AlkaloidsAlkaloids

autumn crocussource of colchicine

Introduction IIntroduction I

Definition of alkaloidsDefinition of alkaloids

Structure: mostly nitrogen containing compounds(heterocyclic ones) with basic nitrogen atoms occurring in the(heterocyclic ones) with basic nitrogen atoms occurring in thenature as salts of organic acids. (Lactic, tartaric, citric, acetic,succinic, maleic and oxalic acid.)

Source: produced by plants or animals (secondary metabolites).

Bioactivity: strong physiological activity.y g p y g y

Application: used as precursors by the pharmaceutical industry.

Primary alkaloids (found in higher amount), secondary alkaloidsy ( g ), y(found in slight amounts)

Introduction IIntroduction III

Classification of alkaloids

A di t th iAccording to their source

According to their chemical structureg

According to the bioactivity

Classes of alkaloids I Classes of alkaloids I

Classes of alkaloids IClasses of alkaloids III

Classes of alkaloids IClasses of alkaloids III (II (accordingaccording totostructurestructure))structurestructure))

Heterocyclic compounds

Indole alkaloids (strychnine, lysergic acid, ergotamine)

Isoquinoline alkaloids (papaverine*)

Morphinan alkaloids (isoquinoline gr.) (morphine*, codeine, thebaine))

Tropane alkaloids (atropine*, hyoscyamine, cocaine*, scopolamine)p )

Pyridine alkaloids (nicotine*)

Piperidine alkaloids (piperine coniine*)Piperidine alkaloids (piperine, coniine )

Quinoline alkaloids (quinine*)

Purine alkaloids (caffeine* theobromine* theophylline*)Purine alkaloids (caffeine*, theobromine*, theophylline*)

Classes of alkaloids IClasses of alkaloids IV (V (accordingaccording totot tt t ))structurestructure))

Heterocycles without nitrogen

Tetrahydrocannabinol*y

Taxol*

N h t li lk l idNon-heterocyclic alkaloids

phenylalkylamine derivatives

ephedrine

Mescaline*Mescaline

Capsaicin*

Alkaloids of Alkaloids of phenylalkylphenylalkyl amine skeletonamine skeleton IIp y yp y y

Ephedrine isolated from various plants in the genus EphedraEphedrine – isolated from various plants in the genus Ephedra(Ephedra sinica)

Structure: 2 (methylamino) 1 phenylpropan 1 ol (it contains twoStructure: 2-(methylamino)-1-phenylpropan-1-ol (it contains twochiral centers), applied as hydrochloride.

CCH3

NHCH3H 2

3

*

* C HHOCCH3

NHCH3H *

* C HHOCH2

NHCH3

*C OHH1* C HHO C HHO

OHOH

Ephedra chinensis(-)-ephedrine (+)-pseudoephedrine adrenalin

Alkaloids of Alkaloids of phenylalkylphenylalkyl amine skeletonamine skeleton IIIIp y yp y y

Ph i l i l i i f h d iPhysiological activity of ephedrineIt is a sympathomimeticum, it increases the blood pressure, it acts

as a bronchodilator used as a decongestantas a bronchodilator, used as a decongestant.

Medical use: therapy of rhinitis and asthma, also used inincontinenceincontinence.

Pseudoephedrine is less active (used as decongestant).

Abuse of ephedrine by athletes ephedrine (in dietaryAbuse of ephedrine by athletes, ephedrine (in dietarysupplements).

Amphetamines (see this family in the lecture Amines)Amphetamines (see this family in the lecture Amines)

CapsaicinesCapsaicines

Isolation: from genus CapsicumIsolation: from genus Capsicum

H3CO

O

H3CO

HO

NH

capsaicin*

H3CON

O

HO

NH

dihydrocapsaicin

Capsicum annuum

Chemistry: they are amides of benzylamine (nonanic- or

nonenic acid moiety)Medical use: capsaicin is used topically to relieve pain (analgesic)

Pyridine, Pyridine, piperidinepiperidine and and pyrrolidinepyrrolidine alcaloidsalcaloidsNicotine andNicotine and anabasineanabasine IINicotine and Nicotine and anabasineanabasine I I

I l ti f S l ( i ht h d f il ) Ni ti t bIsolation: from Solanaceae (nightshade family), Nicotiana tabacum .

