Bioactive components of food and Medicinal plants. Pharmaceutical Nutraceutical

1. KJM5230 - H06
KJM5230 - Biologisk aktive molekyler
(Bioactive Molecules)
The cource discuss the organic chemistry
of important classes of drugs and bioactive natural products.
Synthesis / biosynthesis, mode of action,
bioavailability and stability for chosen drug classes.
Structure activity and structure optimalisation

2. KJM5230 - H06
Book
D. A. Williams; T. L. Lemke. Ò
FoyeÕ
s Principles of Medicinal ChemisrtyÓ5th
Ed.
LippincottWilliams&Wilkins., Philadelphia, 2002. ISBN 0-683-30737-1
Pensum
Part l:
Overwiev + Kap. 1-2; 4-5; 8:
Part II.
Sect. 6 Chemotherapeutical Agents:kap 34-39:
•Natural Products
•Drug Design
•Reseptors - Drug Action
•Drug Metabolism
•Antibiotics/Antimicrobial Agents
•Antiparasitic Agents
•Antifungal Agents
•Antimycobacterial Agents
•Anticancer Agents
•Antiviral Agents

3. KJM5230 - H06
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
Why new drugs?
Resistance
New diseases (Aging, life style)
Less tollerance for side effects
•Activity
•Toxicity
•Bioavailability
•Metabolism
in vitro
in vivo animals
in vivo humans
*Fortunate discovery by accident
“The three princes of Serendip” Persian Fairy tail
Serendip=Sri Lanka

4. KJM5230 - H06
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
Cocaine isol. 1860, local anestethic 1884
Benzylpenicillin 1941
Traditional medicine
Screening
Serendipity

5. KJM5230 - H06
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
HO
NH
O O O
O
OH
O
O
O
O
O
•Lead compounds
Hydrophilic
Aminogroup
(can be protonated)
Spacer
-Cn-X-
X: -CO2-
-CONH-
-NHCO-
Lipophilic
(Aryl)
N
CO2Me
O
O
Cocaine
O
O
N
NH2
Procaine
(1905)
N
H
N
Lidocaine/Xylocaine
(1946)
O
Acid labile ester

6. KJM5230 - H06
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
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
H
N
N
Cl
Epibatidine
painkiller, toxic!
potent inhibitor of certain nicotinic reseptors
N N
Nicotine

7. KJM5230 - H06
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

8. Sub types cholinerge reseptors
Nicotinerge
Muscarinerge
O
H
N
N
H
O
H
O
HO
N
Source
Amanita
muscaria
Nicotine from
Nicotiana tabacum
Acetylcholine
CNS
Effektor celle
Reseptor
Synapse
Acetylkolin
Noradrenalin
Det somatiske nervesystem Det autonome nervesystem
CNS CNS
Det sympatiske
nervesystem
Det parasympatiske
nervesystem
ganglion
Alkaloid Natural Products
Amino alkaloids: N as amine / amide (not in heterocycle)
Source Ephedra sinica
O
HO
N
(+) Muscarine
H
N
OH
(-)Efedrin
Biosynth from phenylalanine
NH2
CO2H
Bioactivity ÅAdrenaline
(Epinephrine) only weaker
H
N
OH
HO
HO
NH2
OH
HO
HO
Noradrenalin -
Neurotransmittor
Adrenalin - Hormone
N
O
O
O
H
ca. 5

9. KJM5230 - H06
Alkaloid Natural Products
Amino alkaloids
NH2
Mescaline
Biosynth from thyrosine
NH2
CO2H
HO
MeO
MeO
OMe
Source
Lophophora williamsi
Pyridine / piperidine alkaloids
N
N
Nicotine
N
O
O
O
O
Cocaine
Source
Erythroxylon coca
N
tropane
(8-methyl- 8-azabicyclo[3.2.1]octane)
N N
H
Pyridine Piperidine

10. KJM5230 - H06
Parasympatolytika
(Antikolinergika)
Tropanalkaloids
N
tropan
Atropa belladonna
Hyoscamus niger
(bulmeurt)
Source Atropa belladonna og Hyoscamus niger
N
O
O
OH
(±) Atropin
Base
N
O
O
OH
H
Muscle relax (guts, eye)
Scopolamin
N
O
O
OH
H
O
racimisation
base
Ester hydrol.
N
O
OH
H
O
HO
OH
Skopin Tropasyre
+
N
HO
O
Skopolin
Pyridine / piperidine alkaloids
N
O
O
O
H
ca. 5
"N"
O
O
R
R>Me
"N": Quart. or tert (protonated. in vivo)
distance as in AcCh
Antagonist:

