(bioactive molecules) the cource discuss the organic chemistry of important classes of drugs and...
TRANSCRIPT
(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
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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
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
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:
KJM5230 - H06
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
KJM5230 - H06
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
KJM5230 - H06
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
KJM5230 - H06
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
KJM5230 - H06
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)
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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