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1
Drug Discovery and Organic Chemistry
Dr. Kendrew K. W. Mak
Department of ChemistryThe Chinese University of Hong Kong
2
Organic Chemistry in NSS Chemistry Curriculum Topic V Fossil Fuels and Carbon Compounds
(b) Homologous series, structural formulae and naming of carbon compounds
(c) Alkanes and alkenes(d) Addition polymers
Topic XI Chemistry of Carbon Compounds(a) Introduction to selected homologous series(b) Isomerism(c) Typical reactions of various functional groups(d) Inter-conversions of carbon compounds(e) Important organic substances (drugs, detergents, polymers,
biomolecules)
3
STSE ConnectionsTopic XI (page 63)
The search for new carbon compounds often requires the synthesis of hundreds of compounds which are variations of their basic structures. Some compounds which have been synthesized may have certain useful aspects, but also dangerous side-effects which prohibit their general use. It is often necessary to look for other compounds with similar structures but without the side-effects.
Often more than one synthetic route may be available to prepare a particular carbon compound. However, some synthetic routes may have undesirable effects on our health and our environment. The bestsynthetic route may not be the one with the fewest steps or the lowest cost. It is, therefore, essential to apply our knowledge of organic chemistry so that useful organic products are developed and manufactured by safe, economic and environmentally acceptable routes.
4
Aims of This Lecture
Introduce the role of organic chemistry in the drug discovery and development processes.
Stimulate students interest in learning organic chemistry.
STSE Connections
5
Contents
Part 1 Drugs, Molecules, Structures and Drug Actions
Part 2 The Drug Discovery Processes
Part 3 Organic Synthesis The Essential Tool for Making Drugs
6
Drugs, Molecules, Structures and Drug Actions
Part 1
O OH
O CH3
O
Aspirin
CH3COO
O
CH3COO
HNCH3
Heroin
O
O
OO
OH
OO
O
HO
NH
OH
OO
O
O
Taxol
Oseltamivir (Tamif luTM)
OEt
O
NH O
O
H3C
H2N
19991999
18991899
18981898
19931993
8
Lets Begin with Aspirin
Analgesic (to relieve pain) Antipyretic (to lower fever) Anti-inflammatory agent (to reduce
inflammation)
Treatment of rheumatoid arthritis ()
Preventing some types of strokes and heart attacks
O OH
O CH3
O
9
Aspirin Had a Very Long History
http://upload.wikimedia.org/wikipedia/commons/0/00/Salix_alba_Morton.jpg
Ancient people found the willow bark had medical properties.
Ancient Egyptian medical literature Ebers Papyrus(written in 1534 BC)
The Papyrus copied some ancient documents 1000 years earlier they knew using willow since 2500 BC
10
Aspirin Had a Very Long History
Ancient Egyptian use willow as a pain reliever and anti-inflammatory therapy.
For treating cough, ear infection and arthritis.
Willow was also described in ancient Sumerian medical text written in around 3000 BC
http://upload.wikimedia.org/wikipedia/commons/8/8b/Ebers7766.jpg
Jeffreys, D. Aspirin: The Remarkable Story of a Wonder Drug. Bloomsbury: London. 2004, pp. 8-11.
11
What is Present in the Willow Bark?
O
HO
OHO
OH
HO
OH
Salicin ()
HydrolysisGlucose +
CH2OHOH
Salicyl alcohol
oxidation
O OH
OH
Salicylic acid ()
Isolated from willow bark in 1827
Sour and irritating when taken orally!
12
Derivatives of Salicylic Acid being hydrolyzed
to salicylic acid and phenol in the small intestine
Sodium salicylate()
Phenyl salicylate (Salol)()
unpleasant toswallow
irritating to the stomach
COO-Na+
OH
COO
OH
introduced by Bayer in 1899
Acetylsalicylic acid (Aspirin, )
COOH
OCCH3O
Salicylic acid()
18861875
COOH
OH
Sneader, W. Drug Discovery: A History. John Wiley & Sons: West Sussex. 2005, pp. 357-359.
13
O OH
OH +H3C O
O
CH3
OO OH
O CH3
O
+O
OHH3C
Salicylic acid()
Acetic anhydride()
Aspirin()
Acetic acid()
Synthesis of Aspirin
14
What Have We Learnt from The Story of Aspirin?