11. KJM5230 - H06
Alkaloid Natural Products
Curare - Poison - Southamerican indians
Mixt. of alkaloids
Several sources i.e. Chondodendron tomentosum
Isoquinoline alkaloids
CNS
Effektor celle
Reseptor
Synapse
Acetylkolin
Noradrenalin
Det somatiske nervesystem Det autonome nervesystem
CNS CNS
Det sympatiske
nervesystem
Det parasympatiske
nervesystem
ganglion
MeO
N
Me
MeO
MeO
NH
Me
MeO
MeO
MeO
MeO
MeO
MeO
OMe
O
O
O
O
MeO
O
HO
O
OH
OMe
N
R
Me
N
Me
Me
R=H: Tubocurarin
R=Me: Wrong struct.
N N
Ex. Mivacurium klorid
Muscle relax, anesthesia
Cl
N
O
O
N
O
O
Cl
Esterase
Cl
N
OH
HO
N
O
O
Cl
HO
OH
Succinsyre
kolin
Suksametonium, Curacit® “Nesset”
N
Isoquinoline

12. KJM5230 - H06
Alkaloid Natural Products
Isoquinoline alkaloids
Morfin isolert fra opium 1803 (Morpheus: gresk søvngud)
O OH
HO
N
O
OH
HO
N
Morfin
O
OH
N
OH
H2N
OH
H
N
H
N
O
O
O
N
H
HO
NH
O
O
S
Met-enkefalin
Tyr N-terminal
hos opiopeptider
Morfinanalogs, binds to opiopeptide (endorfin / enkefalin) reseptors
Derivative of phenantrene
N
Isoquinoline

13. KJM5230 - H06
Naturally occuring and semisynth analgetic opioides
O OH
HO
N
Morphine
O OH
O
N
Codeine
also against cough
slow metabol. to morphine
Small amounts in opium, semisynth from morphine
O OH
O
N
CH3
O OH
HO
N
CH3
H3C
OH
pKa=10.0
OH
pKa ca 17
Base
O OH
O
N
CH3
N
H3C CH3
H3C
Ph OH
CH3-I
O OH
O
N
CH3
H3C
CH3-I
O OH
O
N
H3C
CH2
CH3
I
O OH
O
H3C
N
CH3
CH3
Hoffman
elim

14. KJM5230 - H06
Total synthetic analgetic opioides
SAR - morphine
Model of morphine bound to
m-reseptor
O OH
HO
N
CH3
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
OH increase (often)activity
Ether bridge not neccesary
O O
HO
N
OH
Nalokson
Antidote
O
HO
N
H
OH
Anion
cavity
H-bind acceptor
Lipophilic area
N
OH
O
Ketobemidon
Ketodur®,Ketorax®
Ketogan ®
N
N
O
Fenantyl
Fenantyl®, Leptanal®
(anestetica)
N
O
O
in vivo
HN
O
O
CNS eksitering
Petidin (Meperidin)
Ketodur®,Ketorax®
Moscow theatre
Morfin
O
OH
N
OH

15. KJM5230 - H06
O
N
OH
O
HO
Buprenorfin
Temgesic®, Subutex®
More potent than M. (pain)
Partiell m-agonist:
Antagonister high doses
Naloxon effects (dysfori etc)
N
O
O
Morfin
O
OH
N
OH
Dekstropropoksyfen
Aporex®
(+) most active
less adict. than M.
N
O
m-Agonist
analgetc, not euphoria,
Long duration
Good oral availabil.
Metadon
O OH
HO
N
CH3
O
O
Less active

16. KJM5230 - H06
Biosynthetic routes in Papaver somniferum
Codeine
Noskapin
(not analgetic,
not adiction)
O OH
O
N
CH3
O OH
HO
N
CH3
H3C
O O
O
N
CH3
H3C CH3
Thebaine Morfin
NH
OH
HO OH
OH
Norlaudanosoline
NH
OH
OH
HO
HO
N
O
O
O
O
O O
O
N
O
O
O
O
Papaverine
(against spasms)
NH2
HO
CO2H
Tyr
Naturally occuring and antitussiva opioides
O OH
O
N
CH3
O OH
HO
N
CH3
Morfin
Kodein
O OH
O
N
CH3
O OH
O
N
CH3
N
O
O O
O
N
CH3
Etylmorfin
Cosylan®
Hydrokon
Hydrokon®
Folkodin
Tuxi®

