KJM5230-H04 KJM5230 - Biologisk aktive molekyler urset omhandler organisk kjemiske forhold hos sentrale legemiddelgrupper g bioaktive naturstoffer. mnet omhandler syntese/biosyntese, virkningsmekanisme, biotilgjengelighet og tabilitet for utvalgte stoffklasser. truktur-aktivitets forhold og strukturoptimalisering inngår også i kurset.
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KJM5230-H04 KJM5230 - Biologisk aktive molekyler Kurset omhandler organisk kjemiske forhold hos sentrale legemiddelgrupper og bioaktive naturstoffer. Emnet.
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KJM5230-H04
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
LærebokD. A. Williams; T. L. Lemke. “Foye’s Principles of Medicinal Chemisrty” 5th Ed.LippincottWilliams&Wilkins., Philadelphia, 2002. ISBN 0-683-30737-1
PensumGenerell del – Part l:
Overwiev + Kap. 1-2; 4-5; 7-8:
Spesiell del – Part II.
Sect. 6 Chemotherapeutical Agents:kap 34-39:
•Natural Products•Drug Design•Reseptors - Drug Action•Pysichemical/Biopharmaceut. Properties•Drug Metabolism
•(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
KJM5230-H04
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
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 -•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 tailSerendip=Sri Lanka
KJM5230-H04
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)
•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-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
Sub types cholinerge reseptors
NicotinergeMuscarinerge
NO
O
O H
ca. 5Å
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 sympatiskenervesystem
Det parasympatiskenervesystem
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
OHHO
HO
KJM5230-H04
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
Isolert fraErythroxylon coca
N
tropane
(8-methyl- 8-azabicyclo[3.2.1]octane)
KJM5230-H04
Parasympatolytika(Antikolinergika)
Tropanalkaloider
N
tropan
Atropa belladonna
Hyoscamus niger(bulmeurt)
Isolert fra Atropa belladonna og Hyoscamus niger
Esterhydrolyse også mulig i basisk miljø
N
O
O
OH
(±) Atropin
Base
N
O
O
OHH
α =til C O
(-) Hyoscyamin
NO
O
OH
ca. 5Å
"N"O
O
R
R>Me"N": kvart el. tert (protoner. in vivo)
ca. samme avst. som AcCh
Gen. blokker
Relaksering av tarmmuskel, pupillutvidelse
Scopolamin
Mer CNS dempende enn atropinreisesykeplasterkarmpeløsendepupilutvidendeberoligende“sanhetsserum”
N
O
O
OHH
Oracimisationbase
Ester hydrol.
N
O
OHHO HO
OH
Skopin Tropasyre
+
NHO
O
Skopolin
Pyridine / piperidine alkaloids
KJM5230-H04
Semisyntetiske tropanalkaloider
N
O
O
OH
Atropin
N
O
O
OH N
O
OH
N
NO
O
OH
ca. 5Å
"N"O
O
R
R>Me"N": kvart el. tert (protoner. in vivo)
ca. samme avst. som AcCh
Gen. blokker
Homatropin Tropikamid
øyedr.korterevirketid
Alkaloid Natural Products
Pyridine / piperidine alkaloids
KJM5230-H04
Alkaloid Natural Products
Curare - Pilgift - Søramerikanske indianereBland. Av flere alkaloider med muskeslammende effektFlere plantekilder bl.a. Chondodendron tomentosum
Isoquinoline alkaloids
CNS
Effektor celle
Reseptor
Synapse
Acetylkolin
Noradrenalin
Det somatiske nervesystem Det autonome nervesystem
CNS CNS
Det sympatiskenervesystem
Det parasympatiskenervesystem
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”
KJM5230-H04
Alkaloid Natural ProductsIsoquinoline alkaloids
Morfin isolert fra opium 1803 (Morpheus: gresk søvngud)
O OHHO
N
OOHHO
N
Morfin
O
OHN
OH
H2N
OH
HN H
NO
OO
NH
HO
NH
O
O
S
Met-enkefalin
Tyr N-terminalhos opiopeptider
Morfinanalogs, binds to opiopeptide (endorfin / enkefalin) reseptors
Derivative of phenantrene
KJM5230-H04
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
KJM5230-H04
O OO
NCH3
H3C
OH
Oxycodon (not natural. occur.)
O OHO
NCH3
O OHHO
NCH3
H3CO OO
NCH3
H3C CH3
Thebain Kodein Morfin
H2O2AcOH
O OO
NCH3
H3C
OHH2 / kat.
O OO
NCH3
H3C
OH
Oksykodon
Biosynth.morphine
KJM5230-H04
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-H04
O
N
OH
O
HO
BuprenorfinTemgesic®, Subutex®
More potent than M. (pain)Partiell -agonist:Antagonister i høye doserNaloxon 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-H04
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-H04
Alkaloid Natural Products
Quinoline alkaloidsCinchona 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
Mefloquine
N Cl
HNN
Chloroquine
Dihydroquini(di)ne and der.Chiral ligandsAsym. dihydroxylation (Sharpless)
KJM5230-H04
Alkaloid Natural Products
Indole alkaloids
NH
HN
MelatoninHormone
MeOO
NH
CO2H
NH2
Tryptophan
Essential amino acid
NH
NH2
SerotoninNeurotransmitter
HO
NH
CO2H
Auxine Plant growth hormone
Psilocybe Mexicana
Psilocybe semilanceata(Spiss fleinsopp)
OR
NH
NHalucinogens from Psilocybe sopper
R=H: PsilocinR=PO3H: Psilocybin
Serotoninagonists, not broken down in the bodystrong, continuos nerve impulse
in vivo
Indole natural products
NHMeO
N
H
H
HMeO2C
O
OOMe
OMe
OMe
OMe
Reserpinefrom Rauwolfia sp.Reduce blood pressure
Rauwolfia serpentinaIndia, Thailand etc
KJM5230-H04
NH
NH
R'O
RSecale alkaloids and derivativesfrom Claviceps purpurea (meldrøye)