Derivatives of the amino acid tryptophan

Indol alkaloids and alkaloids with a quinoline ring

Indol alkaloids: (Apocynaceae, Loganiaceae, Rubiaceae)1-Simple derivatves of tryptophan2-Derivatives of tryptophan + C2

3- Derivatives of tryptophan + C5

4-Derivatives of tryptophan +C9 or C10

N

Indol

N

Quinoline

1- Simple derivatives of tryptophan“Indolalkylamines” : -CO2, +OH, +CH3at αN and/or “O”, oxidation

N

CO2H

NH2

-CO2

HHN

NH2

L-TryptophanTryptamine

Tryptophan decarboxylase

12

34

67

5

oxid.N

NH2

H

HO

5-HT, Serotonin

N

CO2H

NH2HO

H

5-Hydroxy-L-Tryptophan

-CO2

Tryptophan decarboxylase

5-HT, Serotonin

5HT (Serotonine) Monoamine neurotransmitter; CV tissue, peripheral NS,

CNS, blood cellsCentral and peripheral physiol. functions: smooth muscle

contraction, vasoconstriction, sleep, food intake, pain,…; metabolized by MAO; platelets-neurons: 5HT re-uptake mechanism; SSRI’s

Migrain: 5HT agonists:sumatripan, elatripan, naratripan, rizatripan,….

N

NH2

H

HO

5-HT, Serotonin

N

NMe2Me2NSO2

HSumatriptan

Psilocybe spp. (Fam. Strophariaceae)

“Magic mushrooms”; ~80 species, hallucinogenic properties (6-20mg)

N

CO2H

NH2

-CO2

HHN

NH2

HN

NHCH3

HN

N CH3

CH3

L-TryptophanTryptamine

Tryptophan decarboxylase

oxid.N

NMe2

OH

H N

NMe2

OP

HPsilocin Psilocybin

PhysostigminePhysostigma venonosum (Leguminosae)

Calabar bean in native culture: ordeal poison;Several alkaloids, major: physostigmine (=eserin); unstable• Reversible inhibitor of cholinesterase, preventing normal

destruction of acetylcholine and enhancing cholinergic activity; miotic (atropine!); ↓ intraocular pressure→ glaucoma treatment; antidote to anticholinergic poisons; reverses the effect of muscle relaxants (curare); Alzheimer’s disease; model for carbamate insecticides

Analogues: Neostigmine, pyridostigmine, rivastigmineO

O

Me3N NMe3

Neostigmine

+

NMeO

O

Me3N

Pyridostigmine

+

N

NCH3

CH3

H3CO

O

MeHN

2- Derivatives of tryptophan + C2

• ß-carboline alkaloids (indol + pyridine)

• Peganum harmala (Zygophyllaceae) “Harman alkaloids” (harman, harmine, harmol)mild hallucinogenic, serotonine antagonist

• Passiflora incarnata (Passifloraceae) “harman alkaloids”, sedative, hypnotic, epilepsy, neuralgies

N NH2 RCHO

NH

NH

R

NH

NH

R

+

Tryptamine

alpha cond.

beta cond.

Beta carboline

Indolenine

N

N

H3CO H

Harmine

1

2

34

5

6

78

9

NH

N

Harman

NH

N1

2

3

45

6

78 9

N

N

H3CO HHarmaline

3- Derivatives of tryptophan + C5

Ergot alkaloids or ergolinesErgot -Rye ergot- Secale cornutum - Claviceps purpureaSecale cereale (rye); ~30 alkaloids; 3,4- substituted indoles! 0.15%

total alkaloids (ergotoxine);

d-Lysergic acid derivatives :-ine; d-isolysergic acid derivatives: -inineSimple amides: water-soluble ergine, ergometrinePeptide alkaloids: water-insoluble Ergotamine-,

ergoxine- and ergotoxine groups

NH

1 2

3

4

5

Indole N

NH

H

H

1 2

3

45

67

8

910

11

12

13

14

Ergoline alkaloids

HOOC

NH

12

12

NH

A B

C

D

78

9

1011

13

14

3

4

5

Ergoline alkaloids

Simplified biosynthesis of ergot alkloids• Based on condensation of tryptophan with DAPP,

methylation of side chain NH2 group, decarboxylation, stepwise oxidation of CH3 group of DAPP, cyclisations