It is a synthetic drug which cannot be found in nature, but has a plant origin.
Compounds having similar structure are likely to have related medical properties.
The drug properties of a compound can be improved by modifying its chemical structure.
15
Opioid Analgesics
http://upload.wikimedia.org/wikipedia/commons/2/2a/Slaapbol_R0017601.JPG
The unripe seed pods of the poppy Papaver somniferum
Using the juice from the unripe seed pods for medical purposes:
As a sedative for children (in Ebers Papyrus)
In the Sumerian culture as early as 3500 BC.
16
HO
O
HO
HNCH3
Morphine
Morphine
First isolated in 1805
The principal alkaloid (~10% w/w) of raw opium
The most important narcotic analgesic in medicine - for relief severe pain
But it is an addictive!
It causes digestion problems
17
Opium
Opium, the dried sap of the poppy, contains:
HO
O
HO
HNCH3
H3CO
O
H3CO
HNCH3
H3CO
O
HO
HNCH3
N
OCH3
OCH3
OCH3H3CO
Morphine ThebaineCodeine Papaverine
Alkaloids ()
Opium contains approximately 20 alkaloids.
18
Synthesis of Heroin and Codeine
HO
HOH
ON
MeCH3O
HOH
ON
Me
Morphine Codeine
CH3COO
CH3COOH
ON
Me
Heroin
Ac2O, AcOHHeat KOH, CH3I
Heroin was accidentally synthesized by Felix Hoffmann (a synthetic chemist in Bayer) while he was searching way to synthesize codeine from morphine.
Heroin is a much more powerful narcotic and cough-suppressant than morphine.
19
How Aspirin Works?
20
How the Nervous System Works?
A nerve impulse (reaching a synaptic cleft causes these vessels to release neurotransmitters.
Neurotransmitters migrate across the cleft to the receptor sites to trigger a nerve impulse in the next neuron, or start a bodily response.
21
Endorphins () and Enkephalins
Enkephalins (a kind of endorphins) are released in the body as the natural pain-killer.
The opium alkaloids play the roles as endorphins.
Enkephalins bind to the opiate receptors and block the release of neurotransmitters that would convey the pain message to the pain.
22
The Key and Lock Model of Drug Action
23
Drug-Receptor Interactions
CH
HH
N ReceptorH
Covalent bond
H4N O Ionic bondCO
Receptor
H O Hydrogen bondO Receptor
HC H C Receptor Hydrophobic Interactions(van der Waals forces)
24
The Drug Discovery Processes
Part 2
25
COOH
OH
Salicylic acid
Lead Compound
COO-Na+
OHSodium salicylate
COO
OH
Phenyl salicylate(Salol)
COOCH3
OH
Methyl salicylate(Major constituent of wintergreen oil)
COOH
OCOCH3
Acetylsalicylic acid(Aspirin)
Lead Compound and Synthetic Derivatives
Lead Compound: A chemical compound that has drug activity. Used as a starting point for chemical modifications in order to improve drug
performance.
N OHH3C
O
OHMorphine
N OCOCH3H3C
O
OCOCH3Heroin
NH3C
OCH3Dextromethorphan
effective cough suppressant
NOCH3H3C
O
OHEtorphine
2000 times more potent than morphinefor tranquilizing large animals
OHCH2CH2CH3
NH3C OC2H5
O
Pethidinevery much less potent
NH3C
OHLevorphanol
more potent but also highly additive
NCH3H3C
H3CCO
CH3
Methadoneequally potent but much less additive
Lead compound
Thomas, G. Medicinal Chemistry, 2nd Ed. John Wiley & Sons: West Sussex. 2007, pp. 79-80.Bruice, P. Y. Organic Chemistry, 5nd Ed. Pearson Prentice-Hall: Upper New Jersay. 2007, pp. 1299-1300.
Drug Discovery ProcessTarget
identification
Leadidentification
Leadoptimization
Preclinicaland clinical
development
Targetvalidation High throughput screening
Natural product screening Virtual screening Combinatorial chemistry Compound library design Structure-based design
Medicinal chemistry Design of focused compound libraries Molecular modeling
(quantitative structure-activity relationships) Structure-based design
Chemical developments in lead identification
Chemical developments in lead optimization
28
Lead Identification
From Traditional Medical Practices (Local folk remedies)
Salicylic acid (from willow barks / salicin)
Morphine (from opium)
Random Screening
Random screening of soil samples in search of new antibiotics in1940s and 1950s --> discovery of two important antibiotics: streptomycin and tetracyclines.
