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

KJM5230 - H06
 Book
D. A. Williams; T. L. Lemke. “Foye’s Principles of Medicinal Chemisrty” 5th Ed.
LippincottWilliams&Wilkins., Philadelphia, 2002. ISBN 0-683-30737-1

Pensum
Part l: •Natural Products
•Drug Design
Overwiev + Kap. 1-2; 4-5; 8: •Reseptors - Drug Action
•Drug Metabolism

Part II. •Antibiotics/Antimicrobial Agents

•Antiparasitic Agents
Sect. 6 Chemotherapeutical Agents:kap 34-39:
•Antifungal Agents
•Antimycobacterial Agents
•Anticancer Agents
•Antiviral Agents
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 -
•Activity in vitro
•Design/Structure Optimisation •Toxicity
•Bioavailability
in vivo animals
•Actual Drug
•Metabolism in vivo humans

Why new drugs?

Resistance
New diseases (Aging, life style)
Less tollerance for side effects
KJM5230 - H06
*Fortunate discovery by accident
“The three princes of Serendip” Persian Fairy tail
Serendip=Sri Lanka
 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)
Traditional medicine Salicylic acid, antipyretic 1875
Screening Cocaine isol. 1860, local anestethic 1884
Serendipity Benzylpenicillin 1941

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 O O
NH OH
O

HO O
O O O O
O

Hydrophilic Spacer
Lipophilic
Aminogroup -Cn-X-
(Aryl)
•Lead compounds (can be protonated) X: -CO2-
-CONH-
-NHCO-

N
CO2Me N
NH2
N O
O O
N
O O H
Cocaine
Procaine Lidocaine/Xylocaine
(1905) (1946)
Acid labile esterKJM5230 - 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

H
Cl N
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 - 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

KJM5230 - H06
 Alkaloid Natural Products
Amino alkaloids: N as amine / amide (not in heterocycle)
OH
H
Biosynth from phenylalanine Bioactivity - Adrenaline
N NH2 (Epinephrine) only weaker
OH
H
CO2H HO N
Det somatiske nerves ystem Det autonome nervesys tem
(-)Efedrin
HO
Det sympatiske Det paras ympatis ke
Adrenalin - Hormone nervesystem nervesystem
CNS CNS CNS
OH

Source Ephedra sinica HO NH2

HO
ganglion
Noradrenalin -
Neurotransmittor Acetylkolin
Noradrenalin

Synapse

Reseptor
HO

N
Sub types cholinerge reseptors Effektor celle

(+) Muscarine Acetylcholine Muscarinerge Nicotinerge

ca. 5Å Nicotine from
HO
Nicotiana tabacum
N
Source O

Amanita O N
H H
muscaria O
N O
N

H
O
H
O
 Alkaloid Natural Products
Amino alkaloids

Biosynth from thyrosine

MeO NH2 NH2
Source
Lophophora williamsi
MeO CO2H
HO
OMe
Mescaline

Pyridine / piperidine alkaloids

N
N N N
H
Pyridine Piperidine Nicotine

N O
O
O
Source tropane
O
Erythroxylon coca (8-methyl- 8-azabicyclo[3.2.1]octane)
Cocaine
KJM5230 - H06
 ca. 5Å
Pyridine / piperidine alkaloids Antagonist: O

R "N"
O
Parasympatolytika
O
(Antikolinergika) N R>Me
O
"N": Quart. or tert (protonated. in vivo)
Tropanalkaloids distance as in AcCh
H
O
N

Source Atropa belladonna og Hyoscamus niger

N
tropan N  til C=O

Base
OH H OH
O O Muscle relax (guts, eye) Atropa belladonna
O O
(±) Atropin (-) Hyoscyamin

Scopolamin
N racimisation Hyoscamus niger
O base N H OH N (bulmeurt)
O HO
OH Ester hydrol. HO
H
+
O O
O OH O

Skopin Tropasyre Skopolin

KJM5230 - H06
 Alkaloid Natural Products N
Isoquinoline alkaloids Isoquinoline
Det somatiske nerves ystem Det autonome nervesys tem Curare - Poison - Southamerican indians
Det sympatiske Det paras ympatis ke Mixt. of alkaloids
CNS
nervesystem
CNS
nervesystem
CNS
Several sources i.e. Chondodendron tomentosum

