Reviewing Camptothecin
Baran Group Meeting
9/ 26/ 2007
Ke Chen
In Fig 1, normally, topoisomerases I introduces a nick in the DNA
backbone allowing the rotation of one strand around another. This
releases the torsional strain which otherwise accumulates in front of
the advancing replication fork (the large arrow). The DNA break is
extremely transient and is religated as it release the other strand.
O
N
N
O
OH
O
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
This quinoline based alkaloid was found in the bark of the Chinese
camptotheca 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 thousands
of 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 a
selective anticancer drug.
The unique mode of action for this potent cytotoxic compound was found to
act via inhibition of an enzyme known as DNA topoisomerase I.
Fig 1
Fig 2
In Fig 2, when camptothecin is present(black oval with C), it binds to the
topoisomerase I-nicked DNA complex. This prevents the religation of the
nicked strand and the release of the enzyme. Eventually, the replication
fork collides with the complex, causing the formation of a double-strand
break.
Hsiang, Y.H. Cancer Res. 1989, 49, 5077.
1
Baran Group Meeting
9/ 26/ 2007
Discovering Camptothecin
Monroe E. Wall (1916–2002)
Born in 1916 in Newark, NJ, Dr. Wall received
his B.S., M.S., and Ph.D. degrees from
Rutgers
University. In 1941, he joined the United States
Department of Agriculture. From 1941 to 1960,
Dr. Wall gained national recognition as a
government scientist in steroid chemistry. In
1960, Dr. Wall joined the Research Triangle
Institute (RTI) to start a chemistry research
group. He became RTI Vice President of
Chemistry and Life Sciences in 1971. Among
numerous contributions to the field of natural
product research, he is best known for the
discovery and development of taxol and
camptothecin. In 1981 He retired from
administration and devoted his time to research
until two weeks before his death at 85.
Timeline of Camptothecin:
1960-1966
Mansukh C. Wani
Born in Nandurbar, India, Dr. Wani received
his B.S. and M.S. degrees from the University
of Bombay. He came to the United States and
finished his Ph.D in chemistry at Indiana
University under the instruction of Professor
Ernest Campaign. After a postdoctoral
fellowship at the University of WisconsinMadison, he accepted a position at RTI from
Dr. Wall in 1962. Together they developed two
of
the
most
promising
anticancer
agents, taxol and camptothecin., which are
benefiting millions of people all over the
world. Dr. Wani is still active at RTI,
supervising junior researchers.
Isolation of active compound from amptotheca acuminata;
determination of structure of camptothecin
O
O
N
N
N
OH
N
O
OH
low solubility in water
O
OH
O
Na+
O
water-soluable but inactive
Clinical trials started in the 1960s but were abandoned shortly thereafter.
1985
Monroe Doctrine: "Get good people, support them with good facilities,
do good science, work hard, and keep doing it."
Ke Chen
Determination of mechanism of action of camptothecin
After Camptothecin returned, like " the phoenix from the ashes", it rekindled
interest in developing analogs of camptothecin that were both water soluble
and retained anticancer activity
1996
FDA approval of two analogs of camptothecin for treatment
of ovarian, lung, breast and colon cancer.
Some numbers and facts...
11729 publications regarding "camptothecin".
114 publications involving total or formal synthese of camptothecin and its
derivatives.
By 2001, the analogs developed included Pharmacia’s Camptosar and
GlaxoSmithKline’s Hycamtin, collectively reporting worldwide sales
approaching $ 800 million.
Synthetic chemists embrace practility and perfection.
