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Some important classes of alkaloids Class Precursors Examples _____________ Piperidine alkaloids L-lysine (C 5 N) PowerPoint Presentation
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Some important classes of alkaloids Class Precursors Examples _____________ Piperidine alkaloids L-lysine (C 5 N) Piperine Pyrrolidine / tropane alkaloids L- ornithine (C 4 N) Cocaine , scopolamine Pyridine alkaloids L- Trp or L-Asp Niacin ( Vit . B 3 ), nicotine

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slide1

Some important classes of alkaloids

Class PrecursorsExamples_____________

Piperidine alkaloids L-lysine (C5N) Piperine

Pyrrolidine/tropane

alkaloids L-ornithine(C4N) Cocaine, scopolamine

Pyridine alkaloids L-Trp or L-Asp Niacin (Vit. B3), nicotine

Catecholamines L-Tyr (C6C2N) Dopamine, adrenaline, mescaline

and tetrahydroisoquinolinesanhalamine

Opiates 2 L-Tyr units Morphine, tubocurarine

Phenylalanine-derived L-Phe(C6C3N) Capsaicin, ephedrine

Indole alkaloids L-TrpSerotonin, ergotamine, LSD, vinblastine

Quinoline alkaloids “ quinine, camptothecin

Purine alkaloids L-Gly, L-Gln, L-Asp Caffeine, theobromine

Building 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.

opiates morphine and related compounds
Opiates: morphine and related compounds
  • Focus:
  • pieces/precursors
  • key assembly steps
  • structure-activity
  • physiological interactions

First methylation

Precursor is formed by combining two C6C2 units, both originating from tyrosine

slide3

Two stereoisomers lead to different classes of alkaloids

From (S)-N-methyl

coclaurine

Further methylation

is common

Berberineis found in many members of the Berberidaceae, the Ranunculaceae, and other families used in traditional medicine. Berberine has antiamoebic, antibacterial, and anti-inflammatory properties.

curare chondrodendron tomentosum
Curare (Chondrodendrontomentosum)

Arrow poison prepared in the rain forests by native South American tribes from bark and stems may contain >30 different plants, C. tomentosumis 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.

slide6

Making the morphine skeleton

Key steps:

oxidative coupling to make the 4th ring

2) reduction and acetylation promotes formation of the furan ring

3) Demethylation then reduction of the ketone

opium
Opium
  • 80% of the world’s illegal opium is grown in Afghanistan, supported by the Taliban.
  • $ 4 billion/year industry
  • Northern alliance initiative to destroy poppy fields pits farmers and corrupt local officials against military
  • U.S. troops are supporting efforts to provide farmers with crop alternatives like pomegranates or grapes
  • However, many farmers told in 2007 that they will receive assistance in establishing legal crops are still waiting for help

R. Draper, “Opium Wars”, National Geographic, Feb. 2011.

properties of opiates
Properties of opiates

Brain has opioid receptors (d, k and m) that mediate adenylcyclase, lower cAMP levels,

increase K+ conductance, close Ca2+ channels, decrease transmission of pain signals

Morphine’s use as analgesic involves overall CNS depression so side effects include drowsiness, lethargy, constipation, unconsciousness

structural basis for bioactivity of opiates
Structural basis for bioactivity of opiates

Enkephalins and endorphins are

endogenous opioid peptide ligands produced

during 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

drugs derived from morphine semi synthetically
Drugs derived from morphine semi-synthetically

Similar activity, can be

produced from morphine

by methylation

Heroin was introduced into cough syrup in 1898

Acetylation decreases polarity, so it

crosses blood-brain barrier quickly. More addictive though.

Synthetic analogues

Effective

analgesic and

less addictive

Used in cough medicine 

Antitussive but not analgesic

“Demerol”

50-100X more active than

morphine due to lipophilicity

Orally active, produces less

euphoria, less withdrawal

Fast, but short-acting analgesia

from l tryptophan indole alkaloids
From L-Tryptophan: Indole alkaloids

Produced from L-tryptophan

plus an isoprene unit,

the indole alkaloids have polycyclic ring structures

Fungi from Claviceps genus are best-known producers because they infect some grain crops, but the indoles are produced by other fungi including AspergillusandPenicillium

Lysergic acid is probably the most well-known, as it is the precursor for hallucinogen LSD (lysergic acid diethylamide) and

the ergot alkaloids – mixed agonist/antagonist effects on 5-HT (serotonin) receptors leads to hallucinations

serotonin

skeleton

ergot not a fun guy
Ergot – not a fun guy

Ergot is the dried sclerotium of the fungus Clavicepspurpureathat 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 norepinephrinewhich 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

ergot not a fun guy14
Ergot – not a fun guy

2) Ergot also acts on the serotonin (5-HT) receptors and the a-dopaminergic receptors causing neurological symptoms:

Headache, vertigo, convulsions, psychotic disturbances, hallucinations

Vasoconstriction 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.

slide15

Indole-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

for more information a trip through lsd and the ergot alkaloids

For more information:A Trip Through LSD and the Ergot Alkaloids

Melissa Medeiros

Natural Products

May 2006

amaryllidaceae alkaloids
Amaryllidaceae alkaloids

synthetic derivative

trans-dihydronarciclasine

narciclasine

(abundant)

pancratistatin

Compounds 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 30-90 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.

slide18

SAR shows this

part of structure

is key...

Goal of study: prepare trans-dihydro derivative of narciclasine that has the anti-cancer activity without the liver toxicity.

slide19

Protection of the OH groups

followed by hydrogenation usually produces a mixture of cis- and trans-isomers.