17. KJM5230 - H06
Alkaloid Natural Products
Quinoline alkaloids
Cinchona pubescens (Kinatre) from South America
N
R
HO N
H
R=OMe: Quinine (Cinchonidine epimer at C-9)
R=H: Quinidine (Cinchonine epimer at C-9)
Quinidine: Antiarytmic
Quinine: Antimalaria
N CF3
CF3
HO
N
H
Mefloquine
N Cl
HN
N
Chloroquine
Dihydroquini(di)ne and der.
Chiral ligands
Asym. dihydroxylation (Sharpless)
N
Quinoline

18. KJM5230 - H06
Alkaloid Natural Products
Indole alkaloids
N
H
HN
Melatonin
Hormone
MeO
O
N
H
CO2H
NH2
Tryptophan
Essential amino acid
N
H
NH2
Serotonin
Neurotransmitter
HO
N
H
CO2H
Auxine
Plant growthhormone
Psilocybe Mexicana
Psilocybe semilanceata
(Spiss fleinsopp)
Indole natural products
Rauwolfia serpentina
India, Thailand etc
OR
N
H
N
Halucinogens from Psilocybe mushroms
R=H: Psilocin
R=PO3H: Psilocybin
Serotoninagonists,
not broken down in the body
strong, continuos nerve impulse
in vivo
N
H
MeO
N
H
H
H
MeO2C
O
O
OMe
OMe
OMe
OMe
Reserpine
from Rauwolfia sp.
Reduce blood pressure
Indole
N
H

19. KJM5230 - H06
N
H
N
H
R'
O
R
Secale alkaloids and derivatives
from Claviceps purpurea (meldr¿ye)
X=H, R'=Me, R=OH: Lysergic acid
X=H, R'=Me, R=NEt2: LSD
X=H, R'=Me, R=-NHCH(Et)CH2OH: Metylergometrin,
Uterus contractions, drug used after birth
X=Br, R'=Me, R=
Bromokriptin, Parlodel¨
Prolactine inhibitor
X=H, R'=Allyl, R=
Kabergolin, Dostinexl ¨
Prolactine inhibitor
X=H, R'=Me, R=
Ergotamin, Anervanel ¨
Drug against migraine
X
N
H
N
O N
O
HO
O
N
NH
O
N
N
H
N
O N
O
HO
O
Vinca rosea
(Catharantus roseus)
From Madagaskar
Perivinkle
N
H
N
HO
MeO2C
MeO
N
R
N
H OCOMe
CO2Me
OH
R=-Me: Vinblastin, Oncovin ¨
R=-CHO: Vinkristin, Velbe ¨
Vinca alkaloids
from Vinca rosea
Anticancer comp.
R
R N
O
O
N
H
H
H
H
R= H; Strycnine
R=OMe; Brucine (1/50 of S. activity)
Muscle spasms
Strychnos alkaloids - from Strychnos nux vomica

20. KJM5230 - H06
Terpenoide Natural Products
O
Isopentenylpyrophosphate
(C-5)
P P
O P P
O
P
O
O
H
3 ATP
OH
HO
O
HO
Mevalonate
(C-6)
N
N N
N
NH2
O
O
OH
HO
P
O
OH
O
P
O
OH
O
P
O
OH
HO
ATP, Adenosine-5'-triphosphate
P
O
Isopentenylpyrophosphate
(C-5)
P P
Rearrange
O
Dimethylallylpyrophosphate
(C-5)
P P
O P P
H
O
trans-Geranylpyrophosphate
(C-10)
P P
Monoterpenes (C-10)
Ex.
OH
Geraniol (+) Limonene
C-10: Monoterpenes
C-15: Sesquiterpenes
C-20: Diterpenes
C-25: Sesterterpenes
C-30: Triterpenes
Natures leaving group

21. KJM5230 - H06
Monoterpenes Voilatile compds, smell, taste etc.
OH
trans-Geraniol
OH
(-)
O
(+) Camphor
The Chiral Pool
Pyrethrines
Insecticides from Chrysanthemum cinerariifolium
R
O
O
R'
C-10
Cl
Cl
O
O
O
Synth. analog
more stable
mixt of isomers
Permetrin, Nix®
Shampoo, Lice, scabies
C-10
O
H
H
OH
Tetrahydrocanabinol
O
O
H
H
OH
Nabilone
Antiemetic (not reg N.)
Cannabinoids,
from Cannabis sativa (Hemp)

