Download alkaloides

KJM5230 - Biologisk aktive molekyler
Kurset omhandler organisk kjemiske forhold hos sentrale legemiddelgrupper
og bioaktive naturstoffer.
Emnet omhandler syntese/biosyntese, virkningsmekanisme, biotilgjengelighet og
stabilitet for utvalgte stoffklasser.
Struktur-aktivitets forhold og strukturoptimalisering inngår også i kurset.
KJM5230-H04
Lærebok
D. A. Williams; T. L. Lemke. “Foye’s Principles of Medicinal Chemisrty” 5th Ed.
LippincottWilliams&Wilkins., Philadelphia, 2002. ISBN 0-683-30737-1
Pensum
Generell del – Part l:
Overwiev + Kap. 1-2; 4-5; 7-8:
•Natural Products
•Drug Design
•Reseptors - Drug Action
•Pysichemical/Biopharmaceut. Properties
•Drug Metabolism
•Antibiotics/Antimicrobial Agents
•Antiparasitic Agents
Sect. 6 Chemotherapeutical Agents:kap 34-39:
•Antifungal Agents
•Antimycobacterial Agents
•Anticancer Agents
•Antiviral Agents
Spesiell del – Part II.
KJM5230-H04
Origin of Drugs / Bioactive Compounds
•Natural Products / Natural Product Derivatives
•Random testing, serendipity
•Screening of Libraries
•(Rational) Drug Design (1. mentioned SciFinder 1970, most papers after 1990)
•Screening/Design/Serendipity
•Lead compound •Design/Structure Optimisation
•Actual Drug
•Activity
•Toxicity
•Bioavailability
•Metabolism
Why new drugs?
Resistance
New diseases (Aging, life style)
Less tollerance for side effects
KJM5230-H04
in vitro
in vivo animals
in vivo humans
Origin of Drugs / Bioactive Compounds: History
Before 1800: Plants, plant extracts, inorganic material
1805: Morphine isolated from opium (sructure proposed 1935, prooved by synth. 1952)
1828: First organic synthesis (urea)
1840-1850: First synthesized org. compds used in medicine: CHCl3, Et2O anestechia)
Ex of early synthetic drugs:
Choral hydrate (sleeping pill) 1869
Acetyl salicylic acid synth 1853, clin trials 1893
Phenazone synth 1884
Benzocaine 1902
Prontocil 1932
Ex of early isolated nat. prod.
Quinine ca 1825
Digitoxin 1841 (structure 1928)
Salicylic acid, antipyretic 1875
Traditional medicine
Cocaine isol. 1860, local anestethic 1884
Screening
Benzylpenicillin 1941
Serendipity
KJM5230-H04
Origin of Drugs / Bioactive Compounds
•Natural Products / Natural Product Derivatives
•Random testing, serendipity*
•Screening of Libraries
•(Rational) Drug Design (1. mentioned SciFinder 1970, most papers after 1990)
•Screening/Design/Serendipity
•Lead compound •Design/Structure Optimisation
•Actual Drug
•Activity
•Toxicity
•Bioavailability
•Metabolism
Why new drugs?
Resistance
New diseases (Aging, life style)
Less tollerance for side effects
KJM5230-H04
in vitro
in vivo animals
in vivo humans
*Fortunate discovery by accident
“The three princes of Serendip” Persian Fairy tail
Serendip=Sri Lanka
Natural Products
•Only source of drugs before last part of 19th century
•Antibiotics 1940 - 1960
•Cyclosporin (immunomodulator) isolated from soil fungus Hardangervidda 1971
•Taxol isolated 1960s, approved drug USA 1992
O
O
O
O
OH
NH
O
HO
O
O
O O
O
O
•Lead compounds
Hydrophilic
Aminogroup
(can be protonated)
N
N
CO2Me
O
Cocaine
NH2
O
O
O
Procaine
(1905)
N
O
N
H
Lidocaine/Xylocaine
(1946)
Acid labile ester
KJM5230-H04
Spacer
-Cn-XX: -CO2-CONH-NHCO-
Lipophilic
(Aryl)
Natural Products
Sources
•Microorganisms (bacteria, fungus) - Antibiotics
•Higher plants, ex. morphine, quinine, taxol
•Sponges (polycellular “animals”, no real organs or cell tissue) ex. agelasines
•Higher animals, fewer examples, epibatidine from South American tree frog
H
N
Cl
N
N
N
Epibatidine
Nicotine
painkiller, toxic!
potent inhibitor of certain nicotinic reseptors
Microorganisms, sponges, plants
No immune system, produce their own antibiotics as defence
Secondary metabolites with great structural diversity, stereochemistry!