R
MeO
N
ganglion Me R=H: Tubocurarin
Acetylkolin O
R=Me: Wrong struct.
Noradrenalin HO

Synapse O
OH
Me N N
Reseptor N
OMe
Effektor celle Me

MeO

Ex. Mivacurium klorid MeO

Muscle relax, anesthesia MeO
Me
MeO
Suksametonium, Curacit® “Nesset” N O
MeO
MeO O
O O O
N O Esterase N OH HO
N O
O N OH HO NH
MeO
O O Me
Cl Cl
Cl kolin Succinsyre Cl
MeO

KJM5230 - H06 MeO OMe

 Alkaloid Natural Products N

Isoquinoline alkaloids Isoquinoline

Morfin isolert fra opium 1803 (Morpheus: gresk søvngud)

HO O OH

Derivative of phenantrene

Morfinanalogs, binds to opiopeptide (endorfin / enkefalin) reseptors

S
O
HO
N N
N H
O
OH O NH
H H
O N N
O
H2 N O
HO O
OH
OH Met-enkefalin
Morfin KJM5230 - H06 Tyr N-terminal
OH hos opiopeptide r
Naturally occuring and semisynth analgetic opioides
Morphine
Codeine
N
N also against cough
slow metabol. to morphine
HO O OH O
O OH
Small amounts in opium, semisynth from morphine

CH3 CH3 CH3

N N H3C CH3 N
N OH
Base H3C
Ph

HO O OH O O OH H3C O O OH

CH3-I
I CH3
OH OH CH2
CH3 N
N N CH CH3
3 Hoffman
pKa=10.0 pKa ca 17 CH3-I elim

H3C O O OH H3C O O OH O
H3C O OH

KJM5230 - H06
 Total synthetic analgetic opioides Model of morphine bound to
m-reseptor
SAR - morphine N
Anion
OH
Must be tert N.
cavity
N-CH3: agonist
N-R (3-4 C, unsat. or ring): antagonist HO O O H
N-R (large): agonist: Ph-CH2CH2 10X more active enn -CH3 Nalokson N
Antidote Lipophilic area

N
CH3 OH increase (often)activity H-bind acceptor

HO O OH
N
HO O OH
OH

O
Ether bridge not neccesary
Morfin OH

Petidin (Meperidin)
Ketodur®,Ketorax® Fenantyl Ketobemidon
Fenantyl®, Leptanal® Ketodur®,Ketorax®
N
(anestetica) Ketogan ®
O
O N
N
N
in vivo O O

OH
HN Moscow theatre
O
O KJM5230 - H06
CNS eksitering
 N Dekstropropoksyfen Metadon
OH Aporex®
O N
N
Morfin OH
O O

O
m-Agonist
analgetc, not euphoria,
(+) most active
Buprenorfin Long duration
less adict. than M.
Temgesic®, Subutex® Good oral availabil.

CH3
N
HO

N
O
O
O HO O OH
O

OH Less active m-agonist

More potent than M. (pain)

N N
Partiell m-agonist:
Antagonister high doses
Naloxon effects (dysfori etc) O O in vivo O
O O O HO O O

Heroin bether m-agonist than morphine

increased BBB penetration
bad m-agonist

KJM5230 - H06
 Naturally occuring and antitussiva opioides
O Papaverine
Biosynthetic routes in Papaver somniferum O
N (against spasms)
O

NH2 O

CO2H NH HO O
NH O N
HO OH HO
OH O O
O
Tyr
HO OH OH Noskapin O
OH
Norlaudanosoline (not analgetic, O
not adiction)

CH3 CH3 CH3

N N N

H3C O O O CH3 H3C O O OH HO O OH

Thebaine Codeine Morfin

CH3 CH3
CH3 N N
N

HO O OH O
O O OH O OH

Morfin
Kodein Etylmorfin
Cosylan®

CH3 CH3
N N
Hydrokon Folkodin
Hydrokon® Tuxi®
O O O O O OH KJM5230 - H06
O N
 Alkaloid Natural Products
Quinoline alkaloids
Cinchona pubescens (Kinatre) from South America

