroin was introduced into cough syrup in 1898Acetylation decreases polarity, so itcrosses blood-brain barrier quickly. More addictive though.Synthetic analoguesEffectiveanalgesic andless addictiveUsed in cough medicine Antitussive but not analgesic“Demerol”50-100X more active thanmorphine due to lipophilicityOrally active, produces lesseuphoria, less withdrawalFast, but short-acting analgesia
12From L-Tryptophan: Indole alkaloids Produced from L-tryptophanplus an isoprene unit,the indole alkaloids have polycyclic ring structuresFungi from Claviceps genus are best-known producers because they infect some grain crops, but the indoles are produced by other fungi including Aspergillus and PenicilliumLysergic acid is probably the most well-known, as it is the precursor for hallucinogen LSD (lysergic acid diethylamide) andthe ergot alkaloids – mixed agonist/antagonist effects on HT (serotonin) receptors leads to hallucinationsserotoninskeleton
13Ergot – not a fun guyErgot is the dried sclerotium of the fungus Claviceps purpurea that develops on the ovary of rye and other grasses consumed by humans or animals.The poisonous properties of ergots are caused by a group of indole alkaloids, the ergot alkaloids or ergolines. Consumption of ergot-infected rye produces a disease called ergotism. Ergot poisoning affects two types of receptors:1) The a-adrenergic receptors for norepinephrine which causes• GI upsets, e.g. diarrhea, abdominal pains, and vomiting.• Circulatory changes, e.g. coldness of hands and feet due to vasoconstriction of the blood vessels to the extremities
14Ergot – not a fun guy2) Ergot also acts on the serotonin (5-HT) receptors and the a-dopaminergic receptors causing neurological symptoms:Headache, vertigo, convulsions, psychotic disturbances, hallucinationsVasoconstriction can cause restricted blood flow in small terminal arteries, death of the tissue, gangrene, and even the loss of hands, feet, or limbs.Gangrenous ergotism was known as St. Anthony’s Fire because the Order of St. Anthony cared for the sufferers during the Middle Ages in Europe when outbreaks of the disease in humans and animals were relatively frequent.
15Indole-isoprenoid is modified by attachment of a small peptide (Phe & Pro usually) Ergotamine’s vasoconstrictive activity has led to its use in treatment of migraines
16For more information: A Trip Through LSD and the Ergot Alkaloids Melissa MedeirosNatural ProductsMay 2006
17Amaryllidaceae alkaloids synthetic derivativetrans-dihydronarciclasinenarciclasine(abundant)pancratistatinCompounds 1 – 6 are found in Narcissus pseudonarcissus (daffodils) and other plants from the Amaryllidaceae family.Pancratistatin (1) selectively induces apoptosis in cancer cells through a mitochondrial pathway, with little effect on normal cells. However, it’s not very abundant.Narciclasine (3) disrupts organization of the actin cytoskeleton of cancer cells at nM.Compound (5) also has potent anticancer activity while its cis-isomer has none.Problems: low water-solubility, low natural abundance of (1) and (5), and toxicity of (3) ... Narciclasine inhibits CYP3A4 (major liver detoxifying cytochrome), which can damage the liver.
18SAR shows thispart of structureis key...Goal of study: prepare trans-dihydro derivative of narciclasine that has the anti-cancer activity without the liver toxicity.
19Protection of the OH groups followed by hydrogenation usually produces a mixture of cis- and trans-isomers.Since the cis-isomer (7) has noanticancer activity, reaction conditions were modified until maximum yield of trans isomer was achieved.Compound 5 did not inhibitany of the cytochromes tested.Result: an effective way toprepare a less toxic drug!
20More indole alkaloids...from Uncaria tomentosa Complex polycyclic indole alkaloids are prevalent in species such as Uncaria tomentosa (Cat’s claw)see: Heitzman, M. E.; Neto, C. C.; Winiarz, E.; Vaisberg, A. J., Hammond, G. B.* Review: Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae), Phytochemistry, 66: 5-29 (2005).