22. KJM5230 - H06
Diterpenes (C-20) Isopentenyl-
pyrophosphate
(C-5)
O P P
H
O
trans-Geranylpyrophosphate
(C-10)
P P
O
trans, trans-Farnesylpyrophosphate
(C-15)
P P
Isopentenyl-
pyrophosphate
(C-5)
O P P
H
Sesquiterpenes
O
all trans-Geranylgeranylpyrophosphate
(C-20)
P
P
Diterpenes
HO
Phytol
N
N
N
N
Mg
O
CO2Me
H
H
H
O
O
Chlorophyll A
Vitaminee E (
O
HO
C-20
Vitamine K1
O
O
Head to tail coupling

23. KJM5230 - H06
Triterpenes (C-20) O
trans, trans-Farnesylpyrophosphate
(C-15)
P P O
P
P
+
tail to tail coupling
Squalene (C-30)
O
HO Lanosterol
H
Squalene
epoxidase
Enzyme-Nu
H
HO
H
H
Enz--Nu
H
Squalene
epoxide
cyclase
(Animals)
H
HO
Cycloartenol
H
HO
H
H
Enz--Nu
H
(Plants)
H
H
B
B
H
Stereoids

24. KJM5230 - H06
Stereoids
A B
C D
1
2
3
4
5
6
7
8
9
10
11
12
13
14 15
16
17
17
10
A / B trans fused
10
A / B cis fused
5a
B / C og C / D always trans (animals)
Cholesterol
Sex hormones
Estrogens
Progesterones
Testosteron and anabolic stereoids
Corticoids
Glucocorticostereoids
Cortison etc. etc.
Mineralcorticostereoidsr
Aldosterone
Digitalis glycosides
Fucidinic acid (antibiotic)
Brassinostereoids (Plant growth hormones)
etc. etc.
HO Lanosterol
(C-30)
H
20 steps
HO
H
H
H
Cholesterol
(C-27)

25. KJM5230 - H06
Sex hormones - Estrogenes
HO
H
H
H
O
Estrone
in vivo
HO
H
H
H
Estradiol
OH
HO
H
H
H
Estriol
OH
in vivo
(low activity)
(fast metabol)
OH
(low activity)
Used in drugs
HO
H
H
H
OH
H K
2 ekviv.
Ethinyl estradiol
(only estrogen im P-pills)
HO
H
H
H
Estradiol
OH
HO
OH
Dietylstilb¿strol
Estrogene agonist, drug before
HO
H
H
H
OH
HO
OH
A B
C D
Estrogene agonists (mimics)
(Cl)n
n(Cl)
PCB
Alkylphenols
HO
O
O
O
O
Phtalates
O
O
OH
HO
Genistein
(isoflavonoid)
OH
Phytoestrogen
(in soya)

26. KJM5230 - H06
Sex hormones - Progesterones (gestagenes, progestrines)
H
H
H
O
Progesterone
O
Metabolism
H
H
H
HO
HO
Many semisynth drugs in use (better bioavalabil.)
Testosterone
H
H
H
O
Testosterone
OH
5
H
H
O
OH
THG (tetrahydrogestrinon)
H
H
O
OH
Gestrinon
Doping - Anabolic stereoids
H
H
H
O
Testosterone
OH
H
H
H
O
Epi-testosteron
Only small androgene / anabole activity
Different biosynt. pathway than T
OH
Normal: T : E ratio ca 6 : 1
Doping T: E increases
E added to hide signs of doping

27. KJM5230 - H06
Semisynthesis sex hormones
HO
H
H H
O
O
Diosgenine
(6% in Yam roots, Dioscorea sp)
H+
Ac2O
AcO
H
H H
O
AcO
CrO3
AcO
H
H H
O
O
O
OR
H+/H2O
AcO
H
H H
O
Key-intermediate
Esterhydrol.,
H2O elim.
AcO
H
H H
O 1)H2 / cat.
2) Ester hydrol.
HO
H
H H
O
1) Ox. sec. ROH
2) Double bond migr. H
H H
O
O
Progesterone
Hydrocortisone etc
HO
H
H H
O
1) Stereosel .red of ketone (NaBH4)
(Attac less hindered side)
2) Ox sec. ROH
3) Double bond migr. H
H H
OH
O
Testosteron
1)red. doublebond
2) Ox sec. ROH
H
H H
O
O
H
Br2 / AcOH H
H H
O
O
H
Br
Br
Base
(- 2 HBr)
H
H H
O
O
Pyrolysis
600 oC
H
H H
O
HO
Estrone