N
Quinoline

H
HO N
R=OMe: Quinine (Cinchonidine epimer at C-9)
R

N R=H: Quinidine (Cinchonine epimer at C-9)

Quinidine: Antiarytmic
Quinine: Antimalaria

HO
N
H
HN
N Dihydroquini(di)ne and der.
N CF3
Chiral ligands
CF3 Asym. dihydroxylation (Sharpless)
N Cl
Chloroquine Mefloquine

KJM5230 - H06
 Alkaloid Natural Products
N
H
Indole natural products Indole

CO2H O
HO NH2 MeO CO2H
HN
NH2
N N
H H N
N H
H Serotonin Melatonin Auxine
Tryptophan Neurotransmitter Hormone Plant growth hormone
Essential amino acid

Indole alkaloids
Halucinogens from Psilocybe mushroms
N
OR
R=H: Psilocin in vivo Rauwolfia serpentina
R=PO3H: Psilocybin India, Thailand etc
N
H Serotoninagonists,
OMe
not broken down in the body
strong, continuos nerve impulse H OMe
N
O
N H OMe
Psilocybe semilanceata MeO
H O
(Spiss fleinsopp) H
Psilocybe Mexicana MeO2C OMe
Reserpine
from Rauwolfia sp.
KJM5230 - H06 Reduce blood pressure
Vinca alkaloids Secale alkaloids and derivatives
R
from Vinca rosea from Claviceps purpurea (meldrøye)
Anticancer comp. O R'
N
HO H X=H, R'=Me, R=OH: Lysergic acid
N X=H, R'=Me, R=NEt 2: LSD
X
N N X=H, R'=Me, R=-NHCH(Et)CH 2OH: Metylergometrin,
N H Uterus contractions, drug used after birth
H H OCOMe HO
MeO2C CO2Me O N
N
MeO OH X=Br, R'=Me, R= N
R N O
Bromokriptin, Parlodel ® H
R=-Me: Vinblastin, Oncovin ® O
Prolactine inhibitor
R=-CHO: Vinkristin, Velbe ® O
NH
X=H, R'=Allyl, R= N
Kabergolin, Dostinexl®
Vinca rosea Prolactine inhibitor N
(Catharantus roseus)
From Madagaskar
Perivinkle HO
O N
X=H, R'=Me, R= N N O
Strychnos alkaloids - from Strychnos nux vomica H
Ergotamin, Anervanel ® O
Drug against migraine
N
R
H H
R N
H
O
HO

R= H; Strycnine
R=OMe; Brucine (1/50 of S. activity)

Muscle spasms KJM5230 - H06

 Terpenoide Natural Products NH2
N N

O O O N N
P
HO P O P O P O O
O OH OH OH
HO 3 ATP
O P
O P P P HO OH
OH P
H Isopentenylpyrophosphate ATP, Adenosine-5'-triphosphate
HO O O O
Mevalonate (C-5)
(C-6)

Rearrange O P P
O P P O P P O P P
H

Isopentenylpyrophosphate Dimethylallylpyrophosphate trans-Geranylpyrophosphate

(C-5) (C-5) (C-10)

C-10: Monoterpenes Monoterpenes (C-10)

C-15: Sesquiterpenes Ex.
C-20: Diterpenes
C-25: Sesterterpenes OH
C-30: Triterpenes
Geraniol (+) Limonene

Natures leaving group

KJM5230 - H06
 Monoterpenes Voilatile compds, smell, taste etc.

