(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

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?ResistanceNew diseases (Aging, life style)Less tollerance for side effects

•Activity•Toxicity•Bioavailability•Metabolism

in vitroin vivo animalsin vivo humans

*Fortunate discovery by accident“The three princes of Serendip” Persian Fairy tail Serendip=Sri Lanka

KJM5230 - H06

Origin of Drugs / Bioactive Compounds: HistoryBefore 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) 1869Acetyl salicylic acid synth 1853, clin trials 1893Phenazone synth 1884Benzocaine 1902Prontocil 1932

Ex of early isolated nat. prod.Quinine ca 1825Digitoxin 1841 (structure 1928)Salicylic acid, antipyretic 1875Cocaine isol. 1860, local anestethic 1884Benzylpenicillin 1941

Traditional medicineScreeningSerendipity

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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

OHO

NH

O O O

O

OH

OO

O

OO

•Lead compounds

HydrophilicAminogroup(can be protonated)

Spacer-Cn-X-X: -CO2- -CONH- -NHCO-

Lipophilic(Aryl)

N

CO2Me

O

OCocaine

O

O

N NH2

Procaine (1905)

NH

N

Lidocaine/Xylocaine(1946)

O

Acid labile ester

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

HN

N

Cl

Epibatidinepainkiller, toxic!potent inhibitor of certain nicotinic reseptors

N N

Nicotine

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

Sub types cholinerge reseptors

NicotinergeMuscarinerge

OH

N

NHO

H

O

HO

NSourceAmanita muscaria

Nicotine fromNicotiana 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 ProductsAmino alkaloids: N as amine / amide (not in heterocycle)

Source Ephedra sinica

O

HO

N

(+) Muscarine

HN

OH

(-)Efedrin

Biosynth from phenylalanine

NH2

CO2H

Bioactivity Adrenaline (Epinephrine) only weaker

HN

OH

HO

HO

NH2

OH

HO

HO

Noradrenalin - Neurotransmittor

Adrenalin - Hormone

NO

O

OH

ca. 5Å

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Alkaloid Natural Products

Amino alkaloids

NH2

Mescaline

Biosynth from thyrosine

NH2

CO2HHO

MeO

MeOOMe

SourceLophophora williamsi

Pyridine / piperidine alkaloids

N

N

Nicotine

N

O

O

O

O

Cocaine

SourceErythroxylon coca

N

tropane

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

N NH

Pyridine Piperidine

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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

OHH

til C=O

(-) Hyoscyamin

Muscle relax (guts, eye)

Scopolamin

N

O

O

OHH

Oracimisationbase

Ester hydrol.

N

O

OHHO HO

OH

Skopin Tropasyre

+

NHO

O

Skopolin

Pyridine / piperidine alkaloids

NO

O

OH

ca. 5Å

"N"O

O

R

R>Me"N": Quart. or tert (protonated. in vivo)

distance as in AcCh

Antagonist:

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Alkaloid Natural Products

Curare - Poison - Southamerican indiansMixt. of alkaloidsSeveral 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

MeON

Me

MeO

MeONH

Me

MeO

MeO

MeO

MeO

MeO

MeO

OMe

O

OO

O

MeO

O

HO

OOH

OMe

NR

Me

NMe

Me

R=H: TubocurarinR=Me: Wrong struct.

N N

Ex. Mivacurium kloridMuscle relax, anesthesia

Cl

NO

ON

O

O

Cl

Esterase

Cl

NOH

HON

O

O

Cl

HOOH

Succinsyrekolin

Suksametonium, Curacit® “Nesset”

N

Isoquinoline

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Alkaloid Natural ProductsIsoquinoline alkaloids

Morfin isolert fra opium 1803 (Morpheus: gresk søvngud)

O OHHO

N

OOHHO

N

Morfin

O

OHN

OH

H2N

OH

H N H

NO

OO

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

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Naturally occuring and semisynth analgetic opioides

