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Prof. Dr. Erick M. CarreiraLaboratorium für Organische Chemie
Eidgenössiche Technische Hochschule (ETH)Zürich, Switzerland
Organic Chemistry in the Quest for Anticancer
Therapeutics
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Why we do, what we do
ESTIMATED NUMBER OF
“REALIAZABLE” MOLECULES
10120–10200
ESTIMATED NUMBER OF
KNOWN MOLECULES
0.000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000001%
108
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How do we find our way?
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At a rate of 10 billion molecules/year,the synthesis project would take between 10110 and 10190 years !!!
Continuing with the thought experiment...
In the search for new pharmaceuticals, how do chemists deal with such odds?
High through-put screening (Combinatorial Chemistry)
Bio-informatics (Genomics)
Biostructural Chemistry
Synthetic Chemistry
Computational Chemistry
Sets the limit to what is realizable or “makeable”
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Top Twenty Drugs (Based on Sales) in 1990
RanitidineAmoxicillinAmipicillinCaptoprilEnalaprilIbuprofenNifedipineCefaclorCimetidineAtenololDiclofenacDiltiazemNaproxenCefalexinLovastatinFamotidineIohexolCefatriaxoneProxicamAlbuterol
AntiulcerAntibioticAntibioticACE-inhibitorACE-inhibitorNSAIDCalcium antagonistAntibioticAntiulcerBeta-BlockerNSAIDCalcium antagonistNSAIDAntibioticAntihypercholesterolemicAntiulcerContrast mediumAntibioticNSAIDBronchodilator
2400200018001500150014001300100010001000100010001000900750600600600600600
(in Millions USD)Therapeutic ClassDrug
Optically Pure
Optically Pure
Optically Pure
Optically Pure
Racemic mixture
Racemic mixture
Racemic mixture
Racemic mixture
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When you lookinto a mirrorit is notyourself you see,but a kindof apish errorposed in fearfulsymmetry
kool uoy nehWrorrim a otniton si ti,ees uoy flesruoydnik a tubrorre hsipa folufraef ni desop.yrtemmys
Mirror by J. Updike
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HSCOOH
NH2
MeMe
SHHOOC
NH2
Me Me
Penicillamin
anti-arthritisch toxisch
süss bitterH2N COOH
O NH2
NH2HOOC
ONH2Asparagin
N
O
ONH
O
O N
O
OHN
O
OThalidomid
beruhigend teratogen
The Bioactivity of Mirror-image Molecules can be Starkly Different
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Die Entwicklung des Arzneimittelmarktes seit 1980
(Geschätzter Jahresumsatz 2000: 100 Mia US$, davon 43% in Europa.)
1980 1990
1994 2000
Single Enantiomer 3%
Achiral 60%
Fermentation/Extraction
20%
Racemic
17%
Single Enantiomer 9%
Achiral 50%
Fermentation/Extraction
26%
Racemic
15%
Achiral
Fermentation/Extraction
27%
Racemic
17%
Single Enantiomer
22%Racemic
17%
Single Enantiomer
34%
Achiral
21%34%
Fermentation/Extraction
28%
Source: Lehman Brothers Pharmaceutical Research and DSM Fine Chemicals
1980 1990
1994 2000
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Benefits to Optically Pure Pharmaceuticals
• Dose reduction
• Simplification of dose-response relationship
• Reduction in intersubject variability
• Minimization of toxicity from enantiomer
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Cancer
1. Arises from the stepwise accumulation of genetic changes which lead a cell to undergo unlimited growth that is unresponsive to homeostatic regulatory mechanisms
2. Molecular and cell biology have identified cell phenotypes that are required for malignant transformations and the specific molecular pathways responsible for faulty programming of the cell
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A Subway Map of Cancer Pathways
Subway stops represent phenotypes required for malignant transformations
Molecular pathways are represented by the subway lines
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Natural Products with Anticancer Activities
Antitumor:isolated from Vinca rosea Anticancer: isolated
from mandrake
Antineoplastic:Isolated from crocus
Anticancer: isolated from Pacific Yew
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Natural Products with Promising Anticancer ActivitiesBreast CancerPromotes assembly of microtubules and inhibits tubulin disassembly
Sold as Paclitaxel
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Ongoing investigations at Novartis, Roche, Brystol Myers Squibb, Schering
Epothilones: Promising Anticancer Leads
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Epothilone-producing myxobacterium (Sorangium cellulosum)
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Epothilone-disrupts microtubulin dynamics (formation and growth)-inhibit cell proliferation at mitosis
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Tubulin is a heterodimeric protein which constitutes the monomeric building blocks of microtubules.