In small amount it is present in eggplant and in tomato.

Ch i t hi l d ( idi i d lidi i idiChemistry: chiral compounds (pyridine ring and pyrrolidine or piperidineskeleton).

NCH

3*

*N

NCH3

12

NH

i ti * b i Ni ti t bnicotine* anabasine

It works as a antiherbivore compound with specific acitivity to insects.They are applied in the agriculture as insecticide

Nicotiana tabacum

They are applied in the agriculture as insecticide.

Nicotine and Nicotine and anabasineanabasine IIII

Physiological activity: it binds to the nicotinic acetyl cholinereceptors, (agonist of cholinerg system), thus causestachycardia, nausea, hypo- or hypertony, migraine, etc.

It acts as a stimulant in mammals, nicotine addiction.

It is toxic (It absorbs through the skin.)

The nicotine content of a cigarette: up to 10-20 mg. In the smoke:g p g0.4-1.2 mg.

The components of smoke: 3000-4000 compounds, 40The components of smoke: 3000 4000 compounds, 40carcinogenic (benzpyrene, benzanthracene, 2-naphthylamine,nitrosamines, etc.)t osa es, etc )

Nicotine and Nicotine and anabasineanabasine IIIIII

Damages caused by smoking: higher incidence of cardiac

infarct, chronic bronchitis, lung carcinoma and other

tumors, etc.

Medical usage: pharmacological research

ConiineConiine

Isolation: from poison hemlock (Conium maculatum)

Structure: 2-propylpiperidine (one chiral center)

It is toxic causing respiratory paralysis. (Its effect is a nicotine likeeffect and a curare like one.))

Socrates was sentenced to death by coniine.

coniine*i h l kpoison hemlock

EpibatidineEpibatidine IIEpibatidineEpibatidine II

Isolation: from an animal (Epipedobates tricolor called asIsolation: from an animal (Epipedobates tricolor, called asphantasmal poison frog) a poison dart frog living in Eucuador. Itstoxin is one of the strongest toxins of frogstoxin is one of the strongest toxins of frogs.

Chemical structure: pyridine derivative with a pyrrolidine sidechain.chain.

HN

NH

HN

N Cl

Epipedobates tricolorepibatidin

N Cl

EpibatidineEpibatidine IIIIpp

Ph i l i l ti it it i i kill 200 ti t tPhysiological activity: it is painkiller 200 times as potent asmorphine.

No addiction Because of its toxicity it is not used in human medicineNo addiction. Because of its toxicity it is not used in human medicine.

NHAnalogues of epibatidine

ONTebanicline –ABT-594

effective analgesic activitywith less toxicity

N Clwith less toxicity.

PiperinePiperine

Isolation f om black peppe (Pipe nig m)Isolation: from black pepper (Piper nigrum).

Structure: it is a piperidine derivative (amide linkage ofunsaturated aromatic carboxylic acid) it is an amide of piperoicunsaturated aromatic carboxylic acid), it is an amide of piperoicacid.

OC

NO

O

Piperin is responsible for the pungency of pepper.

Piper nigrum

TropaneTropane skeletonskeleton

8

H2CHC

H2C

CH2HN1 2

37

8

NH1

27

8

H2C CH

CH2

CH2HN 34

56

2

34

56

7

N-Methyl-8-azabicyclo[3.2.1]octane= piperidine + pyrrolidine rings, symmetrical

Conformation: piperidine: chair, pyrrolidine: envelope

The tropane alkaloids: esters of tropin, or pseudotropin-

isomeric alcoholsisomeric alcohols.

