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Reviewing Camptothecin
1
Ke ChenBaran Group Meeting9/ 26/2007
This quinoline based alkaloid was found in the bark of the Chinesecamptotheca tree.
Camptotheca goes by many names in China, including "happy tree","dragon tree" and "fine tree".
Chinese have used the "happy tree" in traditional medicine for thousandsof years. It has been used for psoriasis, leukemia and diseases of liver,gallbladder, spleen, and stomach.
During the last half century, scientists have discovered its potential as aselective anticancer drug.
The unique mode of action for this potent cytotoxic compound was found toact via inhibition of an enzyme known as DNA topoisomerase I.
Fig 1 Fig 2
In Fig 1, normally, topoisomerases I introduces a nick in the DNAbackbone allowing the rotation of one strand around another. Thisreleases the torsional strain which otherwise accumulates in front ofthe advancing replication fork (the large arrow). The DNA break isextremely transient and is religated as it release the other strand.
In Fig 2, when camptothecin is present(black oval with C), it binds to thetopoisomerase I-nicked DNA complex. This prevents the religation of thenicked strand and the release of the enzyme. Eventually, the replicationfork collides with the complex, causing the formation of a double-strandbreak.
N
N
O
O
OOH
Name Camptothecin
IUPAC name 4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]
indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione
CAS number 7689-03-4
Formula C20H16N2O4
Mol. mass 348.352 g/mol
Hsiang, Y.H. Cancer Res. 1989, 49, 5077.
Discovering Camptothecin
2
Ke ChenBaran Group Meeting9/ 26/2007
Born in 1916 in Newark, NJ, Dr. Wall receivedhis B.S., M.S., and Ph.D. degrees fromRutgersUniversity. In 1941, he joined the United StatesDepartment of Agriculture. From 1941 to 1960,Dr. Wall gained national recognition as agovernment scientist in steroid chemistry. In1960, Dr. Wall joined the Research TriangleInstitute (RTI) to start a chemistry researchgroup. He became RTI Vice President ofChemistry and Life Sciences in 1971. Amongnumerous contributions to the field of naturalproduct research, he is best known for thediscovery and development of taxol andcamptothecin. In 1981 He retired fromadministration and devoted his time to researchuntil two weeks before his death at 85.
Monroe E. Wall (1916–2002)
Monroe Doctrine: "Get good people, support them with good facilities,do good science, work hard, and keep doing it."
Mansukh C. Wani
Born in Nandurbar, India, Dr. Wani receivedhis B.S. and M.S. degrees from the Universityof Bombay. He came to the United States andfinished his Ph.D in chemistry at IndianaUniversity under the instruction of ProfessorErnest Campaign. After a postdoctoralfellowship at the University of Wisconsin-Madison, he accepted a position at RTI fromDr. Wall in 1962. Together they developed twoof the most promising anticanceragents, taxol and camptothecin., which arebenefiting millions of people all over theworld. Dr. Wani is still active at RTI,supervising junior researchers.
Timeline of Camptothecin:
1960-1966 Isolation of active compound from amptotheca acuminata;determination of structure of camptothecin
1985 Determination of mechanism of action of camptothecin
N
N
O
O
OOH
N
N
O
OOH
OH
ONa+
low solubility in water water-soluable but inactive
Clinical trials started in the 1960s but were abandoned shortly thereafter.
1996 FDA approval of two analogs of camptothecin for treatmentof ovarian, lung, breast and colon cancer.
After Camptothecin returned, like " the phoenix from the ashes", it rekindledinterest in developing analogs of camptothecin that were both water solubleand retained anticancer activity
Some numbers and facts...
11729 publications regarding "camptothecin".
114 publications involving total or formal synthese of camptothecin and itsderivatives.
By 2001, the analogs developed included Pharmacia’s Camptosar andGlaxoSmithKline’s Hycamtin, collectively reporting worldwide salesapproaching $ 800 million.
Synthetic chemists embrace practility and perfection.