21Traditional uses of U. tomentosa Aqueous extracts of bark or roots used by Ashaninka in Peruvia rainforest:Allergies, asthmaWound healing, viral infections, feversArthritis, gastric ulcers, rheumatism, inflammationContraception, menstrual irregularities, childbirthSome of these activities are associated with alkaloidsUncaria also contains flavonoids, catechins, cinchonains, caffeic acid and ursolic acid – these may play a role in some of the bioactivities.
23Weaker dopamine receptor antagonist – some locomotordepression observedPentacyclic oxindole alkaloids have immune-boosting effect, upregulate B & T cell productionTetracyclic oxindole alkaloidsblock immune factor, may also inhibit central dopamine release, depressing movement
24More indole alkaloids...terpene indole alkaloids with multicyclic structures Coupling of tryptamine(decarboxylated Trp)with the secoiridoidsecologanin, followedby a variety of cyclizationsforms terpene indolealkaloid skeletons withlots of structural diversity
26Skeletal rearrangements and dimerization lead to vincristine/vinblastine structure Intermediates form through rearrangement of isoprenoid moietiesAnti-cancer agent, used to treatleukemia and lymphoma.
27Strychnine From dried seeds of Strychnos nux-vomica Biosynthesis: Rearrangements in strictosidineHighly toxic convulsantBinds to glycine binding sites in spinal cord, causes asphyxiationHas been used as a rat poison
28Quinine – Antimalarial agent from bark of Cinchona trees Discovered in 1600’s , cured a Peruvian countessDepolymerizes toxic byproducts of PlasmodiumQuinine was originally added to tonic water as aprophylactic against malaria – ginwas later added to mask thebitter taste
29Some important classes of alkaloids Class Precursors Examples _____________Piperidine alkaloids L-lysine (C5N) PiperinePyrrolidine/tropanealkaloids L-ornithine (C4N) Cocaine, scopolaminePyridine alkaloids L-Trp or L-Asp Niacin (Vit. B3), nicotineCatecholamines L-Tyr (C6C2N) Dopamine, adrenaline, mescalineand tetrahydroisoquinolines anhalamineOpiates 2 L-Tyr units Morphine, tubocurarinePhenylalanine-derived L-Phe (C6C3N) Capsaicin, ephedrineIndole alkaloids L-Trp Serotonin, ergotamine, LSD, vinblastineQuinoline alkaloids “ quinine, camptothecinPurine alkaloids L-Gly, L-Gln, L-Asp Caffeine, theobromineBuilding blocks from the acetate, shikimate, or deoxyxylulose phosphate pathways are also frequently incorporated into the alkaloid structures.Many alkaloids acquire their N via transamination reactions (catalyzed by Vitamin B6).Most alkaloids are quite toxic and produced by the plant as a defense against herbivores.
30From amino acids to purines to caffeine and xanthine alkaloids Purine heterocyclicring system is derivedfrom amino acids andvarious one C donorsmuscle relaxant
31Caffeine, Theobromine, and Theophylline The xanthinesCaffeine, Theobromine, and TheophyllineThe purine alkaloids caffeine, theobromine, and theophylline are all methyl xanthines that commonly co-occur in plants. Major sources are stimulant beverages and foods such as tea, coffee, cocoa, and cola.Xanthines competitively inhibit phosphodiesterase, causing an increase in cyclic AMP and adrenaline release. This leads to CNS stimulation, relaxation of bronchial smooth muscle, and induction of diuresis. Inhibition of TNF-a and leukotriene synthesis is thought to occur, reducing inflammation and innate immunity.The effects vary among the three compounds. Caffeine is the best CNS stimulant. As a vasoconstrictor it can be combined with a therapeutic agent to increase effectiveness (e.g. compound analgesics). It has weaker diuretic action.Theobromine has little stimulant action, but has more diuretic activity and also muscle relaxant properties. Theophylline also has low stimulant action and is an effective diuretic, but it relaxes smooth muscle better than caffeine or theobromine and is frequently used in slow-release formulations.