OH O
OH OH
HO OH

OH
trans-Geraniol (-)-citronellol (-) Linalool (+)--Terpineol (-)-Menthol (+)-Carvone Thymol

(+) Camphor -Pinene -Pinene

The Chiral Pool
Pyrethrines
Insecticides from Chrysanthemum cinerariifolium Cannabinoids,
R' from Cannabis sativa (Hemp)
R

O
OH C-10
O H

C-10 H O
O
OH
O H
Tetrahydrocanabinol
Cl Permetrin, Nix® H
O O
Cl O
Shampoo, Lice, scabies
Synth. analog Nabilone
more stable KJM5230 - H06 Antiemetic (not reg N.)
mixt of isomers
 Diterpenes (C-20) Isopentenyl- Isopentenyl-
pyrophosphate pyrophosphate
(C-5) (C-5)
O P P
O P P O P P
O P P H
H

trans-Geranylpyrophosphate trans, trans-Farnesylpyrophosphate

(C-15)
(C-10) Head to tail coupling

Sesquiterpenes
O P P

all trans-Geranylgeranylpyrophosphate
(C-20)

HO
Diterpenes
Phytol

N
Vitamine K1 H O
O N Mg N
N H O
C-20 CO2Me Chlorophyll A
HO H
O
O

Vitaminee E (-Tocopherol)
KJM5230 - H06
Triterpenes (C-20) O P P + P P O

trans, trans-Farnesylpyrophosphate
(C-15) tail to tail coupling

Squalene (C-30)

Enzyme-Nu
Enz--Nu H
Squalene
Squalene epoxide
cyclase B H
epoxidase H

HO Lanosterol
H
HO
O H (Animals)
H
Stereoids
Enz--Nu H

H H
B H H

HO
H Cycloartenol
HO
H (Plants)

KJM5230 - H06
 Stereoids
12 17
11 13
1 C D 16
20 steps 9
10
H 2 14 15
A B 8
17
H H 7 17
3
HO Lanosterol HO 5
H 4 6
(C-30) Cholesterol
(C-27)

Cholesterol

Sex hormones
Estrogens
Progesterones
Testosteron and anabolic stereoids B / C og C / D always trans (animals)

Corticoids A / B trans fused A / B cis fused

Glucocorticostereoids
Cortison etc. etc.
Mineralcorticostereoidsr
Aldosterone

Digitalis glycosides
10
10
Fucidinic acid (antibiotic)
5

Brassinostereoids (Plant growth hormones)

5
KJM5230 - H06
etc. etc.
 Sex hormones - Estrogenes
O OH OH

H in vivo H H OH
in vivo
H H H H H H
HO HO HO
(fast metabol)
Estrone Estradiol Estriol (low activity)
(low activity)

H K Used in drugs
2 ekviv.

Estrogene agonists (mimics)

OH OH
OH
H Ethinyl estradiol
H
(only estrogen im P-pills) OH
H H C D H H OH
HO HO
HO
A B H
HO
H H
HO
Dietylstilbøstrol
Estrogene agonist, drug before Estradiol

Phytoestrogen
Alkylphenols
(in soya) PCB
OH (Cl)n
OH O HO
n(Cl) Phtalates
HO O O

Genistein O
(isoflavonoid) O
KJM5230 - H06
O
 Sex hormones - Progesterones (gestagenes, progestrines)

O HO
Many semisynth drugs in use (better bioavalabil.)
Metabolism
H H

H H H H
O HO
Progesterone

OH OH

H
Testosterone H
5-reduktase
H H H H
O O
H
Testosterone 5-Dihydrotestosterone (5DHT)
More active A-B ring trans
Cis isomer inaktive

OH OH

H H
Doping - Anabolic stereoids H H H H
O O
OH OH
Testosterone Epi-testosteron
H H Only small androgene / anabole activity
H
Different biosynt. pathway than T
H
O O
Normal: T : E ratio ca 6 : 1
THG (tetrahydrogestrinon) Gestrinon Doping T: E increases

E added to hide signs of doping

KJM5230 - H06
 Semisynthesis sex hormones

AcO
O O
H+ OR
O H
Ac2O CrO3 H+/H2O
H O H O H O
H H
H H H H H H O AcO
HO AcO AcO Esterhydrol.,
H2O elim. Key-intermediate
Diosgenine
(6% in Yam roots, Dioscorea sp)

O O

O 1)H2 / cat. H
1) Ox. sec. ROH
H
H 2) Ester hydrol. 2) Double bond migr.
H H H H
H H HO O
AcO Progesterone