O OHHO

N

Morphine

O OHO

N

Codeinealso against coughslow metabol. to morphine

Small amounts in opium, semisynth from morphine

O OHO

NCH3

O OHHO

NCH3

H3C

OH

pKa=10.0

OH

pKa ca 17

Base

O OHO

NCH3

NH3C CH3

H3C Ph OH

CH3-I

O OHO

NCH3

H3C

CH3-I

O OHO

N

H3C

CH2

CH3

I

O OHOH3C

NCH3

CH3Hoffmanelim

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Total synthetic analgetic opioides

SAR - morphine

Model of morphine bound to-reseptor

O OHHO

NCH3

Must be tert N.N-CH3: agonistN-R (3-4 C, unsat. or ring): antagonistN-R (large): agonist: Ph-CH2CH2 10X more active enn -CH3

OH increase (often)activity

Ether bridge not neccesary

O OHO

NOH

NaloksonAntidote

OHO

NH

OH

Anion

cavity

H-bind acceptor

Lipophilic area

N

OH

O

KetobemidonKetodur®,Ketorax®Ketogan ®

N

N

O

FenantylFenantyl®, Leptanal®(anestetica)N

O

O

in vivo

HN

O

O

CNS eksitering

Petidin (Meperidin)Ketodur®,Ketorax®

Moscow theatre

Morfin

O

OHN

OH

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O

N

OH

O

HO

BuprenorfinTemgesic®, Subutex®

More potent than M. (pain)Partiell -agonist:Antagonister high dosesNaloxon effects (dysfori etc)

N

O

O

Morfin

O

OHN

OH

DekstropropoksyfenAporex®

(+) most activeless adict. than M.

N

O

-Agonistanalgetc, not euphoria, Long durationGood oral availabil.

Metadon

O OHHO

NCH3

OO

Less active -agonist

O OO

N

O O

Heroinincreased BBB penetrationbad -agonist

in vivoO OHO

N

O

bether -agonist than morphine

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Biosynthetic routes in Papaver somniferum

Codeine

Noskapin(not analgetic,not adiction)

O OHO

NCH3

O OHHO

NCH3

H3CO OO

NCH3

H3C CH3

Thebaine Morfin

NH

OHHO OH

OH

Norlaudanosoline

NH

OH

OH

HO

HON

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 OHO

NCH3

O OHHO

NCH3

MorfinKodein

O OHO

NCH3

O OHO

NCH3

NOO OO

NCH3

EtylmorfinCosylan®

HydrokonHydrokon®

FolkodinTuxi®

KJM5230 - H06

Alkaloid Natural ProductsQuinoline alkaloids

Cinchona pubescens (Kinatre) from South America

N

R

HO NH

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

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

Quinidine: AntiarytmicQuinine: Antimalaria

N CF3CF3

HONH

MefloquineN Cl

HNN

Chloroquine

Dihydroquini(di)ne and der.Chiral ligandsAsym. dihydroxylation (Sharpless)

N

Quinoline

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Alkaloid Natural Products

Indole alkaloids

N H

HN

MelatoninHormone

MeOO

N H

CO2H

NH2

Tryptophan

Essential amino acid

N H

NH2

SerotoninNeurotransmitter

HO

N H

CO2H

Auxine Plant growth hormone

Psilocybe Mexicana

Psilocybe semilanceata(Spiss fleinsopp)

Indole natural products

Rauwolfia serpentina India, Thailand etc

OR

NH

NHalucinogens from Psilocybe mushroms

R=H: PsilocinR=PO3H: Psilocybin

Serotoninagonists, not broken down in the bodystrong, continuos nerve impulse

in vivo

N HMeO

N

H

H

HMeO2C

O

OOMe

OMe

OMe

OMe

Reserpine from Rauwolfia sp. Reduce blood pressure

Indole

NH

KJM5230 - H06

N H

NH

R'O

RSecale alkaloids and derivatives from Claviceps purpurea (meldrøye)

X=H, R'=Me, R=OH: Lysergic acidX=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

NNH

O

N

N H

N

O N

O

HO

O

Vinca rosea (Catharantus roseus)From Madagaskar Perivinkle

N H

N

HO

MeO2CMeO

NR

N

H OCOMe

CO2MeOH

R=-Me: Vinblastin, Oncovin ®R=-CHO: Vinkristin, Velbe®

Vinca alkaloids from Vinca roseaAnticancer comp.