Microtubules are fundamental component of the cytoskeleton (the beams and conveyor belts of cells-the nanoweb of the cell). Microtubule dynamics is critical during cell division.
A Cell Biology Primer
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Cell Biology Primer:
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Natural Products bind to microtubule assemblies and interfere with the dynamics-arresting cell growth
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Medicinal Chemistry Organic Synthesis
-what are the structural features of the molecule that lead to activity?
Chemical Genetics Small molecules as probes with which to understand cellular processes
-can analogs be generated
-improved activities-reduced side effects
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How do we carve out the important structural features?
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Me
TIPSO
OBz
OH
Me
N
SMe
Me
OHO
RTrocO
Me
O OPg
O
OH
Me
N
SMe
Me
OTESO
ROR2
Me
O OTBS
Me
TIPSO
O
H
Me
TIPSO
OH
O3
Me
O OTBS
Me
TIPSO
NOH
P
OEtO
EtOMe
H
BH3•NH3
TISCl/Et3N
Me
N
SMe
Me
H
OR1 OR
X
N
P
OEtO
EtOMe
O
OH Me
TIPSO
Me
O
N
Me
Me
Ph
OH
O
O OOPg
O
OTrocM e
M e
MeS
NMe
R
I
BuLi
N
SMe
Me
N O
Me
TIPSO
OTBS
N
SMe
Me
OH
Me
TIPSO
PO R
OH
MeO
NMe
MePh
OH
70%
87%
91%95%
(+)-N-Methylephedrine3-methylbutyn-3-olZn(OTf)2 , NEt3, rt
BzCl, NEt3
75%
85%
18-C -6, K2CO3
LiAlH4
94%
t-BuOClEtMgBr, i-P rOH
TBSOTfLiCl, DBU2-Me thylthiazole a ldehyde
S mI2 (75%)Et3 B, Na BH4 (90%)
S OC l2, Et3NBu4NF (75%)
TESC l (79%)AcOH/H2OTP AP(75%)
LDA (86%)TrocCl (91%)
OsO4, P b(OAc)4 (86%)HF•pyrNa OCl2 (76%)
2,4,6-trichlorobenzoylchloride (74%)Zn, NH4Cl, MeOH (84%)3:1 (pyr:[HF•pyr])
Total Synthesis of Epothilone
Jeffrey Bode, E.M. Carreira J. Am. Chem. Soc. 2001, 123, 3611
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A complementary approach to the synthesis problem involves bioengineering
Biosynthesis is accomplished by the concatenation of synthetic enzymatic modules
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Biosynthesis of Epothilones
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Can an analogous modular chemical strategy be developed?
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Construction of Aldol Fragments
Me Me
O
Me
OR O
Me
H3 6
Me Me
O
Me
OH
Me
OR
3 6
Me Me
N
Me
O
Me
OR
3 6Me Me
OR N
H
OH
Me Me753
+
+
The Classic Aldol Approach
The Dipolar Cycloaddition Approach
O
O OOH
OHMe
Me
R1
MeS
NMe
O
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Retrosynthetic Analysis
O
O
Me
Me
O
HO
OHO
R
Me
N
SMe
Me
Me1
6
15
9
O
O
Me
Me
N
O
OHO
R
Me
N
SMe
Me
Me
O
O
Me
Me
OHO
R
Me
N
SMe
Me
MeC
NO
HOC
OPgON
O
OH
Me
S
NMe
Me
OR
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HOC
OPgON
O
OH
Me
S
NMe
Me
OR
N
SMe
Me
NO
OHHO R Me
Analogous Disconnections on Fragments
OHN
SMe
Me HO R Me
OHOH
The Synthesis of Polyketides is Reduced to Modular Nitrile Oxide Cycloadditions
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A Parallel Analysis Can be Applied to Others-
Me
N
SMe
Me
OO
MeOH
Me
O OH O
O
Me
OH
Me
Me
OH
O
O
Me
HO
Me Me
OH
Me
O
Me
O
NH2
O
HO
O
OH
O
Me Me
O
O
Me
O
OH
O
OOOMe
MeMe
N
OMe
O
O
O
Epothilone B tubulin polymerization promoter
Discodermolidetubulin polymerization promoter
Laulimalidetubulin polymerization promoter
Rhizoxintubulin polymerization inhibitor
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Nitrile Oxide Cycloadditions: Aldol Equivalents
CN
O
R1
R2
R2
N
R1
O+
Regio- and stereoselectivity can be difficult to control
CN
OMe
OMgBr CH2Cl2
Me
OH
N O
+
99:1 syn:anti
The Kanemasa Observation:
S. Kanemasa J. Am. Chem. Soc. 1994, 116, 2324
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Are such cycloadditions compatible with more highly functionalized edducts?
