Derivatives of the amino acid tryptophan

1. Derivatives of the amino acid tryptophan Indol alkaloids and alkaloids with a quinoline ring Indol alkaloids: (Apocynaceae, Loganiaceae, Rubiaceae) 1-Simple derivatves of tryptophan 2-Derivatives of tryptophan + C2 3- Derivatives of tryptophan + C5 4-Derivatives of tryptophan +C9 or C10

2. 1- Simple derivatives of tryptophan “Indolalkylamines” : -CO2, +OH, +CH3at αN and/or “O”, oxidation 5-HT, Serotonin

3. 5HT (Serotonine) Monoamine neurotransmitter; CV tissue, peripheral NS, CNS, blood cells Central 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,….

4. Psilocybe spp. (Fam. Strophariaceae) “Magic mushrooms”; ~80 species, hallucinogenic properties (6-20mg)

5. 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, rivastigmine

6. 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

7. 3- Derivatives of tryptophan + C5 Ergot alkaloids or ergolines Ergot -Rye ergot- Secale cornutum - Claviceps purpurea Secale cereale (rye); ~30 alkaloids; 3,4- substituted indoles! 0.15% total alkaloids (ergotoxine); d-Lysergic acid derivatives :-ine; d-isolysergic acid derivatives: -inine Simple amides: water-soluble ergine, ergometrine Peptide alkaloids: water-insoluble Ergotamine-, ergoxine- and ergotoxine groups

8. 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

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

10. Some important ergot alkaloids 1-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”, migraine 3-Bromocryptine: semisynthetic, dopaminergic activity, Parkinson disease, decrease prolactin secretion, supress lactation

11. 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.

12. Clinical features of ergot poisoning: Ergotism 1-Alimentary upsets: diarrhea, abdominal pain, vomiting 2-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”

13. 4- Derivatives of tryptophan + C9 orC10 • 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)

14. Condensation of tryptamine with secologanine Indolenine or ß-carboline type structures; In vivo : enzymatically, in vitro : pH=4.5 ß-carboline-type; pH=6.2 indolenine-type +

15. Rauwolfia serpentina (Apocynaceae) “snakeroot” • Indole alkaloids 0.7-2.5%; 0.15-0.2 reserpine 3 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

16. 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 disease Vincristine: childhood leukaemia, small-cell lung , cervical, breast cancer Vindesine: semisynthetic amide derivative of vinblastine: acute lymphoid leukaemia in children Vinorelbine: semisynthetic, derivative of anhydrovinblastine (orally active) VCR: 0.0002% (1g / 500 kg leaves) Semisynthesis (catharanthin+vindoline →vinblastine →vincristine) Folksmedicine: antidiabetic! Anticancer activity: serendipity discovery

17. Important Catharanthus alkaloids

18. 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-laryngology Arrythmias!

19. 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 killer Toxicity 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

20. Cinchona alkaloids The remarkable fact in the alkaloids of Cinchona is : rearrangement of the indole nucleus into the quinoline system and producing alkaloids having quinuclidine and quinolinenuclei 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)

21. 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)

22. Cinchona spp. (Rubiaceae) Cinchona bark C. 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 andquinidine, cinchonidineandcinchonine 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 falciparumto synthetic drugs → reintroduction of quinine; Mefloquine is 10x more active than quinine [GI-disturbances, dizziness,…]Chloroquine and OH-chloroquine: rheumatoid arthritis

23. 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. investigation Camptothecine active against path. protozoa Leishmania and Trypanosoma spp. 10-OH camptothecine

24. Important semi-synthetic analogues of camptothecine 9-aminocamptothecine Topotecan Irinotecan