2
Camptothecin: From Bench to Bedside
Baran Group Meeting
9/ 26/ 2007
Classical condensation
Ke Chen
O
O
N
O
N
Friedlander quinoline synthesis
O
O
CO2Et
CO2Et
O
50 %
NTs
N
CO2Et
N
O
CO2H
CO2Et
N
O
NaH, EtI, DMF
steps
O
Br
aq. NaOH
N
CHO
CN
O
Na2CO3, DMF, 70 oC
76-97 %
O
CO2Et
NH2
CO2H
CN
O
OH
N
Ts
N
O
N
O
rt, 65-100 %
O
O
N
CN
O
O
O
N
CO2Et
O
O Et
N
OH
N
O
N
Et
CO2Et
O
1 eq LDA
CO2Et
o
-78 C
Et
O
NTol
d. r. = 82 :18
NH2
O
CO2Et
O
NTs
O
Et
p-TsOH, tol
reflux, 73 %
CO2Et
CO2Et
LDA, RT
1. First asymmetric synthesis
O
N
EtO2C
Et
OH
dl-camptothecin
CO2Et
2. 1,4-Asymmetric induction in the diastereoselective ethylation was achieved
using an N-tosyl-(R)-proline derivative
N
O
1. First synthesis reported
OH
2. One of the key steps involves the annulation of an ester
carbonate and unsaturated lactam
Stork G., Schultz A. G. J. Am. Chem. Soc. 1971, 36, 4074-4075.
O
Tagawa H. Tetrahedron Lett. 1989, 30, 2639-2640.
3
Baran Group Meeting
9/ 26/ 2007
Camptothecin: From Bench to Bedside
Classical condensation
CO2Me
O
1. quinine-water
2. recrystalization
HO
Et
HO2C
CO2H
O
OCO2Me
1. O2, eosine
O
2. SOCl2
O
Cl
N
O
O
N
Et
OCO2Me
O
NH2
O
O
O
1. HBr, 140 oC
N
p-TsOH, tol
reflux, 75 %
dl-CPT
O 2. Me NH, CuCl
2
2
MeO2C
O2, DMF
pyr
O
O
O
NTol
Et
O
85 % overall
3. MeOCOCl, Et3N
OH
CO2H
N
CO2Me
O
1. PhCHO, NaHMDS
2. O3
3. TMSCHN2
O
O
Ke Chen
O
(S)-camptothecin
N
Danishefsky S. J. J. Org. Chem. 1993, 58, 611-617.
Danishefsky S. J. J. Am. Chem. Soc. 1971, 93, 5575.
NH
O
Corey E. J. J. Org. Chem. 1975, 40, 140-2141.
R2
Friedlander quinoline synthesis
CO2Me
H
N
H
CO2Me
•
MeO2C
H
CO2Me
Et3N
R1
92 %
N
O
O
R2
R1
Et
N
O
O
major
Two analogs:
Et
CO2Me
+
CO2Me
(CH2O)n/H
95 %
O
R1
O
N
CO2Me
t-BuOK/EtI
N
(CH2O)n/H+ R2
N
CO2Me
O
DME, 91 %
CO2Me
O
HO
O
O
N
O
HO
O
N
N
N
N
O
O
O
OH
O
OH
O
4
Camptothecin: From Bench to Bedside
Baran Group Meeting
9/ 26/ 2007
O
Modern organic chemistry
Ke Chen
Other recent applications of 1,4-addition to pyridinium salts
N
N
Me
O
F
N
CO2Me
N
OH
LDA
O
N
F
OTf
DCM, rt
Me
CO2Me
N
CO2Me
Me
Br
H
OTf
Br
N
-30 oC
1.5 h
O
OLi
O
O
SePh
Methylervitsine
H
N
Me
LDA, THF
O
PhSeBr
?
intermediate
O
30 min
N
I-
CO2Me
O
O
-78 oC, 30 mins
Bennasar M. L.. J. Chem. Soc., Chem. Commun. 1995, 125.
then DDQ
O
O
N
N
N
O
N
CO2Me
O
Br
Bn
Bn
N
Br
O
NH2
O
OH
O
Bennasar M. L.. J. Chem. Soc., Chem. Commun. 2000, 2459.
Bennasar M. L.. J. Org. Chem. 2002, 67, 7465.