Atropine IAtropine I

Isolation f om deadl nightshade (At opa belladonna) also inIsolation: from deadly nightshade (Atropa belladonna), also in other plants of Solanaceae.

NNH3C

H

O O

O C

C CH2OHHOOC

H

*

HOH2C HAtropa belladonna

Tropic acidatatropineropine**

StructureStructure:: ester of tropin with (+/-) i.e. (racemic) tropic acid.The main alkaloid is hyosciamine isomerized to atropine duringi l ti B i d d lt l h tisolation. Basic compound, used as a salt, sulphate.

Atropine IAtropine III

Ph i l i l ff t th l ti it i hibit thPhysiological effects: parasympatholyticum, it inhibits theeffect of acetylcholine on muscarin receptors.

Atropine derivatives in medicine: dilate pupils(ophthalmology), acts as a spasmolytic of bronchialspasms. Treatment for poisoning by organophosphateinsecticides and nerve gases.

Overdose: tachycardia, nausea, hallucination, etc.

HyoscyamineHyoscyamine

It is the levorotatory isomer of atropine

Scopolamine or Scopolamine or hyoscinehyoscinepp yy

Isolation: Japanese belladonna (Scopolia japonica)p ( p j p )

NH3C

OH

O

C O

CH

CHOH2

Scopolia japonica

Structure: very similar to that of atropine containing an extra epoxy group.y p g p y g p

Physiological effect: parasympatholyticum, it inhibits the effect of

acetylcholine on muscarin receptors.

Usage in medicine: against sea sickness and intestinal cramping

CocaineCocaine II

Isolation: Erythroxylon coca (1860)Isolation: Erythroxylon coca (1860)

Erythroxylon cocay y

Structure: ester of pseudotropine (stereoisomer of tropine)ccocaineocaine**

having two ester groups (four chiral centers).

CocaineCocaine IIII

Physiological effects: topical anaesthetic, stimulant of the CNS

d th t i t tand the autonomic nervous system, etc.

Overdose: blocks breathing, cardiac infarction, ischemia, stroke,

hyperthermia

Medical usage: topical anaesthetic for nasal and lacrimal ductMedical usage: topical anaesthetic for nasal and lacrimal duct

surgery (rarely used)

Dependency: very strong psychological dependency.

QuinolineQuinoline and and isoquinolineisoquinoline alkaloidsalkaloidsQuinine IQuinine IQuinine IQuinine I

CH CH2*

CH N

2

H2CH2CHO

**

**

H3CO

Isolation from Cinchona pubescens

Cinchona pubescensqquinineuinine**

N

Isolation from Cinchona pubescens (isolation from the bark of the tree). Mosquito, vector

of malaria

Structure: isoquinoline skeleton, quinuclidine ring (alifatic tertiaryamine) with four chiral centers and two basic groups, it is applied as a

l h t hl idsulphate or chloride.

Quinine IQuinine IIIQQ

Bioactivity: It was the first effective medicine for malaria

d b Pl di f l i t itcaused by Plasmodium falciparum – a protozoan parasite.

Antipyretic activity and effect on the CNS.

Other use of quinine: it is a flavour component of tonic

t d bitt lwater and bitter lemon.

Importance of syntheticp y

derivatives of quinine.

PapaverinePapaverine

Isolation: from poppy (Papaver somniferum) it is an opium alkaloidIsolation: from poppy (Papaver somniferum), it is an opium alkaloid.

H3CO

NH3CO

H2C OCH3

OCH3

Structure: isoquinoline skeleton with benzyl group (methoxy

ppapaverineapaverine**

Structure: isoquinoline skeleton with benzyl group (methoxysubstituents), weak baseSynthetic derivative: drotaverine with ethoxy groupsy y g pPhysiological activity: it is a smooth muscle relaxantMedical usage: spasmolytic agent (the gastrointestinal tract, bile ductsand ureter)

Opium alkaloids IOpium alkaloids Ipp

Isolation: from poppy (Papaver somniferum) opium alkaloidIsolation: from poppy (Papaver somniferum) = opium alkaloid.