(+) lysergic acid, simple amides [ergine, ergometrine] and peptide alkaloid ergotamine

Some important ergot alkaloids1-Ergometrine (ergnovine, ergobasine): oxytocic [p.o., s.c., i.m.];

very quick acting; vasoconstrictor (↓ bleeding in Caesarian operations);α-adrenerging / 5HT receptors

1-1-Methylergonovine: semisynthetic derivative of “1”, longer acting and more potent {Methergine}

1-2-Methysegide: semisynthetic derivative of “1”, migraine prophylaxis

2-Ergotamine: partial agonist of α-adrenerging and 5HT receptors (high doses: antagonist!); vasoconstrictor, acute attacks of migraine (+caffeine), [p.o., s.c., i.m.]

2-1-Dihydroergotamine : semisynthetic derivative of “2”, migraine3-Bromocryptine: semisynthetic, dopaminergic activity, Parkinson

disease, decrease prolactin secretion, supress lactation

Some important ergot alkaloids (cont.)4- LSD [lysergic acid diethylamide]; semisynthetic, psychodelic; NO

ther. use! Interferes with normal seratogenic transmission. Most active psychotomimetic drug (6000x more potent than mescaline!). Perceptual changes (shape, colour, sound), disintegration of the “self”; p.o: 30mcg! Alternation between beautiful vision and nightmare! Influenced by the mood of the user!; flashbacks! Not addictive: schizophrenia

5-Ergotoxine: used in mild dementia (improvement of the senility) but not safe.

Clinical features of ergot poisoning: Ergotism

1-Alimentary upsets: diarrhea, abdominal pain, vomiting2-Circulatory changes: coldness of hands and feet due to

vasoconstrictor effect, decrease in the diameter of the blood vessels (especially of those supplying the extremities)→ death of the tissue → development of gangrene → shedding of hands, feet “St. Anthony fire”: “gangrenous form”

3- Neurological symptoms: headache, convulsions, psychotic disturbances, hallucinations “convulsive form”

4- Derivatives of tryptophan + C9 or C10

• Mainly distributed in the families:• Apocynaceae: Rauwolfia serpentina (reserpine,

serpentine, ajmalicine) Catharanthus roseus (vincristine,

vinblastine), Vinca minor (vincamine)• Loganiaceae : Strychnos nux vomica (strychnine and

brucine)• Rubiaceae : Cinchona succirubra (quinine, quinidine,

cinchonine, cinchonidine)• Nyssaceae: Camptotecha accuminata (camptothecine)

Condensation of tryptamine with secologanineIndolenine or ß-carboline type structures; In vivo : enzymatically,

in vitro : pH=4.5 ß-carboline-type; pH=6.2 indolenine-type

NH

NH2

Tryptamine

+

O

CHO

MeO2C

O-Glu

Secologanine

NH

NH

O

O-Glu

MeOOC

Beta carboline

N

NH

Indolenine

OMeO2C

O-Glu

Rauwolfia serpentina (Apocynaceae) “snakeroot”• Indole alkaloids 0.7-2.5%; 0.15-0.2 reserpine3 groups of alkaloids: Reserpine -, serpentine [alstonine] - and ajmaline- groups• Used in India from snake-bite to insanity!• Powdered R. serpentina: antihypertensive, tranquilizer, sedative; “tranquilizer

era”• Reserpine, deserpidine: antihypertensive, mild tranquilizer but prolonged use

caused depression which was not observed when root extract was used; reserpine: promotion of breast cancer???

• Ajmalicine [=raubasine]: spasmolytic, anxiolytic, antihypertensive• Ajmaline: in treatment of cardiac arrythmias• These alkaloids can be separated due to their basicity: Serpentine: strongly basic (quaternary; yellow color) Ajmaline and related compounds: intermediate basicity Reserpine, rescinamine, deserpidine, ajmalicine: weak bases

N

N

OCH3

OCH3

OH

OCH3O

O

O

H

H3CO

Reserpine

Madagascar Periwinkle: Catharanthus roseus (=Vinca rosea) (Apocynaceae)

More than 150 alkaloids; Indole alkaloids, Indol/indolenine alkaloids “binary alkaloids”; “bisindole alkaloids”