O
N
C6H11N=C
AcONa, MeOH, 65 oC
NC
71 %
C6H11
N
H
O
Lavilla R. Org. Lett 2006, 8, 5789-5792.
5
Discovering Camptothecin
Baran Group Meeting
9/ 26/ 2007
Ke Chen
Diels-Alder Reaction:
MeO
EtO
OMe
OMe
EtO
N
rt
OEt
NSO2Me
O
OEt
MeO
N
N
H
O
N
reflux
N
CN
82 %
CN
Ms OEt
OEt
N
N
O
Me3OBF4
OEt
CO2Et
Revised alternative:
CO2Et OEt
OMe
OMe
O
N
N
86 % ee
OEt
N
N
N
N
H
OEt
N
75 %
HO
OMe
CN
CN
OEt
Sharpless
Dihydroxylation
N
reflux
CO2H
OEt Modified
O
Ac2O
O
O
OMe
OAc
NaClO2
N
N
OEt
HO
O
1. HBr
2. K2CO3
O
N
N
N
NaH2PO4
OEt
HO
OH
O
OH
O
O
O
N
O
N
48 %
N
CN
CN
74 %
O
Boger, D. L.. Tetrahedron 2002, 58, 6343.
Fortunak J. Tetrahedron Lett. 1996, 37, 5679-5682.
6
Camptothecin: From Bench to Bedside
Baran Group Meeting
9/ 26/ 2007
[4+1] Radical Annulation:
Curran and Shibasaki:
CO2H
O
O
1. PCl5
2. HBr
N
HN
CN
3. MeOH
CO2H
CO2Me
Br
OMe
OMe
CO2Me
Br
N
OTBS
Et
PhNC
Me3SnSnMe3
OTBS
CN
Et
OMe
1. ICl
2. HCl-EtOH
71 % (2 steps)
CO2Me
Et
OTMS
98 %, 84 % ee
N
N
O
TMSI, cat H2O
CH3CN, 87 %
O
I
O
Et
OH
HN
O
I
O
Et
OH
> 99 % ee after
recryst. from MeOH-CHCl3
Over 100 derivatives of camptothecin have been prepared by Dr. Curran's
research group utlizing this approach.
O
N
EtCN, -40 oC, 18 h
O
O
dl-Camptothecin
5 mol % SmLn
1.5 equiv TMSCN
SMT
SMT
N
O
N
Br
Ke Chen
R
O
PhNC
N
N
N
R
R
O
O
N
N
N
N
CO2Me
R
Shibasaki M.; Curran D. P. J. Am. Chem. Soc. 2001, 123, 9908-9909.
Shibasaki M. J. Am. Chem. Soc. 2000, 122, 7412-7413.
Et
Curran D. P. J. Am. Chem. Soc. 1992, 114, 5863-5864.
7
Camptothecin: the Future
Baran Group Meeting
9/ 26/ 2007
1. MesLi
2.
N
Structure-Activity Relationships:
N
Li
N
N
1. I2
2. NaBH4, H2O
NCHO
OLi
OMe
3. n-BuLi
N
Ke Chen
B
one pot
OMe
N
O
A
C N
HO
D
N
O
N
E O
I
N
I
TMSCl, NaI
OH
N
O
2.
(CH2O)n, CH3CN
OMe
N
OH
1. n-BuLi
O
O
O
Hycamtin
OH
O
O
CO2R*
O
O
Et
Et
OR*
LiO
O
N
O
HO
HCl
N
iPrOH
N
H
O
DME
Cl
N
N
t-BuOK
I
O
O
O
10 additional CPT
derivatives in various
stages of clinical trials
N
N
O
O
Camptosar
OH
O
O
N
N
(Ph3P)2Pd(OAc)2
Cl
O
OH
O
O
N
N
KOAc, CH3CN
O
OH
O
"Trees hold the answer to saving the planet. Scientists are discovering more
remarkable 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."
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.
Reese Halter
Comins D. L. Org. Lett 2001, 3, 4255-4257.
8