28. KJM5230 - H06
Corticostereoids
Mineralcorticoid
O
H
H H
O
OH O
OH
Aldosterone
Regulation of elektrolyttic ballance
increase re-uptake of Na (and hence H20)
Glucocorticoid
H
H H
O
O
OH
HO OH
Hydrokortison
Effect on metabolism (karbohydrates, lipids, proteins)
Antiinflammatoric
Numerous semisynth. analogs as drugs
Various antiinflam. activity, mineralcorticoid side effects
H
H
H
O
Progesteron
O
Risopus
nigricans
H
H
H
O
O
HO
Oks H
H
H
O
O
O
NaBH4 H
H
H
O
O
HO
H
H H
O
O
OH
HO OH
Hydrokortison

29. KJM5230 - H06
Digitalis glycosides (cardenolides)
Digitalis purpurea
(foxglowe, revebjelle)
-Treatment of hart disease 1500 BC (Egypt)
-Increase hart contraction
-Tox.
O
OH
OH
OH
CH3
-D-digitoxose
A-B and C-D cis condens.
Digitoxin
Digitoxin® R= H
Digoxin
Lanoxin® R= OH
H
H OH
R
H
O
(Digitoxose)3
O O Aglycone: Biolog. activity
(KH part; solubility etc..)
H
H H
H
All trans
H
H
H
H
A-B cis, B-C trans. C-D cis
R
R R
R
Stability
•Acid: Cleavage of sugars (acidic hydro acetals)
•Base:
H
H OH
R
H
O
R
O O
OH
OH
O
O
HO
OH
O
O
HO
enol
OH
O
O
O
Aldehyde
taut.
Double bond
migr,
O
O
Hemiacetale
O
HO
OH
H
O
O
O
Acetale

30. KJM5230 - H06
Phenolic Natural Products
Biosynthesis from shikimate (- alkaloids)
CO2H
OH
OH
HO
Shikimate
CO2H
HO
OH
OH
Gallate
[ox]
O
O
O
P
Phosphoenol-
pyruvate
- H2O
CO2H
O
OH
Chorismate
CO2 N
H
CO2H
NH2
Trp
Alkaloids
Rearrange
ÅClaisen
OH
Chorismate
HO2C CO2
O
CO2H
OH
NH2
Tyr
Alkaloids
CO2H
NH2
Phe
Alkaloids
CO2
Cinnamate

31. KJM5230 - H06
From cinnamate
Voilatile compds,
smell, taste etc.,
Not monoterpenes
CO2
Cinnamate
Cinnemal
O
Anetol
OMe
Eugenol
OH
OMe
O
Vaniline
OH
OMe
OH
Thymol
Monoterpene
CO2
Cinnamate
2
O
O
O
OMe
OMe
MeO
OH
O
Podophyllotoxin
From Podophyllum peltarum
May apple
Antiviral, veneric warts
Toxic - lead for anticancer drugs
O
O
O
OH
OMe
MeO
O
Etoposide
O
O O
HO
HO

32. KJM5230 - H06
From cinnamate
CO2H CO2H
OH
CO2H
O
Glu
O
Glu
CO2H
O O
Coumarin
O O O
OH
OH
O
Dicoumarol
-Anticoagulant - Vit K antagonist
-Sweet clower disease
O O
OH
O
Warfarin - Marevan®
O
O
R
Vit. K
O O
O
O
O
H
H
Aflatoxine B1
Aflatoxines
-From Aspergillus flavus (fungus)
-Attacks nuts etc.
-Carcinogenic
O
O O
R
R'
R=R'=H: Psoralen
R=H, R'=OMe: Xantotoxin (8-MOP) -
Metoksalen - Geroxalen (R)
Psoralenes
-Isolated from various plants
-Photochemotherapy against psoriasis
-[2+2] cycloadd. With cytocin / thymin in DNA
O
O O
R
R'
HN
N
O
O
O
O O
R
R'
HN
N
N
N
O
O NH2
O
N
N
NH2
O
h