Vinblastine , vincristine, vinrosidine, vinleurosine, leurosidine, ajmaline, serpentine,…Vinblastine, vincristine: cancer chemotherapy (antimitotic)

Vinblastine: Hodgkin’s diseaseVincristine: childhood leukaemia, small-cell lung , cervical, breast cancerVindesine: semisynthetic amide derivative of vinblastine: acute lymphoid

leukaemia in childrenVinorelbine: semisynthetic, derivative of anhydrovinblastine (orally active)VCR: 0.0002% (1g / 500 kg leaves)Semisynthesis (catharanthin+vindoline →vinblastine →vincristine)Folksmedicine: antidiabetic! Anticancer activity: serendipity discovery

Important Catharanthus alkaloids

Common Periwinkle: Vinca minor (Apocynaceae)• 0.3-1% alkaloids in the leaves: Vincamine [major], vincadine, minovincine,…• Folksmedicine: astringent, wound healing, • ↑ in O2 and glucose consumption→↑ cerebral blood flow→ vasodilator

-Treatment of cerebral senility problems (psychological and behavioral)-Treatment of disorders of vascular origin in ophthalmology and oto-rhino-

laryngologyArrythmias!

Strychnos nux-vomica (Loganiaceae)Strychnine and brucine [indolenine alkaloids] are the main alkaloids of the seeds; both very toxic; 100mg strychnine is fatal for an adult! CNS-stimulant; “general tonic”, vermin killerToxicity similar to tetanus toxicity: anxiety, increased sensitivity to noise and light, convulsive attacks, contractions of diaphragm, asphyxia, death. Antagonist: Barbiturate, homoepathic preparations; physiologic and neuro-anatomic research

Cinchona alkaloidsThe remarkable fact in the alkaloids of Cinchona is : rearrangement of the indole

nucleus into the quinoline system and producing alkaloids having quinuclidine and quinoline nuclei based on condensation of tryptamine with C-9. Important Cinchona alkaloids: quinine and quinidine, or cinchonidine and cinchonine are pairs of diastereoisomers , and have opposite chiralities at two centers , at C-8 and C-9 (Quinine: 8S, 9R; quinidine: 8R, 9S)

N

N

Quinoline nucleus

Quinuclidine nucleus

4

2

5

6

1

7

89

1'

3'

5'

6'

7' 8'

9'

10'

3

10

11

2

Cinchona alkaloids• The important Cinchona alkaloids are quinine and quinidine, or cinchonidine

and cinchonine are pairs of diastereoisomers , and have opposite chiralities at two centers , at C-8 and C-9 (Quinine: 8S, 9R; quinidine: 8R, 9S)

Cinchona spp. (Rubiaceae) Cinchona barkC. succirubra, C. ledgerina, C. calisaya: Alkaloids, phenolics [cinchotannic acid], org. acids [quinic acid], saponins, vol. oils [linalool, limonene,..] ; 4 alkaloids make up to 60% of total alkaloids: quinine and quinidine, cinchonidine and cinchonine as salts of quinic and cinchotannic acids.Quinine: antimalarial , effervescent tonic waters, skeletal muscle relaxant, treatment & prevention of nocturnal leg cramps, flu-like cond.

Quinidine: cardiac depressant, cardiac arrythmias; overdose: diastolic arrest, mild antimalarial effect

Cinchonine, cinchonidine: mild antimalarial effect

Cinchonism: overdose of Cinchona products → temporary loss of hearing, impaired sight

Synthetic antimalarial agents: resistance of Plasmodium falciparum to synthetic drugs → reintroduction of quinine; Mefloquine is 10x more active than quinine [GI-disturbances, dizziness,…]Chloroquine and OH-chloroquine: rheumatoid arthritis

Camptotheca acuminata (Nyssaceae)All parts of the Chinese tree C. acuminata contain camtothecine; broad

spectrum anticancer activity; poor H2O-sol., toxicity

Camptothecine nucleus obtained by modification of indole system: ß-carboline (6-5-6-ring system→6-6-5-ring system)

Semisynthetic derivatives clin. used as topo I inhibitors in treatment of ovarian, colorectal ca,..

Synthetic analogues under clin. investigationCamptothecine active against path. protozoa Leishmania and Trypanosoma

spp. 10-OH camptothecine

Important semi-synthetic analogues of camptothecine

9-aminocamptothecine

Topotecan

Irinotecan