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: •Natural Products
•Drug Design
Overwiev + Kap. 1-2; 4-5; 7-8: •Reseptors - Drug Action
•Pysichemical/Biopharmaceut. Properties
•Drug Metabolism

Spesiell del – Part II. •Antibiotics/Antimicrobial Agents

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

Why new drugs?

Resistance
New diseases (Aging, life style)
Less tollerance for side effects

KJM5230-H04
 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-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 - •Activity
•Design/Structure Optimisation in vitro
•Toxicity
•Bioavailability in vivo animals
•Actual Drug in vivo humans
•Metabolism

Why new drugs?

Resistance
New diseases (Aging, life style)
Less tollerance for side effects
KJM5230-H04
*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
NH OH
O

HO O
O O O O
O

•Lead compounds Hydrophilic Spacer

Lipophilic
Aminogroup -Cn-X-
N (Aryl)
N (can be protonated) X: -CO2-
CO2Me NH2 N -CONH-
O -NHCO-
O O
N
O O H
Cocaine
Procaine Lidocaine/Xylocaine
(1905) (1946)
Acid labile ester

KJM5230-H04
 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-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)

OH H Biosynth from phenylalanine Bioactivity ≈ Adrenaline (Epinephrine) only weaker

N NH2 Det somatiske nervesystem Det autonome nervesystem
OH H
CO2H N Det sympatiske Det parasympatiske
HO nervesystem nervesystem
(-)Efedrin CNS CNS CNS
HO
Source Ephedra sinica
ganglion
Acetylkolin
Noradrenalin

Synapse

Reseptor
HO
Effektor celle
N Sub types cholinerge reseptors
O

(+) Muscarine Acetylcholine Muscarinerge Nicotinerge

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

H
O

KJM5230-H04
 Alkaloid Natural Products
Amino alkaloids

Biosynth from thyrosine

MeO NH2 NH2 Source
CO2H
Lophophora williamsi
MeO HO
OMe
Mescaline

Pyridine / piperidine alkaloids

N
Nicotine

N O
O Isolert fra
O
Erythroxylon coca
O

Cocaine tropane
(8-methyl- 8-azabicyclo[3.2.1]octane)

KJM5230-H04
Pyridine / piperidine alkaloids ca. 5Å
Gen. blokker
Parasympatolytika
R>Me
(Antikolinergika) O
O
"N" "N": kvart el. tert (protoner. in vivo)
N R O
O ca. samme avst. som AcCh
Tropanalkaloider
H
O
N

Isolert fra Atropa belladonna og Hyoscamus niger

tropan α til C=O
N N Relaksering av tarmmuskel,
Base
pupillutvidelse
OH H OH
O O Esterhydrolyse også mulig Atropa belladonna
O O i basisk miljø
(±) Atropin (-) Hyoscyamin

Scopolamin
N racimisation Hyoscamus niger
O base N H OH N (bulmeurt)
O HO
OH Ester hydrol. HO
H
+
O O
O
Mer CNS dempende enn atropin
O OH
reisesykeplaster
Skopin Tropasyre Skopolin karmpeløsende
pupilutvidende
KJM5230-H04
beroligende
“sanhetsserum”
 Alkaloid Natural Products

Pyridine / piperidine alkaloids

ca. 5Å
Gen. blokker

Semisyntetiske tropanalkaloider O
O R>Me
R "N" "N": kvart el. tert (protoner. in vivo)
N O
O ca. samme avst. som AcCh
H
O

N
N
N
OH OH
OH
O N øyedr.
O
O O korterevirketid
Atropin O

Homatropin Tropikamid

KJM5230-H04
 Alkaloid Natural Products
Isoquinoline alkaloids
Det somatiske nervesystem Det autonome nervesystem Curare - Pilgift - Søramerikanske indianere
Det sympatiske Det parasympatiske Bland. Av flere alkaloider med muskeslammende effekt
CNS
nervesystem
CNS
nervesystem
CNS
Flere plantekilder bl.a. 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-H04 MeO OMe

 Alkaloid Natural Products
Isoquinoline alkaloids
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-H04 Tyr N-terminal
OH hos opiopeptider
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 H3 C CH3 N
N OH
Base H3 C
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

H3 C O O OH H3 C O O OH O
H3 C O OH

KJM5230-H04
Oxycodon (not natural. occur.)
CH3
N
OH

H3C O O O

CH3 CH3 CH3

Biosynth. N N N

morphine

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

Thebain Kodein Morfin

H2O2
AcOH
CH3 CH3
N N
OH OH
H2 / kat.

H3 C O O O H3 C O O O
Oksykodon

KJM5230-H04
 Total synthetic analgetic opioides Model of morphine bound to
-reseptor
Anion
SAR - morphine N
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-H04
CNS eksitering
 N Dekstropropoksyfen Metadon
OH Aporex®
O N
N
Morfin OH
O O

O
-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 μ-agonist

More potent than M. (pain)

N N
Partiell -agonist:
Antagonister i høye doser
Naloxon effects (dysfori etc) O O in vivo O
O O O HO O O

Heroin bether μ-agonist than m orphine

increased BBB penetration
bad μ-agonist

KJM5230-H04
 Naturally occuring and antitussiva opioides
O Papaverine
Biosynthetic routes in Papaver somniferum O
N (against spasms)
O

NH2 O

CO 2 H 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

Kodein Morfin
Etylmorfin
Cosylan®

CH3 CH3
N N
Hydrokon Folkodin
Hydrokon® Tuxi®
O O O O O OH KJM5230-H04
O N
 Alkaloid Natural Products
Cinchona pubescens (Kinatre) from South America
Quinoline alkaloids

H
HO N

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

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

Quinidine: Antiarytmic
Quinine: Antimalaria

HO
N N
HN H

N CF3
N Cl
CF3
Chloroquine
Mefloquine

Dihydroquini(di)ne and der.