Camptothecin: From Bench to Bedside
3
Ke ChenBaran Group Meeting9/ 26/2007
N
N
O
O
OOH
CHO
NH2
N
O
CO2Et
CO2Et
N
N
CO2H
CO2Et
N
N
O
Et CO2Et
OCO2Et
Et CO2Et
OCO2Et
Et CO2Et
OH
EtO2C
N
N
O
O
O
Et
CO2Et
Stork G., Schultz A. G. J. Am. Chem. Soc. 1971, 36, 4074-4075.
aq. NaOH
50 %
1 eq LDA
-78 oC
LDA, RT
dl-camptothecin
1. First synthesis reported
2. One of the key steps involves the annulation of an estercarbonate and unsaturated lactam
Classical condensation
Friedlander quinoline synthesis
N
N
O
O
OOH
N
O
O
OCN
O
CO2EtO
NTs
N
O
O
OCN
CO2Et
N
O
O
OCN
O
CO2EtO
NTs
Et
N
O
O
OOH
O
Tagawa H. Tetrahedron Lett. 1989, 30, 2639-2640.
Br
NTs
CO2H
Na2CO3, DMF, 70oC
76-97 %
NaH, EtI, DMF
rt, 65-100 %
NH2
NTol
p-TsOH, tolreflux, 73 %
1. First asymmetric synthesis
2. 1,4-Asymmetric induction in the diastereo-selective ethylation was achievedusing an N-tosyl-(R)-proline derivative
steps
d. r. = 82 :18
4
Ke ChenBaran Group Meeting9/ 26/2007
Classical condensation
Friedlander quinoline synthesis
NH2
NTol
p-TsOH, tolreflux, 75 %
NH
CO2MeMeO2C
•CO2Me
HH
Et3N
92 % N
O
CO2Me
CO2Me
t-BuOK/EtI
DME, 91 %N
O
CO2Me
CO2Me(CH2O)n/H
+
95 %N
O
CO2Me
O
O
N
O
CO2Me
O
O
O
N
N
O
O
O
MeO2C
1. HBr, 140 oC
2. Me2NH, CuCl2O2, DMF
N
N
O
O
OOH
N
N
O
O
OOH
HOHO
Et
Danishefsky S. J. J. Org. Chem. 1993, 58, 611-617.Danishefsky S. J. J. Am. Chem. Soc. 1971, 93, 5575.
Two analogs:
Camptothecin: From Bench to Bedside
Corey E. J. J. Org. Chem. 1975, 40, 140-2141.
O
HO2C
CO2H
O
Et
OHCO2H
HO
OO
O
Et OCO2Me
OO
O
Et OCO2Me
O
Cl
N
NH
1. quinine-water
2. recrystalization
3. MeOCOCl, Et3N
pyr(S)-camptothecin
1. O2, eosine2. SOCl2
N
O
CO2Me
O
O1. PhCHO, NaHMDS2. O33. TMSCHN2
85 % overall
dl-CPT
N
R2
R1
O
CO2Me(CH2O)n/H
+
N
R2
R1
O
O
O
N
R2
R1
O
Et
O O
major
Camptothecin: From Bench to Bedside
5
Ke ChenBaran Group Meeting9/ 26/2007
Bennasar M. L.. J. Chem. Soc., Chem. Commun. 2000, 2459.Bennasar M. L.. J. Org. Chem. 2002, 67, 7465.
N Br
N
N
O
O
OOH
OTf
N
F
CO2Me
N Br
NCO2Me
F
N Br
NCO2Me
O
O
O
O
OTf
DCM, rt
30 min
O O
O
O O
OLi
LDA, THF
-78 oC, 30 mins
-30 oC
1.5 h
then DDQ
N
N
O
O
OOH
Modern organic chemistry
N
OMe
N
CO2Me
Me
I-
NMe
Me
H
HCO2Me
SePh
O
Methylervitsine
LDA
intermediate
PhSeBr?
Bennasar M. L.. J. Chem. Soc., Chem. Commun. 1995, 125.
N
O
Bn
Br
NH2
C6H11N=C
AcONa, MeOH, 65 oC
71 %
N
Bn
NC
NH
OC6H11
Lavilla R. Org. Lett 2006, 8, 5789-5792.