33Caffeine and adenosine Caffeine readily crosses the blood-brain barrier, and once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (competitive inhibition)Adenosine is found in every part of the body, but it has special functions in the brain. Concentrations of brain adenosine are thought to be increased by metabolic stresses such as anoxia or ischemia. It also may have a specific role in control of the sleep-wake cycle.Brain adenosine may also protect the brain by suppressing neural activity and increasing blood flow through A2A and A2B receptors located on vascular smooth muscle. By counteracting adenosine, caffeine reduces resting cerebral blood flow – it’s a vasoconstrictor.Adenosine is released in the brain through a complex mechanism. It is not likely that adenosine is the primary neurotransmitter for any group of neurons, but rather is released together with other transmitters by a number of neuron types.
34So you can’t start the day without Joe? You’re not alone! Is caffeine addictive? Several classes of adenosine receptors are known, and there is evidence that A 2A receptors interact with the dopamine system, which is involved in reward and arousal.Tolerance: because caffeine is primarily an antagonist of adenosine receptors, regular caffeine consumers may adapt to its continuous presence by increasing the number of adenosine receptors.This reduces the stimulatory effects (tolerance adaptation) and makes one much more sensitive to adenosine, so that reducing caffeine intake results in withdrawal symptoms.
35From Drugs and the Human Body, 6th edition, K. Liska
36Chocolate and pet poisoning Dogs are most often affected, due to their ability to find chocolate and the common 'sweet tooth' they develop, but cats and other mammals are susceptible to the toxic effects of chocolate, too.Theobromine is the major stimulant in chocolate. Its effects:CNS and cardiovascular stimulantIncreases blood pressure (mild)Nausea and vomitingAre some chocolates more toxic than others? Yes. Unsweetened chocolate contains 8-10 times the amount of Theobromine as milk chocolate. Semi-sweet or dark chocolate falls roughly in between the two.The toxic dose of Theobromine (or caffeine) for pets is mg/kg body weight. However, reports by the ASPCA have noted problems at doses much lower than this - i.e. 20mg/kg.Using the 20mg/kg as a measure of "problems can be seen” a 50 lb (23 kg) dog would have to consume 9 oz of milk chocolate. Some dogs won't see problems at this rate but others may.
38BackgroundA Dutch cohort study in 2002 and others found that higher coffee consumption correlates with lower risk of Type-2 diabetes.Coffee constituents that have been previously shown to affect glucose metabolism include caffeine, chlorogenic acid, lignans, trigonelline.Caffeine also reported to induce energy expenditure by boosting thermogenesis.However some cohort studies suggest that decaf also reduces risk.Is caffeine the active constituent against diabetes?
39Mouse modelKK-A3’ mice spontaneously develop type-2 diabetes by 6 weeks oldObesity, hyperglycemia, high triglycerides and fatty liver also developHyperinsulinemia is observed, suggesting that insulin resistance occurs in peripheral tissues.Altered signaling in adipose tissues: decreased adiponectin (a adipocytokine) and increased MCP-1 (monocyte chemoattractant protein) and TNF-a which induce insulin resistance.Study looked at mechanism of coffee’s action against type-2 diabetes and the effect of caffeine alone on development of hyperglycemia.
40ExperimentsExpt 1: Diabetic mice were given diluted coffee vs. plain drinking water for 5 weeks ad libitumBlood drawn and blood glucose measured weeklyInsulin tolerance test given at 5 weeksAt study end, mice were sacrificed and tested for serum insulin, triglycerides, total cholesterol, and pro-inflammatory markers MCP-1 and IL-6.Liver and adipose tissues were removed and examined for cholesterol, TG and phospholipid content.Expt 2: Same study was repeated with caffeine solution (250ug/mL) vs. plain drinking water
41Coffee treatment lowered blood glucose and insulin tolerance in the mouse model
42Coffee treatment significantly reduced liver weight, most types of body fat, liver lipid content, insulin and TAG levels, and inflammatory markers
43ConclusionsCoffee improved insulin sensitivity and decreased hyperglycemia (high blood sugar)Expression of inflammatory cytokines such as MCP-1, IL-6 and TNFa in adipose tissue was lower in the coffee treatment group.Coffee decreased adipose tissue inflammation, thus improving insulin resistance.Caffeine alone also reduced hyperglycemia, inflammation in some but not all fat tissues.Both coffee and caffeine improved fatty liver.