Secondary metabolites have no known metabolic role in cells
Three main classes: alkaloids, terpenoids, phenolics
KJM5230-H04
Alkaloid Natural Products
•Largets class of secondary metabolites, >6500 compds known
•Contains N, most compds basic (alkaline)
•Often highly toxic
•Found in certain higher plants (seldom in bacteria)
•Little is known regarding why alkaloides are produced
•Biosynthesis from amino acids
KJM5230-H04
Alkaloid Natural Products
Amino alkaloids: N as amine / amide (not in heterocycle)
Biosynth from phenylalanine
OH H
N
Bioactivity - Adrenaline (Epinephrine) only weaker
NH2
CO2H
HO
(-)Efedrin
Det somatiske nerves ystem
Det autonome nervesys tem
CNS
Det sympatiske Det paras ympatis ke
nervesystem
nervesystem
CNS
CNS
OH H
N
HO
Source Ephedra sinica
ganglion
Acetylkolin
Noradrenalin
Synapse
Reseptor
HO
O
N
(+) Muscarine
Sub types cholinerge reseptors
Acetylcholine
Muscarinerge
ca. 5Å
HO
Source
Amanita
muscaria
O
O
O
N
Effektor celle
Nicotinerge
Nicotine from
Nicotiana tabacum
N
O
O H
N
H
H
N
O
KJM5230-H04
H
Alkaloid Natural Products
Amino alkaloids
Biosynth from thyrosine
MeO
NH2
MeO
OMe
NH2
HO
CO2H
Source
Lophophora williamsi
Mescaline
Pyridine / piperidine alkaloids
N
N
Nicotine
N
N
O
O
O
Isolert fra
Erythroxylon coca
O
tropane
Cocaine
(8-methyl- 8-azabicyclo[3.2.1]octane)
KJM5230-H04
Pyridine / piperidine alkaloids
Parasympatolytika
(Antikolinergika)
ca. 5Å
Gen. blokker
O
O
Tropanalkaloider
O
N
R
N
O
O
"N"
R>Me
"N": kvart el. tert (protoner. in vivo)
ca. samme avst. som AcCh
H
Isolert fra Atropa belladonna og Hyoscamus niger
tropan
N
 til C=O
N
Base
OH
OH
H
O
Relaksering av tarmmuskel,
pupillutvidelse
Esterhydrolyse også mulig
i basisk miljø
O
O
O
(±) Atropin
Atropa belladonna
(-) Hyoscyamin
Scopolamin
racimisation
base
N
O
H
OH
Ester hydrol.
N
H
O
HO
+
O
O
HO
O
O
OH
Skopin
N
OH
Tropasyre
KJM5230-H04
Skopolin
Hyoscamus niger
(bulmeurt)
Mer CNS dempende enn atropin
reisesykeplaster
karmpeløsende
pupilutvidende
beroligende
“sanhetsserum”
Alkaloid Natural Products
Pyridine / piperidine alkaloids
ca. 5Å
Semisyntetiske tropanalkaloider
O
O
N
O
O
N
Gen. blokker
R
"N"
O
H
N
N
OH
OH
OH
O
N
O
O
Atropin
R>Me
"N": kvart el. tert (protoner. in vivo)
ca. samme avst. som AcCh
O
O
Homatropin
Tropikamid
KJM5230-H04
øyedr.
korterevirketid
Alkaloid Natural Products
Isoquinoline alkaloids
Det somatiske nerves ystem
Det autonome nervesys tem
CNS
Det sympatiske Det paras ympatis ke
nervesystem
nervesystem
CNS
CNS
Curare - Pilgift - Søramerikanske indianere
Bland. Av flere alkaloider med muskeslammende effekt
Flere plantekilder bl.a. Chondodendron tomentosum
R
MeO
N
ganglion
Me
O
Acetylkolin
Noradrenalin
R=H: Tubocurarin
R=Me: Wrong struct.