Other recent applications of 1,4-addition to pyridinium salts
Discovering Camptothecin
6
Ke ChenBaran Group Meeting9/ 26/2007
N
N
N
O
O
OOH
Diels-Alder Reaction:
OMe
NSO2Me
CO2Et
EtO
OEt
EtO OEt
rt
N
OMe
MsN
CO2EtOEt
OEt
OEtOEt
N
OMe
N OEt
OEt
OMe
N
OMe
N OEt
OEt
O
HO
ModifiedSharpless
Dihydroxylation
N
OMe
N OEt
OEt
O
HO
NaClO2
NaH2PO4
OH
1. HBr2. K2CO3
Boger, D. L.. Tetrahedron 2002, 58, 6343.
NH
O
N O
CNCO2H
Ac2O
reflux N
N
O
CN
N
N
O
CNN
N
O
CN
HO
OAc
O
O
74 %48 %
75 %
Fortunak J. Tetrahedron Lett. 1996, 37, 5679-5682.
86 % ee
NH
O
N O
CN
Me3OBF4
reflux N
N
O
CN
82 %
MeOMeO
Revised alternative:
Camptothecin: From Bench to Bedside
7
Ke ChenBaran Group Meeting9/ 26/2007
[4+1] Radical Annulation:
Curran D. P. J. Am. Chem. Soc. 1992, 114, 5863-5864.
Shibasaki M.; Curran D. P. J. Am. Chem. Soc. 2001, 123, 9908-9909.Shibasaki M. J. Am. Chem. Soc. 2000, 122, 7412-7413.
CN
CO2H
CO2H
1. PCl52. HBr
3. MeOH
HN
Br
O
CO2Me
N
Br
O
CO2Me
Et
PhNCMe3SnSnMe3
N
N
O
Et
CO2Me
dl-Camptothecin
N
Br
O
R
N
O
RN
N
R
O
N
N
R
O
PhNC
N
N
O
Et
CO2Me
N OTBS
OMe
SMT
HN O
O
I O
Et OH
O
N
CN
OTBS
OMe
SMT
Et OTMS
N O
OMe
I O
Et OH
5 mol % SmLn1.5 equiv TMSCN
EtCN, -40 oC, 18 h
98 %, 84 % ee
1. ICl2. HCl-EtOH
71 % (2 steps)
TMSI, cat H2OCH3CN, 87 %
> 99 % ee afterrecryst. from MeOH-CHCl3Over 100 derivatives of camptothecin have been prepared by Dr. Curran's
research group utlizing this approach.
Curran and Shibasaki:
Camptothecin: the Future
8
Ke ChenBaran Group Meeting9/ 26/2007
N OMe
1. MesLi
2. N NCHO
3. n-BuLi N OMe
NLi
N
OLi
1. I22. NaBH4, H2O
N OMe
I
OH
one pot
TMSCl, NaI
(CH2O)n, CH3CNN O
O
I
1. n-BuLi
2.
CO2R*
O
N O
O
LiOOR*
O
Et
HCl
iPrOH
NH
O
O
O
Et
HO
N Cl
It-BuOK
DME
N
N
O
O
OOH
ClN
N
O
O
OOH
(Ph3P)2Pd(OAc)2
KOAc, CH3CN
Comins D. L. Org. Lett 2001, 3, 4255-4257.
This remains the most efficient route reported (six steps, 12.5 % overall yield).
Scientists from GSK are utilizing this approach to synthesize analogs of CPT.
N
N
O
O
OOH
A B C
D
E
Structure-Activity Relationships:
N
N
O
O
OOH
HO
N
N
N
O
O
OOH
ON
O
N
Hycamtin
Camptosar
10 additional CPTderivatives in variousstages of clinical trials
"Trees hold the answer to saving the planet. Scientists are discovering moreremarkable facts about trees, forests and animal interactions than ever before.The work of these scientists is immeasurably protecting humanity and all life,now and into the future."
Reese Halter