Taxol
29
Taxol: A Famous Anti-Cancer Drug
O
O
OO
OH
OO
O
HO
NH
OH
OO
O
O
Taxol
In 1960, the National Cancer Institute (NCI) and the United State Department of Agriculture (USDA) started a very ambitious programme to collect and screen plant products as potential anti-cancer agents.
114,000 plant extracts from 35,000 samples were screened.
Barks of a Pacific yew tree (Taxusbrevifolia) was collected 1962, and it was found to be cytotoxic in 1964.
Pure sample of the active ingredient, taxol, was isolated in 1966.
Goodman, J. Walsh, V. The Story of Taxol: Nature and Politics in the Pursuit of an Anti-cancer Drug. Cambridge University Press: Cambridge. 2001, Chapter 1.
30
Compound collections, data bases and synthesis
All large pharmaceutical companies maintain extensive compound libraries (10K to > 2M compounds).
By high-throughput screening (HTS). A robot system can screen >100,000 compounds per day.
Combinatorial chemistry () produce large numbers of compounds required for high-throughput screening. It synthesizes a large number of compounds simultaneously from some building blocks.
Computational approaches (virtual screening, de novo drug design)
Thomas, G. Medicinal Chemistry, 2nd Ed. John Wiley & Sons: West Sussex. 2007, Chapter 1.
Lead Identification
31
Non-random screening
Compounds which are weakly active are chosen as lead, and compounds which are structurally similar to them are screened selectively.
Lead Identification
Compound libraries are generated to mimic or blocking the effects of a natural mediator (developed Tamiflu)
Compound libraries are generated from the chemical structure of a known, existing active drug. the me-too approach
32
Lead Identification
Rational Approach to Drug Discovery
Basic research into the disease process and its causes.
Assessment of the biochemical and biological processes of the disease and/or this cause.
To decide what intervention is most likely to bring about the desired result (identify a key ligand, protein, DNA, etc).
Study the structural information of the possible target site (protein structure, DNA structure)
Use molecular modeling technique to study whether a potential drug (ligand) can superimpose to the target site DOCKING.
33
How Tamiflu Prevents the Avian Flu and Swine Flu From Spreading?
Neuraminidase (NA) is an essential enzyme for viral replication
It catalyzes the cleavage of sialicacid residues from glycoproteins and liberates the budding virion.
NA forms a complex with sialic acid
Strategy:Design and make a compound that binds to NA to inhibit its function.
34
O
O
OH
OH
HOOH
NH
HNO
H3C
NH2HN
OOH
HOOH
HOOH
O OH
NH
H3C
O
Sialic acid Zanamivir (RelenzaTM)
Corey, E.J.; Czak, B.; Krti, L. Molecules and Medicine; Wiley: New Jersey, 2007; p 150
Developed in 1989 using structure-based design
Limited clinical use because of its poor bioavailability (~ 2%)
The First Neuraminidase Inhibiting Drug
35
OOH
HOOH
HOOH
O OH
NH
H3C
O
Sialic acid Oseltamivir (TamifluTM)
OEt
O
NH O
O
H3C
H2N
Corey, E.J.; Czak, B.; Krti, L. Molecules and Medicine; Wiley: New Jersey, 2007; p 150
Developed by C. U. Kim at Gilead Sciences in early 1990sMarketed as Tamiflu by Roche
The First Orally Active Neuraminidase Inhabiting Drug
36
Lead Optimization / Lead Modification
Once a lead compound is identified, molecular modification of the lead compound will be carried out to:
Optimize the potency of the lead compound (minimize cost and dosage). Chirality Minimize the side-effects of the lead compound. Ease of formulation (solubility, dissolution and stability)
The classical example : From salicylic acid to aspirin
COOH
OH
COOH
OCOCH3
Too corrosive to be taken orally.Causing digestive problems(e.g. stomach bleeding)
Much less corrosiveEqually potent
37
Lead Optimization
Functional Group Modification
Solubility and drug design Stereochemistry and drug design Structure-activity relationships (SARs)
Identification of the Active Part: The Pharmacophore Metabolism
38
Lead OptimizationSolubility and drug design
A potent drug should have a good balance between: solubility in aqueous media solubility in lipid tissues
to optimize the absorption and transportation to the site of action.