R

R N

OO

N

H

H

H

H

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

Muscle spasms

Strychnos alkaloids - from Strychnos nux vomica

KJM5230 - H06

Terpenoide Natural Products

O

Isopentenylpyrophosphate

(C-5)

P PO P P

O

P

OOH

3 ATPOH

HO

OHO

Mevalonate(C-6)

N

N N

N

NH2

OO

OHHO

PO

OHOP

O

OHOP

O

OHHO

ATP, Adenosine-5'-triphosphate

P

O

Isopentenylpyrophosphate

(C-5)

P PRearrange

O

Dimethylallylpyrophosphate

(C-5)

P PO P P

HO

trans-Geranylpyrophosphate

(C-10)

P P

Monoterpenes (C-10)Ex.

OH

Geraniol (+) Limonene

C-10: MonoterpenesC-15: SesquiterpenesC-20: DiterpenesC-25: SesterterpenesC-30: Triterpenes

Natures leaving group

KJM5230 - H06

Monoterpenes Voilatile compds, smell, taste etc.

OH

trans-Geraniol

OH

(-) -citronellol (-) Linalool

OH

OH

(+)--Terpineol (-)-Menthol

HO

(+)-Carvone

O

OH

Thymol

O

(+) Camphor -Pinene -Pinene

The Chiral Pool

PyrethrinesInsecticides from Chrysanthemum cinerariifolium

R

OO

R'

C-10

Cl

ClO

O

O

Synth. analogmore stablemixt of isomers

Permetrin, Nix®

Shampoo, Lice, scabies

C-10

O

H

HOH

Tetrahydrocanabinol

O

O

H

HOH

NabiloneAntiemetic (not reg N.)

Cannabinoids, from Cannabis sativa (Hemp)

KJM5230 - H06

Diterpenes (C-20) Isopentenyl-pyrophosphate(C-5)

O P PH

O

trans-Geranylpyrophosphate

(C-10)

P PO

trans, trans-Farnesylpyrophosphate(C-15)

P P

Isopentenyl-pyrophosphate(C-5)

O P PH

SesquiterpenesO

all trans-Geranylgeranylpyrophosphate(C-20)

PP

DiterpenesHO

Phytol

N

NN

N

Mg

O

CO2Me

H

H

H

O

O

Chlorophyll A

Vitaminee E (-Tocopherol)

O

HO

C-20

Vitamine K1

O

O

Head to tail coupling

KJM5230 - H06

Triterpenes (C-20) O

trans, trans-Farnesylpyrophosphate(C-15)

P P OPP+

tail to tail coupling

Squalene (C-30)

O

HO LanosterolH

Squaleneepoxidase

Enzyme-Nu

H

HOH

H

Enz--Nu

H

Squalene epoxide cyclase

(Animals)

H

HO CycloartenolHHO

H

H

Enz--Nu

H

(Plants)

H

HB

B

H

Stereoids

KJM5230 - H06

Stereoids

A B

C D1

2

3

45

6

7

8

910

11

1213

14 15

16

17

17 17

10

5

A / B trans fused

10

A / B cis fused

5

B / C og C / D always trans (animals)

Cholesterol

Sex hormonesEstrogensProgesteronesTestosteron and anabolic stereoids

CorticoidsGlucocorticostereoids

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)

KJM5230 - H06

Sex hormones - Estrogenes

HO

H

HH

O

Estrone

in vivo

HO

H

HH

Estradiol

OH

HO

H

HH

Estriol

OH

in vivo

(low activity)

(fast metabol)

OH

(low activity)

Used in drugs

HO

H

HH

OH

H K

2 ekviv.

Ethinyl estradiol(only estrogen im P-pills)

HO

H

HH

Estradiol

OH

HO

OH

DietylstilbøstrolEstrogene agonist, drug before

HO

H

HH

OH

HO

OH

A B

C D

Estrogene agonists (mimics)

(Cl)n

n(Cl)

PCBAlkylphenols

HO

OO

O

O

PhtalatesO

OOH

HO

Genistein(isoflavonoid)

OH

Phytoestrogen(in soya)

KJM5230 - H06

Sex hormones - Progesterones (gestagenes, progestrines)

H

HHO

Progesterone

O

MetabolismH

HHHO

HO

Many semisynth drugs in use (better bioavalabil.)