HO
O
Synapse
OH
Me
N
Reseptor
N
OMe
Me
Effektor celle
N
MeO
Ex. Mivacurium klorid
Muscle relax, anesthesia
N
O
N
Esterase
N
OH
Cl
OH
HO
HO
N
O
O
Cl
Cl
kolin
Me
N
O
MeO
MeO
O
O
MeO
MeO
Suksametonium, Curacit® “Nesset”
O
MeO
Succinsyre
O
O
O
NH
MeO
Me
Cl
MeO
KJM5230-H04
MeO
OMe
Alkaloid Natural Products
Isoquinoline alkaloids
Morfin isolert fra opium 1803 (Morpheus: gresk søvngud)
N
O
HO
OH
Derivative of phenantrene
Morfinanalogs, binds to opiopeptide (endorfin / enkefalin) reseptors
S
O
HO
N
N
OH
O
O
HO
O
O
H
N
H2 N
OH
O
NH
H
N
O
Met-enkefalin
OH
Morfin
N
H
KJM5230-H04
OH
Tyr N-terminal
hos opiopeptide r
Naturally occuring and semisynth analgetic opioides
Morphine
Codeine
N
HO
O
also against cough
slow metabol. to morphine
N
OH
N
O
O
CH3
N
CH3
H3C
Base
HO
O
OH
Small amounts in opium, semisynth from morphine
OH
H3C
O
O
N
N
CH3
Ph
CH3
OH
OH
O
H3C O
OH
CH3-I
OH
pKa=10.0
OH
N
CH2
N CH
CH3
3
CH3-I
pKa ca 17
H3C O
O
OH
I
H3C O
KJM5230-H04
O
OH
CH3
N
CH3
Hoffman
elim
H3C O
O
OH
Oxycodon (not natural. occur.)
CH3
N
OH
H3C O
O
O
Biosynth.
morphine
H3C O
N
CH3
O
N
O CH3
H3C O
Thebain
CH3
O
N
OH
HO
Kodein
CH3
N
OH
CH3
N
OH
H2 / kat.
O
O
H3C O
O
O
Oksykodon
KJM5230-H04
O
Morfin
H2O2
AcOH
H3C O
CH3
OH
Model of morphine bound to
m-reseptor
Total synthetic analgetic opioides
SAR - morphine
Anion
N
Must be tert N.
N-CH3: agonist
N-R (3-4 C, unsat. or ring): antagonist
N-R (large): agonist: Ph-CH2CH2 10X more active enn -CH3
CH3
N
OH
cavity
O
HO
O
Nalokson
Antidote
OH increase (often)activity
N
Lipophilic area
H-bind acceptor
HO
N
HO
O
OH
OH
O
Ether bridge not neccesary
Morfin
Petidin (Meperidin)
Ketodur®,Ketorax®
N
O
OH
Fenantyl
Fenantyl®, Leptanal®
(anestetica)
Ketobemidon
Ketodur®,Ketorax®
Ketogan ®
N
O
N
N
in vivo
O
O
OH
Moscow theatre
HN
O
O
CNS eksitering
H
KJM5230-H04
O
OH
Dekstropropoksyfen
Aporex®
N
OH
Metadon
O
N
N
Morfin
OH
O
O
m-Agonist
analgetc, not euphoria,
Long duration
Good oral availabil
O
(+) most active
less adict. than M.
Buprenorfin
Temgesic®, Subutex®
N
HO
CH3
N
O
O
O
OH
More potent than M. (pain)
Partiell m-agonist:
Antagonister i høye doser
Naloxon effects (dysfori etc)
HO
O
O
OH
Less active m-agonist
N
O
O
O
N
O
in vivo
O
Heroin
increased BBB penetration
bad m-agonist
KJM5230-H04
HO
O
O
O
bether m-agonist than morphine
Naturally occuring and antitussiva opioides
O
Biosynthetic routes in Papaver somniferum
Papaverine
(against spasms)
N
O
O
O
NH2
CO2H
NH
HO
HO
O
NH
HO
OH
OH
Tyr
HO
OH
OH
OH
Norlaudanosoline
N
O
H3C O
O
O
CH3
N
HO
OH
O
O
O
N
OH
O
Morfin
Kodein
N
CH3
CH3
O
N
Hydrokon
Hydrokon®
O
O
N
O
O
CH3
OH
Etylmorfin
Cosylan®
CH3
Folkodin
Tuxi®
OH
KJM5230-H04
O
Noskapin
(not analgetic,
not adiction)
CH3
O CH3
Thebaine
N
N
O
N
H3C O
O
O
O
O
O
CH3
OH
Codeine
N
HO
CH3
O
Morfin
OH
Alkaloid Natural Products
Cinchona pubescens (Kinatre) from South America
Quinoline alkaloids
H
N
HO
R=OMe: Quinine (Cinchonidine epimer at C-9)
R
N
R=H:
Quinidine (Cinchonine epimer at C-9)
Quinidine: Antiarytmic
Quinine: Antimalaria
N
HN
N
Cl
Chloroquine
HO
N
H
N
CF3
CF3
Mefloquine
Dihydroquini(di)ne and der.