A drug should be hydrophilic enough: to dissolve in the aqueous gastric fluid for absorption to be effectively transport via the systemic circulation to the site of action
A drug should be lipophilic enough: to pass through the appropriate lipid membrane to reach the site of action
39
Lead OptimizationSolubility and drug design
HO
HOH
ON
MeCH3COO
CH3COOH
ON
Me
Morphine Heroin
Acetic Anhydride
Less lipophilic More lipophilicCan pass through the blood-brain barrier more effectively.
Very polar, More hydrophilic
Very polar, More hydrophilic
Less polar, More lipophilic
Less polar, More lipophilic
40
Stereochemistry and Drug Actions The Tragedy of Thalidomide
NH
O O
HN
NH
OO
HN
(R)-ThalidomideSedative
(S)-ThalidomideTeratogen
Thalidomide - Sold in the form of racemate in 1958 - 1960
For suppressing morning-sickness during early pregnancy
Resulted in 12,000 of deformed births.
41
Structure-ActivityRelationship of TaxolStructure-ActivityRelationship of Taxol
42
Organic Synthesis The Essential Tool for Making Drugs
Part 3
43
Chemical Techniques in Drug Discovery and Development
Compound isolation and purificationIsolate the active compounds from natural sourcesIsolate the desired compound with good purity from a synthesis
Structural identificationNuclear magnetic resonance spectroscopy (NMR)Infrared spectroscopy (IR)Mass spectrometry (MS)X-ray crystallography
Organic synthesisBuilding up the compound library for screening (lead identification)Making derivatives for lead modificationSynthesize an approved drug with good efficiency
Theoretical ChemistryMolecular modeling for rational drug design
44
Compound Isolation and Purification
Salicin / Morphine
Plant extracts for medical uses: ~ 2500 3000 BC
Isolated as pure forms: salicin (1827); morphine (1805)
Aspirin First synthesis: 1853
No follow-up because could not purify and identify the structure of the product.
Second synthesis: 1897
45
Activity for StudentsIsolation of caffeine from tea leaves
N
N N
N
O
O
H3C
CH3
CH3
Caffeine
Black Tea / English TeaBlack Tea / English Tea
Green TeaGreen Tea
Ground CoffeeGround Coffee
Instant CoffeeInstant Coffee
46
Tea Leaves Solid-Liquid Extraction(water)
Water InsolubleCellulose
Water SolubleCaffeineOther water-soluble substances
Liquid-Liquid Extraction(dichloromethane / water)
Soluble in WaterProteinsAminoOther water-soluble substances
Soluble in CH2Cl2CaffeinePigments(removed by recrystallization)
Base(CaCO3)
Isolation of Caffeine From Tea Leaves(A commonly used method)
47
Extraction of Limonene from Citrus Fruit Peels
(R)-(+)-Limonened-Limonene
Main component (~ 90%) of the essential oil of oranges.
Orange peel zest (outer peel) contains about 0.5 1.0% of limonene.
Method 1 : Isolation of Limonene by Extraction into a Solvent
Method 2 : By Steam Distillation
Method 1 : Isolation of Limonene by Extraction into a Solvent
Method 2 : By Steam Distillation
48
Vitamin C Natural Sources
O OH
HOOH
HO OH
Vitamin C
6 carbon atoms5-membered ringLactone (cyclic ester)4 hydroxyl groups2 chiral centers
90Broccoli
50Orange
23Pork liver
90Kiwifruit
190Red pepper
200Blackcurrant
Amount (mg / 100 g)
Plant source
Vitamin C supplements and in drinks
110,000 tonnes of Vitamin C is synthesized from D-glucose annually.