TestosteroneH

HHO

Testosterone

OH

5-reduktaseH

HHO

5-Dihydrotestosterone (5DHT)More active A-B ring transCis isomer inaktive

OH

H

H

HO

OH

THG (tetrahydrogestrinon)

H

HO

OH

Gestrinon

Doping - Anabolic stereoidsH

HHO

Testosterone

OH

H

HHO

Epi-testosteronOnly small androgene / anabole activityDifferent biosynt. pathway than T

OH

Normal: T : E ratio ca 6 : 1Doping T: E increases

E added to hide signs of doping

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

OO

O

OR

H+/H2O

AcO

H

H H

O

Key-intermediateEsterhydrol., H2O elim.

AcO

H

H H

O 1)H2 / cat.2) Ester hydrol.

HO

H

H H

O

1) Ox. sec. ROH2) 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. ROH3) Double bond migr. H

H H

OH

O

Testosteron1)red. doublebond2) Ox sec. ROH

H

H H

O

OH

Br2 / AcOH H

H H

O

OH

Br

BrBase(- 2 HBr)

H

H H

O

O

Pyrolysis600 oC

H

H H

O

HOEstrone

KJM5230 - H06

Corticostereoids

Mineralcorticoid

O

H

H H

O

OH OOH

AldosteroneRegulation of elektrolyttic ballanceincrease 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 drugsVarious antiinflam. activity, mineralcorticoid side effects

H

HHO

Progesteron

O

Risopus nigricans

H

HHO

O

HOOks H

HHO

O

ONaBH4 H

HHO

O

HOH

H H

O

O

OH

HO OH

Hydrokortison

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.

DigitoxinDigitoxin® R= H

DigoxinLanoxin® R= OH

H

H OH

R

HO(Digitoxose)3

O O Aglycone: Biolog. activity(KH part; solubility etc..)-lactone

H

H H

H

All trans

H

H

H

H

A-B cis, B-C trans. C-D cisR

R RR

Stability•Acid: Cleavage of sugars (acidic hydro acetals)•Base:

H

H OH

R

HOR

O O

OH

OH

OOHO

OH

OOHO

enolOH

OOO

Aldehyde

taut.Double bond migr,

OO

Hemiacetale

O

HO

OH

H

OO

O

Acetale

KJM5230 - H06

Phenolic Natural Products

Biosynthesis from shikimate (- alkaloids)

CO2H

OHOH

HO

Shikimate

CO2H

HOOH

OH

Gallate

[ox]

O

O

O

P

Phosphoenol-pyruvate

- H2O

CO2H

OOH

Chorismate

CO2 NH

CO2H

NH2

Trp

AlkaloidsRearrange

Claisen

OH

Chorismate

HO2C CO2

O

CO2H

OH

NH2

Tyr

Alkaloids

CO2H

NH2

Phe

Alkaloids

CO2

Cinnamate

KJM5230 - H06

From cinnamate

Voilatile compds, smell, taste etc., Not monoterpenes

CO2

CinnamateCinnemal

O

Anetol

OMe

Eugenol

OHOMe

O

Vaniline

OHOMe

OH

Thymol

Monoterpene

CO2

Cinnamate

2

O

OO

OMeOMeMeO

OH

O

Podophyllotoxin

From Podophyllum peltarumMay apple

Antiviral, veneric warts

Toxic - lead for anticancer drugs

O

OO

OHOMeMeO

O

Etoposide

O

OO

HO

HO

KJM5230 - H06

From cinnamate

CO2H CO2H

OH

CO2H

OGlu

OGlu

CO2HO O

Coumarin

O O O

OHOH

O

Dicoumarol-Anticoagulant - Vit K antagonist-Sweet clower disease

O O

OH

O

Warfarin - Marevan®

O

O

R

Vit. K

O O

O

O

OHH

Aflatoxine B1

Aflatoxines-From Aspergillus flavus (fungus)-Attacks nuts etc.-Carcinogenic

OO 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

OO O

R

R'

HN

N

O

O

OO O

R

R'

HN

N

NNO

O NH2

ONN

NH2

O

h