Chiral ligands
Asym. dihydroxylation (Sharpless)
KJM5230-H04
Alkaloid Natural Products
Indole natural products
CO2H
NH 2
N
H
Tryptophan
Essential amino acid
HO
NH2
O
MeO
N
H
Serotonin
Neurotransmitter
CO2H
HN
N
H
Melatonin
Hormone
N
H
Auxine
Plant growth hormone
Indole alkaloids
N
OR
Halucinogens from Psilocybe sopper
R=H: Psilocin
R=PO3H: Psilocybin
N
H
Rauwolfia serpentina
India, Thailand etc
in vivo
Serotoninagonists,
not broken down in the body
strong, continuos nerve impulse
OMe
N
Psilocybe semilanceata
(Spiss fleinsopp)
Psilocybe Mexicana
MeO
KJM5230-H04
N H
H
H
MeO2C
OMe
H
O
O
OMe
Reserpine
from Rauwolfia sp.
Reduce blood pressure
OMe
Vinca alkaloids
from Vinca rosea
Anticancer comp.
HO
Secale alkaloids and derivatives
from Claviceps purpurea (meldrøye)
R
O
N
R'
H
X=H, R'=Me, R=OH: Lysergic acid
X=H, R'=Me, R=NEt 2: LSD
N
N
H
N
N
H
MeO2C
MeO
H
X
OCOMe
CO2Me
N
OH
R
R=-Me: Vinblastin, Oncovin ®
R=-CHO: Vinkristin, Velbe®
Vinca rosea
(Catharantus roseus)
From Madagaskar
Perivinkle
Strychnos alkaloids - from Strychnos nux vomica
N
R
H
R
N
O
H
H
HO
R= H; Strycnine
R=OMe; Brucine (1/50 of S. activity)
Muscle spasms
KJM5230-H04
X=H, R'=Me, R=-NHCH(Et)CH2OH: Metylergometrin,
Uterus contractions, drug used after birth
HO
O
N
X=Br, R'=Me, R=
N
N
O
Bromokriptin, Parlodel ® H O
Prolactine inhibitor
O
NH
X=H, R'=Allyl, R=
N
Kabergolin, Dostinexl®
N
Prolactine inhibitor
N
X=H, R'=Me, R=
H
Ergotamin, Anervanel ®
Drug against migraine
HO
O
N
O
N
O
Terpenoide Natural Products
NH2
N
N
HO
O
3 ATP
O
OH
HO
H
O
O
P
P
P
P
P
Isopentenylpyrophosphate
O
Mevalonate
(C-6)
O
O
P
N
N
O
O
O
HO P O P O P O
OH OH OH
P
O
HO
OH
ATP, Adenosine-5'-triphosphate
(C-5)
Rearrange
O
P
P
P
O
P
P
O
H
P
P
Isopentenylpyrophosphate
Dimethylallylpyrophosphate
trans-Geranylpyrophosphate
(C-5)
(C-5)
(C-10)
Monoterpenes (C-10)
Ex.
C-10: Monoterpenes
C-15: Sesquiterpenes
C-20: Diterpenes
C-25: Sesterterpenes
C-30: Triterpenes
KJM5230-H04
OH
Geraniol
(+) Limonene
Monoterpenes
Voilatile compds, smell, taste etc.
OH
O
OH
OH
OH
HO
OH
trans-Geraniol
(-)-citronellol
(-) Linalool
(+)--Terpineol
(-)-Menthol
Thymol
(+)-Carvone
O
-Pinene
(+) Camphor
-Pinene
The Chiral Pool
Pyrethrines
Insecticides from Chrysanthemum cinerariifolium
Cannabinoids, from Cannabis sativa (Hemp)
R'
R
O
H
O
OH
C-10
H
C-10
O
Tetrahydrocanabinol
Permetrin, Nix®
Cl
O
Cl
O
O
O
OH
H
Shampoo, Lice, scabies
Synth. analog
more stable
mixt of isomers
H
KJM5230-H04
O
Nabilone
Antiemetic (not reg N.)