The Reichstein Process of Synthesizing Vitamin C
O OH
OH
HOHO
OH
D-glucose
123
4 56
+ H2 (Ni)
CH2OHCC
OHHHHO
C OHHC OHHCH2OH
1
2
3
4
56
D-sorbitol
Microbial oxidation(fermentation)
acetobacter
CH2OHCC
OHHO
C OHHC OHHCH2OH
1
2
3
4
56
D-sorbose
O
H+ CH2OH
H
O H
H OO
O
OKMnO4 / H+
1
23
45
6
COOHCC
OHO H
CH OHC HHOCH2OH
1
4
5
6
2
3 esterification
- H2O
OO
OHH
H OHHO
HO
Vitamin C~ 60% yield
(f rom D-glucose)
1456
23
4 chemical synthetic steps + 1 fermentation
Reported in 1933Reported in 1933
50
Restraints of Organic Synthesis
Chemoselectivity To perform a required structural change.
Regioselectivity To orient the reacting partners in a correct
fashion.
Diastereoselectivity To create the correct orientations of various parts of
the molecule with respect to each other.
Enantioselectivity To enable the formation of a molecule in one
handedness or as one mirror image isomer.
51
Industrial Synthesis of Salicylic Acid
OH CO2, NaOH
~ 120oC, 100 atm
OH
O-Na+
O
H+OH
OH
O
Regioselective
Chemoselectivity(to carry out a desired functional transformation)
52
The Reichstein Process of Synthesizing Vitamin C
O OH
OH
HOHO
OH
D-glucose
CCC
OHHHHO
C OHHC OHHCH2OH
O H
D-glucose(Fischer projection)
1
2
3
4
56
123
4 56
+ H2 (Ni)
CH2OHCC
OHHHHO
C OHHC OHHCH2OH
1
2
3
4
56
D-sorbitol
Microbial oxidation(fermentation)
acetobacter
CH2OHCC
OHHO
C OHHC OHHCH2OH
1
2
3
4
56
D-sorbose
Acetobacter is the bacteria for converting ethanol to acetic acid (vinegar production).
The oxidation of D-sorbitol to D-sorbose is difficult due to the required regioselectivity.
CH2OHCC
OHHO
C OHHC OHHCH2OH
1
2
3
4
56
D-sorbose
H
HO
HO
H
HOH2C
H OH O
CH2OH
H
HO
HO
H
HOH2C
H OH CH2OH
O
H+
H+
CH2OH
OH
HOH2C
H
OH H
H HOO
OH
CH2OH
HOH2C
H
OH H
H HOO
O
H+
O
H+
OH
H
O H
H OO
O
O
2 6-membered cyclic acetals(less stable)
CH2OH
H
O H
H OO
O
O
1 5-membered cyclic acetal1 6-membered cyclic acetal
(more stable)
1
2
34
5
61
2
34
5
61
2
3456
OOH
H
OH
CH2OHOH
HOH
H
H
H
1
2
34
5
6UnstableIncorrect stereochemistry forforming the cyclic acetal
(a)
(b)
(route b)
(route a)
(route a)
Formation of cyclic hemiacetal(diastereoselective)
CH2OH
H
O H
H OO
O
OKMnO4 / H+
1. oxidation of the -CH2OH group2. deprotection3. open up the 5-membered hemiacetal
COOH
H
O H
H OO
O
OH+
1
23
45
61
23456
COOHCC
OHO H
CH OHC HHOCH2OH
1
23
4
5
6
esterification
- H2O
OO1
2
3
4
O
OH
H
tautomerizationH
H OHHO 5
6
OO
OHH
H OHHO
HO
Regioselective
Vitamin C~ 60% yield
from D-glucose
The Roches Process
Rohloff, J. C. et. al. J. Org. Chem. 1998, 63, 4545-4550.
CO2HHO
HOOH
shikimic acid(extracted from Chinese star anise)
CO2Et
OMs
O
O
3 steps 2 stepsCO2EtO
O
CO2EtO
HON3
CO2EtO
HN
CO2EtO
AcHNN3
2 steps
CO2EtO
AcHNNH2.H3PO4
10 Steps, ~ 21% yield
The commercial synthesis of TamifluThe commercial synthesis of Tamiflu
56
Drawbacks of the Roches Process
The limited availability of shikimic acid
CO2HHO
HOOH
shikimic acid(extracted from Chinese star anise)
CO2EtO
AcHNNH2.H3PO4
13 g of dried plant gives 1.3 g of shikimic acid(just enough for making ten 75 mg capsules)
To meet the annual worldwide demand of 300 million doses, 840 tons of star anise is needed.