Chiral ligands
Asym. dihydroxylation (Sharpless)

KJM5230-H04
 Alkaloid Natural Products
Indole natural products

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

Indole alkaloids

Halucinogens from Psilocybe sopper

N
OR Rauwolfia serpentina
R=H: Psilocin in vivo
R=PO3H: Psilocybin India, Thailand etc
N
H Serotoninagonists, OMe
not broken down in the body OMe
strong, continuos nerve impulse N H
O
N H OMe
Psilocybe semilanceata MeO O
H H
(Spiss fleinsopp) Psilocybe Mexicana OMe
MeO2C
Reserpine
from Rauwolfia sp.
KJM5230-H04 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)CH2OH: 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
R=-Me: Vinblastin, Oncovin ® Bromokriptin, Parlodel® H 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-H04

 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 P P
OH O P P HO OH
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)

Monoterpenes (C-10)
Ex.
C-10: Monoterpenes
C-15: Sesquiterpenes OH
C-20: Diterpenes Geraniol (+) Limonene
C-25: Sesterterpenes
C-30: Triterpenes

KJM5230-H04
 Monoterpenes Voilatile compds, smell, taste etc.

OH O
OH OH
HO OH

OH
trans-Geraniol (-)−β-citronellol (-) Linalool (+)-α-Terpineol (-)-Menthol (+)-Carvone Thym ol

(+) Camphor α-Pinene β-Pinene

The Chiral Pool

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

O OH C-10
H
O
H
C-10 O O

OH
O Tetrahydrocanabinol H

Cl Permetrin, Nix® H
O O
Cl O
Shampoo, Lice, scabies
Synth. analog Nabilone
more stable KJM5230-H04 Antiemetic (not reg N.)
mixt of isomers
 Diterpenes (C-20) Isopentenyl- I sopentenyl-
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)

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 (α-Tocopherol)
KJM5230-H04
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 Cy c lo arte no l
HO
H (Plants)

KJM5230-H04
 Stereoids
12 17
11 13
1 C D 16
20 steps 9
10
2 14 15
H
A B 8
17β
17α
H H 3 7
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

Corticoids A / B trans fused A / B cis fused

Glucocorticostereoids
Cortison etc. etc.
Mineralcorticostereoidsr
Aldosterone

Digitalis glycosides
10β
10β
Fucidinic acid (antibiotic)
5α

Brassinostereoids (Plant growth hormones)

5α
etc. etc. KJM5230-H04
 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

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

Genistein O
(isoflavonoid) O
KJM5230-H04
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
5α-reduktase
H H H H
O O
H
Testosterone 5α-D ihydrotestosterone (5D HT)
More active A-B ring trans
Cis isom er 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 H Different biosynt. pathway than T
O O

THG (tetrahydrogestrinon) Gestrinon 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+ O
OR
CrO3 H
O Ac2O O O H+/H2O
H H H
H H
H H H H O AcO
H H
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-H04
 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-H04
 Digitalis glycosides (cardenolides)

-Treatment of hart disease 1500 BC (Egypt)

-Increase hart contraction
-Tox.
O O Aglycone: Biolog. activity
γ (KH part; solubility etc..)
R α
β γ-lactone
Digitoxin
H CH3
OH Digitoxin® R= H
H OH O
(Digitoxose)3 O
H
OH
Digoxin
β-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-H04
 Phenolic Natural Products

Biosynthesis from shikimate (- alkaloides)

O
CO 2 H CO2H CO 2 H
O CO 2 H
O
[ox] NH2
HO OH HO OH P O CO 2 N
OH H Trp
OH OH
Phosphoenol- Chorismate
Gallate Shikimate pyruvate

- H2O Rearrange Alkaloids

≈Claisen
CO 2 H
CO 2 CO 2H
HO 2 C CO 2
NH2
NH2
O
Alkaloids
OH
OH
Cinnamate Phe Chorismate Tyr

Alkaloids

KJM5230-H04
From cinnamate
Monoterpene

CO2 O O

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

Me O OMe
Cinnamate OMe
OO
Podophyllotoxin HO
HO

O
O
O
O
O

MeO OMe
OH
Etoposide

KJM5230-H04
 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. Withcytocin / 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 Warfarin - Marevan®
Metoksalen - Geroxalen (R)
R'
O
O Aflatoxines
N N -From Aspergillus flavus (fungus)
O O N N
HN R NH2 HN R -Attacks nuts etc.
O O NH2 -Carcinogenic
N hν N O
O O O O O O
R' R' O O O
H H
KJM5230-H04 O Aflatoxine B1