Diterpenes (C-20)
P
O
Isopentenylpyrophosphate
(C-5)
O P
P
P
O
P
P
H
Isopentenylpyrophosphate
(C-5)
O P
P
H
trans, trans-Farnesylpyrophosphate
(C-15)
trans-Geranylpyrophosphate
(C-10)
Sesquiterpenes
O
P
all trans-Geranylgeranylpyrophosphate
(C-20)
HO
Diterpenes
Phytol
O
N
Vitamine K1
O
N Mg N
C-20
HO
O
Vitaminee E (-Tocopherol)
KJM5230-H04
O
O
H
CO2Me
H
N
O
H
Chlorophyll A
P
Triterpenes (C-20)
O
P
P
trans, trans-Farnesylpyrophosphate
(C-15)
+
P
P
O
tail to tail coupling
Squalene (C-30)
Enzyme-Nu
Enz--Nu
Squalene
epoxide
cyclase B
Squalene
epoxidase
H
H
H
HO
HO
O
Lanosterol
H
(Animals)
H
H
Stereoids
Enz--Nu
B
H
H
H
H
H
HO
HO
H
KJM5230-H04
H
Cycloartenol
(Plants)
Stereoids
12
13
11
1
20 steps
2
H
H
HO
H
Lanosterol
(C-30)
HO
B
A
H
C
D
8
16
14 15
17
7
3
Cholesterol
(C-27)
9
10
17
4
5
6
Cholesterol
Sex hormones
Estrogens
Progesterones
Testosteron and anabolic stereoids
Corticoids
B / C og C / D always trans
A / B trans fused
Glucocorticostereoids
Cortison etc. etc.
Mineralcorticostereoidsr
Aldosterone
A / B cis fused
Digitalis glycosides
Fucidinic acid (antibiotic)
5
Brassinostereoids (Plant growth hormones)
etc. etc.
10
10
5
KJM5230-H04
17
Sex hormones - Estrogenes
OH
O
H
H
H
in vivo
H
H
H
H
HO
HO
OH
in vivo
(fast metabol)
H
H
H
HO
Estradiol
Estrone
(low activity)
OH
Estriol
(low activity)
Used in drugs
K
2 ekviv.
Estrogene agonists (mimics)
OH
OH
Ethinyl estradiol
(only estrogen im P-pills)
H
H
H
OH
H
C
D
HO
A B
HO
HO
H
H
H
Dietylstilbøstrol
Estrogene agonist, drug before
OH O
n(Cl)
HO
HO
Phtalates
O
O
Genistein
(isoflavonoid)
Estradiol
Alkylphenols
(Cl)n
H
HO
PCB
OH
OH
H
HO
Phytoestrogener
(in soya)
OH
O
O
KJM5230-H04
O
Sex hormones - Progesterones (gestagenes, progestrines)
HO
O
H
H
Many semisynth drugs in use (better bioavalabil.)
Metabolism
H
H
H
H
HO
O
Progesterone
OH
H
H
OH
Testosterone
H
5-reduktase
H
H
O
O
H
H
5-Dihydrotestosterone (5DHT)
More active A-B ring trans
Cis isomer inaktive
Testosterone
OH
OH
H
OH
OH
O
Epi-testosteron
Only small androgene / anabole activity
Different biosynt. pathway than T
O
O
THG (tetrahydrogestrinon)
Gestrinon
H
O
H
H
H
H
Testosterone
H
H
H
H
Doping - Anabolic stereoids
Normal: T : E ratio ca 6 : 1
Doping T: E increases
E added to hide signs of doping
KJM5230-H04
Semisynthesis sex hormones
AcO
O
O
H
H
H+
Ac2O
H
H
CrO3
O
H
H
H
AcO
HO
H
O
OR
O
O
H
O
H
H
H+/H2O
AcO
Esterhydrol.,
H2O elim.
Diosgenine
(6% in Yam roots, Dioscorea sp)
Key-intermediate
O
O
H
H
1)H2 / cat.
2) Ester hydrol.
O
1) Ox. sec. ROH
2) Double bond migr.
H
H
H
H
H
H
HO
H
O
AcO
Progesterone
O
H
H
1) Stereosel .red of ketone (NaBH4)
(Attac less hindered side)
2) Ox sec. ROH
3) Double bond migr.