90% of Chinese star anise is used for making Tamiflu
Chinese Star AniseFrom www.wikipedia.org
CO2HHO
HOOH
shikimic acid(extracted from Chinese star anise)
CO2Et
OMs
O
O
3 steps 2 stepsCO2EtO
O
CO2EtO
HON3
CO2EtO
HN
CO2EtO
AcHNN3
2 steps
CO2EtO
AcHNNH2.H3PO4
10 Steps, ~ 21% yield
The use of the potentially explosive azide-containing intermediates.
Drawbacks of the Roches Process
58
An Azide-free RouteDeveloped by Roche
Karpf, M.; Trussardi, R. J. Am. Chem. Soc. 2001, 66, 2044-2051.
CO2HHO
HOOH
shikimic acid
6 stepsCO2EtO
O
CO2EtO
AcHNNH2.H3PO4
11 Steps, ~ 21% yield
CO2EtO
HOHN
CO2EtO
HONH2
CO2EtO
H2NHN
CO2EtO
AcHNHN
The route does not involve potentially explosive azide-containing intermediates.
+CO2CH2CF3
NB O
HPhPhH
o-Tol
NTf2
CO2CH2CF3
3 steps
NOBoc
I
NOBoc
NOBoc
Br
CO2EtBocHN
CO2Et
AcHNO
BocHN
CO2EtBocHN
BrNHAc
2 steps
CO2Et
AcHNO
H3NH3PO4
11 steps, 30% yield No shikimic acid No azide intermediates
Corey, Yeung and Co-workers Approach
Yeung, Y. -Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310-3611.
EnantioselectiveDiels-Alder Reaction
Regioselective and diastereoselectiveaddition reaction
Efforts Made By Japanese ChemistsShibasakis Method 3rd Generation
CO2EtO
AcHNNH2.H3PO4
12 steps, ~ 2.8% yield
(2 steps)OTMS
O
ClCl
ON3
O
O
N3
OHNH
OO
NHBoc
OHNHAc
NHBoc
ONHAc
NHBoc
(2 steps)O
NHAc
NHBocNC
OHNHAc
NHBocNC
(2 steps)O
NHAc
NHBocNCresolution bychiral HPLC
(2 steps)
Yamatsugu, K.; kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.2007, 48, 1403-1406.
Poor overall yield Resolution by chiral HPLC
impractical for large-scale synthesis
Chemists Are Still Working Out a Shorter Route
Trost, B. M.; Zhang, T. Angew. Chem. Int. Ed. 2008, 47, 3759-3761.
OO
CO2EtPhthN CO2EtSPh
PhthN CO2EtPhthN
CO2EtPhthN
SESN
CO2EtPhthN
SESHNO
CO2EtPhthN
SESNOAc
CO2EtPhthN
AcHNO
CO2EtH2N
AcHNO
8 steps, 30% yield
Good yield obtained from a short synthesis (concise and efficient)
Palladium catalyzed asymmetric allylic alkylation
62
Is total synthesis always practical for making a drug?
63
Early Studies of the Medical Uses of Taxol
May 1964: Found to be cytotoxic (toxic to cell)Sept 1966: Isolated in pure form
1971: Its chemical structure published
Apr 1984: Clinical trial began(60,000 lbs of barks required)
May 1988: Shown to be effective for treating ovarian cancer(anticipated that 360,000 trees had to be destroyed to meet the US demand)
Jan 1993: Taxol available on the market(29 years after its first discovery)
64
Difficulties in Developing Clinical Applications of Taxol
The natural supply is very limited. Complicated extraction steps. Very low yield: 0.004% of bark. Three mature 100-year old trees
to yield 1 g of taxol. (dosage: ~150 mg/week)
Destructive harvesting.