If so…
Generalized, versatile strategy for polyketide synthesisConvergent fragment coupling of polyketides
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A General Strategy for the Construction of Polyketides:
TBSO N
MeMe OH
Me
O
Me
Me
OH
Me
OH
Me
TBSO N
H
Me
OHTBSO N
H
Me
OH
TBSO N
MeMe OH
O
Me
TBSO N
MeMe OH
Me
O
TBSO N
MeMe OH
Me
O
anti synsyn syn
syn antianti anti
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P
N
Cl
O
EtOEtO
Me
OH
MeOH
N O
MeTBSOMe
N
SMe N
SMe
O
P
NO
EtOEtO
Me
O
MeOH
P
NO
EtOEtO
Me
O
MeOTBS
+
iPrOH
EtMgBr
CH2Cl2, rt77 %
87 %
LiHMDS-78 °C → rt
TBSOTf,Et2N
iPr90 %
OTIPS OTIPS
OTIPSOTIPS
O
O OOH
OHMe
Me
MeS
NMe
O
Fragment SynthesisEpothilone A
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N
SMe
H
O
EtOP Me
OEtO
Me
N O
OH
Me
Me
N O
OH
N
SMe
Me
OH
Me
Me
N O
N
SMe
O
EtOP
H
OEtO
Me
NOH
+
79%
93%
LiCl, DBUMeCN
TPAP, NMO
CH2Cl2, rt
Synthesis of Epothilone BO
O OOH
OHMe
Me
MeS
NMe
OMe
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O
Me
N O
N
SMe
Me
Mg
BrBr
TIPSO
Me
MgBr
Me
N O
N
SMe HO Me Me
TIPSO
81% 10:1 dr
Epothilone B
Chelation-Controlled Addittion
O
O OOH
OHMe
Me
MeS
NMe
OMe
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NOH
R1 Cl
R4
OHR3
R2
R1
N O
R4
OHR3 R2
+iPrOH
EtMgBr
CH2Cl20 °C - rt1 equiv 1.0 - 1.3 equiv
1,2-syn to hydroxyl moeity
N
Me
Pg1OOH
OH
Me
Me
N
Me
Pg1O
Me
O
Me OH
N
Me
Pg1OOH
OH
MeMe
OH
MeMe
OH
Me
Me
N
Me
Pg1O
Me
O
Me OH
N
Me
Pg1O
Me
O
Me OH
N
Me
Pg1O
Me
O
Me OH
N
Me
Pg1O
Me
O
Me OH
N
Me
Pg1O
Me
O
Me OH
N
Me
Pg1O
Me
O
Me OH
N
Me
Pg1O
Me
O
Me OH
ROH
RCNO
anti-anti-syn syn-syn-syn syn-anti-syn anti-syn-syn
syn-anti-dyn anti-syn-syn anti-anti-syn syn-syn-syn
Key Methodology: Modular Synthesis of Polypropionates
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General Protocol
TBSO
H
NOH
Me
TBSO
Me
Me
N O
OHMe
1. tert-BuOCl, CH2Cl2,
2. Allylic Alcohol,iPrOH, EtMgBrCH2Cl2, 0oC - rt
-78 oC
J. W. Bode, N. Fräfel, D. Muri, E. M. Carreira Angew. Chem. 2001, 113, 2128; J. W. Bode, N. Fräfel, D. Muri, E. M. Carreira Angew. Chem. Int. Ed. Engl. 2001, 40, 2082.