1) Stereosel .red of ketone (NaBH4)

O
(Attac less hindered side) OH
2) Ox sec. ROH
H 3) Double bond migr. H Hydrocortisone etc
H H H H
HO O
Testosteron
1)red. doublebond
2) Ox sec. ROH
O O O O

H Base Pyrolysis H
Br2 / AcOH H H
Br (- 2 HBr) 600 oC
H H H H H H H H
O O O HO
H H Estrone
Br

KJM5230 - H06
 Corticostereoids

Mineralcorticoid
OH O
OH
O
Aldosterone
H
Regulation of elektrolyttic ballance
H H increase re-uptake of Na (and hence H20)
O

Glucocorticoid
OH
O
HO OH
Effect on metabolism (karbohydrates, lipids, proteins)
H Antiinflammatoric
H H
O Numerous semisynth. analogs as drugs
Hydrokortison Various antiinflam. activity, mineralcorticoid side effects

OH
O O O O O
Risopus HO O HO OH
HO
nigricans Oks H NaBH4 H
H H H
H H H H H H H H
H H
O O O O
O
Progesteron Hydrokortison

KJM5230 - H06
 Digitalis glycosides (cardenolides)

-Treatment of hart disease 1500 BC (Egypt)

-Increase hart contraction
-Tox.
O O Aglycone: Biolog. activity
 (KH part; solubility etc..)
R 
 -lactone
Digitoxin
H CH3
OH Digitoxin® R= H
H OH O
(Digitoxose)3 O
H Digoxin
OH -D-digitoxose
OH Lanoxin® R= OH
A-B and C-D cis condens.
All trans A-B cis, B-C trans. C-D cis
Digitalis purpurea R R
R R
(foxglowe, revebjelle) H H
H H H H
H H

Stability
•Acid: Cleavage of sugars (acidic hydro acetals)
•Base: O O
O O O O O O O HO O O O
HO HO O
R
OH H
O O
H Double bond taut.
migr, OH
H OH OH OH OH
R O enol Hemiacetale Acetale
H Aldehyde

KJM5230 - H06
 Phenolic Natural Products

Biosynthesis from shikimate (- alkaloids)

O
CO2H CO2H CO2H
O CO2H
O
[ox] NH2
HO OH HO OH P O CO2 N
OH H Trp
OH OH
Phosphoenol- Chorismate
Gallate Shikimate pyruvate

- H2O Rearrange Alkaloids

- Claisen
CO2H
CO2 CO2H
HO2C CO2
NH2
NH2
O
Alkaloids
OH
OH
Cinnamate Phe Chorismate Tyr

Alkaloids

KJM5230 - H06
From cinnamate
Monoterpene

CO2 O O

Voilatile compds,
OMe OMe
smell, taste etc., OH

Cinnamate OMe OH OH Not monoterpenes

Thymol
Cinnemal Anetol Eugenol Vaniline

From Podophyllum peltarum

OH May apple
O Antiviral, veneric warts
CO2 O
O
2 O Toxic - lead for anticancer drugs

MeO OMe
Cinnamate OMe
OO
Podophyllotoxin HO
HO

O
O
O
O
O

MeO OMe
OH
Etoposide

KJM5230 - H06
From cinnamate

CO2H CO2H CO2H

OH CO2H
O O O O
Glu Glu
Coumarin

Dicoumarol
-Anticoagulant - Vit K antagonist OH OH
Psoralenes -Sweet clower disease
-Isolated from various plants
O OO O
-Photochemotherapy against psoriasis
O
-[2+2] cycloadd. With cytocin / thymin in DNA O
OH Vit. K
R
R
R=R'=H: Psoralen O O O
R=H, R'=OMe: Xantotoxin (8-MOP) -
O O O (R) Warfarin - Marevan®
Metoksalen - Geroxalen
R'
O
O Aflatoxines
O
N N
O
-From Aspergillus flavus (fungus)
N N
HN R NH2 HN R -Attacks nuts etc.
O O NH2 -Carcinogenic
N h N O
O O O O O O
R' R' O O O
H H
KJM5230 - H06 O Aflatoxine B 1