It is very insoluble in water.
http://commons.wikimedia.org/wiki/File:Yew_bark_Taxol_PD.jpg
65
O
O
OO
OH
OO
O
HO
NH
OH
OO
O
O
Taxol An Extreme ChallengeFor Organic Synthesis
4 fused ring structure
8-membered ring
4-membered ring
11 chiral centers
EtO
O
OB
O
Ph
O
O
O
EtO
O O
OBO
Ph O
OH
O
OH
OTBS
OTBDPS
OH
OBn
OHOH
OTBDPS
O
OBn
OO
HOAc
OH
O
OH
NHN
SO2Ar
+A C
O
OTBDPS
O
HOH O
OTBS
Ph
A C
Building the C ring
Building the A ring
Joining A ring and C ring
Total Synthesis of Taxol(Part 1)
O
O
OO
OH
OO
O
HO
NH
OH
OO
O
O
Developed by Prof. K. C. Nicolaou(1994)
O
OTBDPS
O
HOH O
OTBS
Ph
A C
O
O O
OH O
OPh
A C
O
HH
O
O
O
H O
Ph
C
O
HO OH
O
O
A B
Building the B ring
racemic
O
O
Cl
O
O
O
H O
Ph
C
O
HO OH
O
O
A B
O
O
O
O
O
H O
Ph
C
O
HO O
O
O
A B
O
O
H O
Ph
C
O
HO O
O
O
A B
O
O
O
+
Total Synthesis of Taxol(Part 2)
Resolving the racemic mixture
Total Synthesis of Taxol(Part 3)
O
O
H O
Ph
C
O
HO OH
O
O
A B
O
O
H OHAc
C
O
O O
O
O
A B
TESAc
O Ms
O
O
H
Ac
C
O
O O
O
O
A B
TESAc
O
O
O
H
Ac
C
OH
O O
O
A B
TESAc
O
HO
PhO
N
O
O
OTES
O
O
H
Ac
C
OH
O O
O
A B
TESAc
O
O
PhO
O
PhOH
NHO
Ph
Building the D ring
Adding the Tail
The total synthetic route involved > 40 stepsOverall yield < 2%
69
Semi Synthesis of Taxol
O
OH
H
AcOH
HO O
OO
HO
PhO
10-Deacetylbacctain IIIhttp://commons.wikimedia.org/wiki/File:Taxus_baccata_tree.jpg
Isolated from the leaves of the American and European yew
Up to 0.2% yield of dry leaves. The leaves are re-grown rapidly after
harvested, providing a steady source of starting material.
http://commons.wikimedia.org/wiki/File:Yew_Berries.jpg
4 steps
80% yieldTaxol
70
Modern Biochemistry Technology Made Taxol Synthesis Easier
By Plant Cell FermentationBy Plant Cell Fermentation
Starting materials: Feedstock for cell growth consisting sugars, amino acids, vitamins and trace elements.
Biosynthesis: Feeding the feedstock to a specific taxus cell line in aqueous medium in large fermentation tanks.
Isolation: Extract from the fermentation mixture, purify by chromatography and crystallization.
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O
O
OO
OH
OO
O
HO
NH
OH
OO
O
O
Lead OptimizationGetting a Better Derivative
Taxolalmost insoluble in water
difficult to administrate by IV infusion
O
O
OHO
OH
OO
O
HO
NH
OH
O
O
O
O
Taxoteremore soluble in water
more potent
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Scope of Organic Synthesis
Organic SynthesisOrganic Synthesis
Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis; VCHWiley: Weinheim, 1996; p 4
Target Oriented(Total Synthesis)Target Oriented
(Total Synthesis) Methods OrientedMethods Oriented
Natural ProductsNatural Products
DesignedMoleculesDesignedMolecules
ReagentsReagents CatalystsCatalysts Synthetic Strategies
Synthetic Strategies
SyntheticTactics
SyntheticTactics
TheoreticallyInteresting Molecules
TheoreticallyInteresting Molecules
BiologicallyInteresting Molecules
BiologicallyInteresting Molecules
MedicallyInteresting Molecules
MedicallyInteresting Molecules
Materials ScienceInteresting Molecules
Materials ScienceInteresting Molecules
73
Can We Participate the Drug Discovery Research?
74
Computer Aided Drug Design -Docking
To superimpose the three-dimensional structure of a potential drug (ligand) on its possible target site.
A small molecule docked to a protein
http://en.wikipedia.org/wiki/File:Docking.jpg
75
Participating the Drug Discovery @Home
Distributed Computing
E.g. World Community Gridhttp://www.worldcommunitygrid.org/
Projects
Influenza Antiviral Drug SearchHelp Fight Childhood Cancer.