Morphine is the most abundant alkaloid (10%) in opium (50 other).

János Kabay (1896-1936)János Kabay (1896-1936),pharmacist inventor (newprocedure for the extractionp o du o a oof morphine from drytrashed poppy straw).

Papaver somniferum

Opium alkaloids: morphine, codeine, thebaine, papaverine, narcotin,Opium alkaloids: morphine, codeine, thebaine, papaverine, narcotin, narcein

Opium alkaloids IIOpium alkaloids II

Morphine*:Structure Morphine*:

morphinan skeleton withpiperidine ring

StructureR1O

piperidine ring,

Codeine: monomethoxyderivative; Medical use:

O R4

N*

**

* derivative; Medical use:cough medicine

naloxone: N-alllyl derivativeR2O

N

R3

*

*

ywith oxo group; Medicaluse: used as an antidote in

R1 R2 R3 R4 name

OH OH CH3 H morphine

opiate overdose, (heroin ormorphine overdose), narcotic

t i t

OCH3 OH H codeine

naloxone*

CH3

OH =O OHCH2CH=CH2

antagonist.* = no double bond

Opium alkaloids IIOpium alkaloids IIII

Physiological effect: morphine binds to opioid receptor –as the

endorphinesendorphines

Medical use: narcotic analgesic

Side effects: constipation, myosis, euphoria

Overdose: respiratory depression coma pinpoint pupilsOverdose: respiratory depression, coma, pinpoint pupils

Morphine addiction: tolerance, psychological and physiological

dependence are extremely high.

Opium alkaloids IOpium alkaloids IVV

Thebaine H COThebaine H3CO

O

N

H3CO

N

CH3

Structure: it differs from morphine (two methyl groups and an

extra double bond)extra double bond)

Physiological effect: convulsant, toxic.

U d i th h ti l i d tUsage: used as a precursor in the pharmaceutical industry

Opium alkaloids Opium alkaloids VV

HeroineHeroineH3CCOO

O H

N

H3CCOO

NCH3

Structure: diacetyl derivative of morphinePhysiological effect: as that of morphine, but its bioavailability ismuch better (more hydrophobic), myosis, cold, wet skin, weakbreathing, narcosis.Medical use: noMedical use: no

Opium alkaloids Opium alkaloids VIVI

Morphine analogues (opioid analgesics)Morphine analogues (opioid analgesics)HO

O H

NO

O

N CH3 OC6H5

CH3

NCH3

CH3

HOCH3

Structure

O CH3

pethidine methadone morphineStructurepethidine: a piperidine derivativemethadone: a tertiary amine derivativePhysiological effect: similar to morphineMedical use: opioid analgesics, treatment of opioid dependence

IndoleIndole alkaloidsalkaloids

Ergot alkaloids

StrichnineStrichnine

Yohimbine

Strichnine, brucine: very toxic alkaloids (no medical

use); brucine is used for resolution of racemic mixturesuse); brucine is used for resolution of racemic mixtures.

Vinca alkaloids

Ergot alkaloids IErgot alkaloids I

Lysergic acidyse g c ac dIsolation: Claviceps purpurea (ergot fungus)

Claviceps purpureaThere are about 12 ergot alkaloids.It is a precursor for a wide range of ergoline alkaloids.Structure: it a fused ring system composed of an indole and a

g

quinoline skeleton.

Ergot alkaloids IErgot alkaloids III

ErgotamineL-Pro

Lysergic acidErgotamine

NCH3

H

NH

OO

N

CH3N

OH

O

H

Lysergic acid

H HO

H CH2

L-Phe

Structure: an amide derivative of lysergic acid.

NH

y gPhysiological effect: it has a complex mechanism of action (similarity to

neurotransmitters as serotonin, dopamine, and epinephrine) binding to theirreceptors.receptors.