OH
Hydrocortisone etc
H
H
H
H
O
HO
Testosteron
1)red. doublebond
2) Ox sec. ROH
O
H
H
O
H
AcO
H
O
Br2 / AcOH
Base
(- 2 HBr)
H
Br
H
H
O
Br
H
O
O
Pyrolysis
600 oC
H
H
H
O
KJM5230-H04
H
H
H
HO
H
Estrone
Corticostereoids
Mineralcorticoid
OH O
OH
O
Aldosterone
Regulation of elektrolyttic ballance
increase re-uptake of Na (and hence H20)
H
H
H
O
Glucocorticoid
OH
O
OH
HO
H
H
Effect on metabolism (karbohydrates, lipids, proteins)
Antiinflammatoric
H
Numerous semisynth. analogs as drugs
Various antiinflam. activity, mineralcorticoid side effects
O
Hydrokortison
O
Risopus
nigricans
H
H
HO
H
O
O
Oks
H
H
O
O
O
H
H
H
O
H
H
H
Progesteron
OH
HO
HO
NaBH4
H
O
OH
O
O
H
H
H
O
Hydrokortison
KJM5230-H04
Digitalis glycosides (cardenolides)
-Treatment of hart disease 1500 BC (Egypt)
-Increase hart contraction
-Tox.
Aglycone: Biolog. activity
O
O

(KH part; solubility etc..)

R
-lactone

H
H
(Digitoxose)3 O
CH3
OH
O
H
OH
OH
OH
-D-digitoxose
Digitoxin
Digitoxin® R= H
Digoxin
Lanoxin® R= OH
A-B and C-D cis condens.
A-B cis, B-C trans. C-D cis
All trans
Digitalis purpurea
(foxglowe, revebjelle)
R
R
R
H
H
R
H
H
H
H
H
Stability
•Acid: Cleavage of sugars (acidic hydro acetals)
•Base:
O
O
HO
R
O
O
HO
O
O
O
O
H
R O
H
OH
OH
Double bond
migr,
HO O
O
O
O
OH
H
H
O
taut.
OH
enol
KJM5230-H04
O
OH
OH
Aldehyde
H
Hemiacetale
Acetale
O
Phenolic Natural Products
Biosynthesis from shikimate (- alkaloides)
O
CO2H
CO2H
CO2H
O
[ox]
HO
OH
CO2H
O
HO
OH
OH
Gallate
Shikimate
O
P
OH
NH2
CO2
N
H
OH
Phosphoenolpyruvate
Trp
Chorismate
- H2O
Rearrange
Alkaloids
- Claisen
CO2
CO2H
NH2
CO2H
HO2C
CO2
O
OH
Cinnamate
Phe
NH2
Chorismate
Alkaloids
KJM5230-H04
Alkaloids
OH
Tyr
From cinnamate
Monoterpene
O
CO2
O
OMe
OMe
Cinnamate
Cinnemal
Anetol
OH
OH
Eugenol
Vaniline
From Podophyllum peltarum
May apple
OH
CO2
OMe
O
OH
Thymol
Antiviral, veneric warts
O
O
Toxic - lead for anticancer drugs
O
2
MeO
Cinnamate
Voilatile compds,
smell, taste etc.,
Not monoterpenes
OMe
OMe
OO
HO
HO
Podophyllotoxin
O
O
O
O
O
MeO
OMe
OH
Etoposide
KJM5230-H04
From cinnamate
CO2H
CO2H
CO2H
OH
CO2H
O
Glu
O
Glu
O
O
Coumarin
Dicoumarol
-Anticoagulant - Vit K antagonist
-Sweet clower disease
Psoralenes
-Isolated from various plants
-Photochemotherapy against psoriasis
-[2+2] cycloadd. Withcytocin / thymin in DNA
OH
O
OO
O
O
O
OH
Vit. K
R
R
O
OH
O
R=R'=H: Psoralen
R=H, R'=OMe: Xantotoxin (8-MOP) Metoksalen - Geroxalen
O
R'
O
N
HN
O
NH2
R
O
O
N
h
N
O
O
R'
O
N
HN
N
R
O
O
Warfarin - Marevan®
(R)
O
O
O
NH2
N
Aflatoxines
-From Aspergillus flavus (fungus)
-Attacks nuts etc.
-Carcinogenic
O
O
O
O
R'
KJM5230-H04
O
H
O
O
H
O
Aflatoxine B 1