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TBSO
H
NOH
Me
TBSO
H
NOH
Me
TBSO
H
N
Me
TBSO
H
NOH
Me
TBSO
H
NOH
Me
Me
Me
OH
Me
Me
OH
Me
OH
Me
Me
OH
Me
Me
OH
TBSO
Me
Me
N O
OHMe
TBSO
Me
Me
N O
OHMe
TBSO
Me
Me
N O
OHMe
TBSO
Me
Me
N O
OHMe
TBSO
Me
Me
N O
OH
82 %
87 %
68 %
73 %
83 %
1
2
3
4
5
Entry NO Precursor Allylic Alcohol Cycloadduct Yield
OH
A General Strategy for the Construction of Polyketides:
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TBSO
Me
Me
N O
OHMe
TBSO
Me
Me
N O
OHMe
TBSO
Me
Me
N O
OHMe
TBSO
Me
Me
N O
OHMe
TBSO
Me
Me
O OH
OTESMe
TBSO
Me
Me
O OH
OTESMe
TBSO
Me
Me
O OH
OTESMe
TBSO
Me
Me
O OH
OTESMe
1. TESCl, NEt3
2. Ra-Ni, H2, B(OH)3
Yields: 90-95%
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RO
Me
Me
O OH
OR1Me
RO
Me
Me
O OH
OR1Me
RO
Me
Me
O OH
OR1Me
RO
Me
Me
O OH
OR1Me
RO
Me
Me
NOH
OHMe
RO
Me
Me
NOH
OHMe
RO
Me
Me
NOH
OH
TBSO
Me
Me
NOH
OH
Me
Me
Stereochemical Correlations
cis olefin syn aldol
trans olefin anti aldol
Me
Me
O
OH
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Amphotericin: The Clinician's Drug of Choice for Fungal Infections
Me O
O OH OH
OH
OH OH
OH
O
OMycosamine
MeHO
Me
CO2H
OH
II. Future Applications of the Catalytic Chemistry to Bio-organic Chemistry
Serious Side effects; much interpatient variation
Mechanism of action largely unknown
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Amphotericin: The Clinician's Drug of Choice for Fungal Infections
Me O
O OH OH
OH
OH OH
OH
O
OMycosamine
MeHO
Me
CO2H
OH
PolyeneAmphotericin B
Nystatin
FormulationLiposomalLipid ComplexColloidal DispersionLiposomal
NameAmbisomeAbelcetAmphotecAmphocilNyotran
CompanyNeXstarThe Liposome Co.Sequua in USAZeneca in UKAronex
StatusMarketed in UKMarketed in UK and USAPhase 4MarketedPhase 2/3
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Me O
O OH OH
OH
OH OH
OH
O
OH
MeHO
Me
CO2H
OH
Rigid, Hydrophobic(Polyene) Spacer
Hydrophilic(Polyol) Spacer
Hairpin TurnsHairpin Turns
Structural Analysis: Amphotericin
The chemoselective synthetic manipulation of this natural product, as well as the construction of “smart” designed probes is non-trivial
“…however, we are aware that selective modification of the hydroxyl groups involves very difficult chemical synthesis task…probably only through synthesis can derivatives be prepared…”
Molecular Pharmacology 1997, 52, 560
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Amphotericin B
Channel Model
Extrazellulär
Cytoplasma
AmBCholesterin
O O
OH
O
O
O
CH3
NH2
H3C
HOCH3
H3C
OH OH
OH
OH OH
OHOH
COOH
OHAmphotericin B
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Me O
O OH OH
OH
OH OH
OH
O
OMycosamine
MeHO
Me
CO2H
OH
Calculations suggest that it is critical in organizing channel
Implicated in the formation of double channels
Suggested to interact with sterol
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Me
OH
MeHO
O
Me
OH
HO MeMeMe
OH
Me
OH
HO
O
Erythronolide A Seco-Acid
Ongoing Applications in Polyketide Syntheses
O
O
O
OH
OH
Me
Me
Me
OH
OH
Me
Me
Me
Me
HO
Dieter Muri
Syn-Propionate aldols
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TBSO
OHMe
O
Me
N
Me
OH
TBSO
Me
O
Me
Me
N
N
Me
O
Me HO
N
Me
O
MeMe
TBSO
HO Me
OH
Me
N
Me
O
Me Me
EtIN
Me
Me
O
Me
TBSO
O
+
91 % 65 %
+
Fragment Coupling O
O
O
OH
OH
Me
Me
Me
OH
OH
Me
Me
Me
Me
HO
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O
N
OHO
Me
Me
Me
O
N
Me
Me
Me
Me
HO
Et
O
OHOH
Me
Me
Me
OH
OH
O
Me
Me
HO
OO
NH
N
OHO
Me
Me
Me
O
N
Me
Me
Me
Me
HO
N N
Me Me
O O
MeMe OHMe
HO
Me
OHMe
OH
O
O
OHOH
Me
Me
Me
OH
OH
Me
Me
Me
Me
HO
O
Diversity Oriented Synthesis
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Arbeitsgruppe
P. Aschwanden
N. Becker
D. Cereghetti
C. Czeckelius
L. Fader
R. Faessler
A. Fettes
C. Fischer
L. Scherer
J. Waser
T. Watanabe
N. Wurtz
J. Yasuoka
P. Zarotti
W. Zhao
A. Zumbuehl
S. Jonnson
T. Knoepfel
A. Lerchner
N. Lohse
C. Marti
D. Muri
S. Reber
T. Ritter
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Arnold and Mabel Beckman Foundation
Pharmacia Upjohn
Merck & Co.Pfizer Inc.Eli Lilly
David and Lucile Packard Foundation
Camille and Henry Dreyfus FoundationAlfred P. Sloan Foundation
Astra-ZenecaAT & T
Novartis
ETH-Zürich and KGF FundsF. Hoffmann-La Roche
Schweizerischer Nationalfonds