Medical use: treatment of acute migraine; gynaecology: immediately post-partum to decrease uterine bleeding.

Ergot alkaloids IErgot alkaloids IIIII

LSD* (L se gic acid dieth lamide) HO

LSD* (Lysergic acid diethylamide)

*

* NCH3

H

NH3C

CH3

H

Structure: diethylamide of lysergic acid, it is a semisynthetic drug.NH

Physiological effect: hallucinogenic, psychological effects as closed andopen eye visuals, an altered sense of time.

Side effects: flash back

Medical use: no

Addiction: non-addictive

NorharmaneNorharmane alkaloidsalkaloidsVincaVinca alkaloids Ialkaloids IVincaVinca alkaloids Ialkaloids I

Isolation: Vinca minorIsolation: Vinca minor

NN

H

H3COHO N

NH

O

CH3O

H3CO

O

O

vincamine ethyl apovincaminate Vinca minorvincamine ethyl apovincaminate Vinca minor

Structure: vincamine belongs to a special class of indole alkaloids

(norharmane skeleton=indole+pyridine)

VincaVinca alkaloids Ialkaloids III

Physiological effect: vincamine proved to beantihypertensive in 1954, but because of low activity wasnot marketed.

The semisynthetic derivative, vinpocetine (ethylThe semisynthetic derivative, vinpocetine (ethylapovincaminate) was prepared as a more effective cerebraldilatordilator.

Medical use: applied as nootropic for the improvement ofmemory (it helps to maintain the memory andmemory (it helps to maintain the memory andconcentration)

TetrahydrocannabinolTetrahydrocannabinol (THC) I(THC) Iyy ( )( )

It is the major alkaloid of the hashish or marihuana, grass

Isolation: Cannabis indicaIsolation: Cannabis indicaCH3

H

HOH

**

Cannabis sativatetrahydrocannabinol*

OH3C

H3CCH3

Structure: it is not a basic compound; it is an aromatic

terpenoid with low water solubility

y

terpenoid with low water solubility

TetrahydrocannabTetrahydrocannabininolol (THC) I(THC) IIIyy ( )( )

Physiological activity: it binds to the cannabinoid receptors, it

acts on the CNS, causing euphoria, hallucinogenic, disturbance

of the perception, increases the appetite, antiemetic, etc.

Medical use: therapy of cancer or radiation therapy as analgesicMedical use: therapy of cancer or radiation therapy as analgesic

and antiemetic agent, therapy of glaucoma.

No physical or psychological dependence.

Synthetic derivative: nabilon without hallucinogenic effect usedSynthetic derivative: nabilon without hallucinogenic effect used

for the same therapy.

TaxolTaxol or or paclitaxelpaclitaxel II

Isolation from Pacific yew tree (Taxus brevifolia)Isolation from Pacific yew tree (Taxus brevifolia)

O OO

O NH O

O O OH

OHO

OH

OO

HO

OO

Structure: oligoester derivatives of tetracyclic diterpene alkaloids

Taxus brevifoliattaxolaxol**

(special oxetane ring)Special building unit: phenylisoserine attached to taxane skeleton.P d i f h b k f T b if liProduction: from the bark of Taxus brevifolia.

TaxolTaxol IIII

Physiological activity-mechanism of action: it acts on the N-terminal end of β-tubuline stabilizing the microtubule polymerand protecting it from disassembly; it inhibits the mitosis,(inhibits the spindle function).

M di l l i t t bl dd b t h dMedical use: lung, ovarian, prostate, bladder, breast cancer, headand neck cancer, Kaposi’s sarcoma

Sid ff t h ll i ti d itiSide effects: hyperallergic reactions, nausea and vomiting,diarrhoea, alopecia, water retention, etc.

Some other vinca alkaloids as vincrystin and vinblastine act onSome other vinca alkaloids as vincrystin and vinblastine act onthe microtubules in opposite way inhibiting thepolymerization of microtubulespolymerization of microtubules.