Since the cis-isomer (7) has no

anticancer activity, reaction conditions were modified until maximum yield of trans isomer was achieved.

Compound 5 did not inhibit

any of the cytochromes tested.

Result: an effective way to

prepare a less toxic drug!

slide20

More indole alkaloids...from Uncariatomentosa

Complex polycyclic indole alkaloids are prevalent in species such as Uncariatomentosa (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).

traditional uses of u tomentosa
Traditional uses of U. tomentosa

Aqueous extracts of bark or roots used by Ashaninka in Peruvia rainforest:

  • Allergies, asthma
  • Wound healing, viral infections, fevers
  • Arthritis, gastric ulcers, rheumatism, inflammation
  • Contraception, menstrual irregularities, childbirth
  • Some of these activities are associated with alkaloids
  • Uncaria also contains flavonoids, catechins, cinchonains, caffeic acid and ursolic acid – these may play a role in some of the bioactivities.
slide23

Weaker dopamine receptor

antagonist – some locomotor

depression observed

Pentacyclicoxindole alkaloids have immune-boosting effect, upregulate B & T cell production

Tetracyclicoxindole alkaloids

block immune factor, may also inhibit central dopamine release, depressing movement

more indole alkaloids terpene indole alkaloids with multicyclic structures
More indole alkaloids...terpeneindole alkaloids with multicyclic structures

Coupling of tryptamine

(decarboxylatedTrp)

with the secoiridoid

secologanin, followed

by a variety of cyclizations

forms terpeneindole

alkaloid skeletons with

lots of structural diversity

some interesting terpene indole alkaloids
Some interesting terpeneindole alkaloids

Yohimbine

  • From Pausinystaliayohimbe
  • Folk use: Aphrodisiac, weight loss
  • Pharmacology: dilates blood vessels, binds a-adrenergic receptors

Reserpine, deserpidine

  • From Rauwolfiaserpentina
  • Folk use: treat snake bite, insanity
  • Pharmacology: lowers blood pressure, tranquilizer, depletes stored catecholamines
skeletal rearrangements and dimerization lead to vincristine vinblastine structure
Skeletal rearrangements and dimerization lead to vincristine/vinblastine structure
  • Intermediates form through rearrangement of isoprenoid moieties

Anti-cancer agent, used to treat

leukemia and lymphoma.

strychnine
Strychnine
  • From dried seeds of Strychnosnux-vomica
  • Biosynthesis: Rearrangements in strictosidine
  • Highly toxic convulsant
  • Binds to glycine binding sites in spinal cord, causes asphyxiation
  • Has been used as a rat poison
quinine antimalarial agent from bark of cinchona trees
Quinine – Antimalarial agent from bark of Cinchona trees

Discovered in 1600’s , cured a Peruvian countess

Depolymerizes toxic byproducts of Plasmodium

Quinine was originally added to tonic water as a

prophylactic against malaria – gin

was later added to mask the

bitter taste 

slide29

Some important classes of alkaloids

Class PrecursorsExamples_____________

Piperidine alkaloids L-lysine (C5N) Piperine

Pyrrolidine/tropane

alkaloids L-ornithine(C4N) Cocaine, scopolamine

Pyridine alkaloids L-Trp or L-Asp Niacin (Vit. B3), nicotine

Catecholamines L-Tyr (C6C2N) Dopamine, adrenaline, mescaline

and tetrahydroisoquinolinesanhalamine

Opiates 2 L-Tyr units Morphine, tubocurarine

Phenylalanine-derived L-Phe(C6C3N) Capsaicin, ephedrine

Indole alkaloids L-TrpSerotonin, ergotamine, LSD, vinblastine

Quinoline alkaloids “ quinine, camptothecin

Purine alkaloids L-Gly, L-Gln, L-Asp Caffeine, theobromine

Building 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.

from amino acids to purines to caffeine and xanthine alkaloids
From amino acids to purines to caffeine and xanthine alkaloids

Purine heterocyclic

ring system is derived

from amino acids and

various one C donors

muscle relaxant

the xanthines
The xanthines

Caffeine, Theobromine, and Theophylline

  • The 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.
caffeine and adenosine
Caffeine 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.
so you can t start the day without joe you re not alone
So 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.
chocolate and pet poisoning
Chocolate 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 stimulant
    • Increases blood pressure (mild)
    • Nausea and vomiting
  • Are 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 100-200mg/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.

http://vetmedicine.about.com/cs/nutritiondogs/a/chocolatetoxici.htm

background
Background
  • A 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?
mouse model
Mouse model
  • KK-A3’ mice spontaneously develop type-2 diabetes by 6 weeks old
  • Obesity, hyperglycemia, high triglycerides and fatty liver also develop
  • Hyperinsulinemia is observed, suggesting that insulin resistance occurs in peripheral tissues.
  • Altered signaling in adipose tissues: decreased adiponectin (a adipocytokine) and increased MCP-1 (monocytechemoattractant 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.
experiments
Experiments
  • Expt 1: Diabetic mice were given diluted coffee vs. plain drinking water for 5 weeks ad libitum
  • Blood drawn and blood glucose measured weekly
  • Insulin tolerance test given at 5 weeks
  • At 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
slide42

Coffee treatment significantly reduced liver weight, most types of body fat, liver lipid content, insulin and TAG levels, and inflammatory markers

conclusions
Conclusions
  • Coffee 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.