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Chemistry 150, Fall 2008
“The Pain Inducing, Cancer
Remedy”: The Occurance,
Bioactivity, Biosynthesis, and
Synthesis of Vincristine
Vincristine was approved by the Food and Drug
Administration (FDA) in 1984. It is available in the trade
under the names Oncovin, Vincasar, and Vincrex. This drug
was previously known as leurocristine (LCR). The derivatives
of the vinca alkaloids include vincristine, vinblastine,
vindesine, and vinopocetine.
II. Biological Activity
Vincent Ting, Fall 2008
Introduction
Vincristine is an anti-neoplastic drug found in the
Madagascar periwinkle (Catharanthus roseus). It is clinically
used to treat a range of cancers including various lymphomas
and sarcomas, advanced testicular cancer, breast cancer and
acute leukemia.12 Vincristine belongs to a group of bisindole
alkaloids derived from tryptophan.
Vincristine disrupts the formation of microtubules cells,
which inhibits the replication of cancer cells. It is generally
used as a chemotherapy drug for cancer patients to slow the
growth of cancer cells. Vincristine sulfate is widely used to
treat leukemia, malignant lymphomas, meuroblastoma,
Hodgkin’s disease, Wilm’s tumor, and many other cancers.
N
N
H
OH
CO2Me
MeO
Vincristine
N
H
OAc
OH
N H CO2Me
CHO
Figure 1. Vincristine, used to treat various types of cancer
and can be found in the Madagascar periwinkle.
I. Occurrence
Vincristine is found in Catharanthus roseus, more
commonly known as the Madagascar periwinkle. This plant
was formerly named Vinca roseus. The genus Catharanthus
has eight species, seven of which are endemic to the island of
Madagascar and the eighth is found in the subcontinent of
India. In the wild, the Catharanthus roseus is an endangered
plant due to its habitat destruction. However, it is widely
cultivated and globally grown in tropical and subtropical
areas.
Figure 2. Catharanthus roseus. source (http://www.biologie.
uni-regensburg.de/Botanik/Schoenfelder/kanaren/images/
Catharanthus_roseus.jpg)
Figure 3. Vial of Vincristine. Source (http://www.vghks.gov.
tw/ph/%B3B%A4%E8%B6%B0/drug/vincristine.files/image0
04.jpg)
Vincristine can only be administered intravenously and if
introduced into the spinal cord fluid, it ensures almost
absolute death. Patients experience paresthesias because
vincristine causes damage to small nerve fibers carrying the
sensations of pain and temperature. Another side affect would
be a disturbance of nerve fibers that help muscles around the
colon that move stool, which means that the patient will
experience constipation. Toxic effects may include numbness,
pain, tingling, headaches, rashes, a change in blood pressure,
dizziness, nausea, vomiting, hearing problems, and hair loss.
Effects are more common to those with poor liver function.
Short-term pretreatment with vincristine expresses
impressive protective effects in cultured adult mouse
myocytes subjected to acute oxidative stress.3 However, it can
damage the patient’s bone marrow or because of its
neurotoxicological effects, so the amount administered is
severely limited.2 The organism expresses thermo allodyna
and mechanical hypersensitivity after taking vincristine.
Vincristine expresses unfavourable side effects, but is very
efficient in treating various types of cancers.
Vinca alkaloids inhibit microtubule formation by binding to
tubulin.6 All four clinically available vinca alkaloids cause
neuropathy, but vincristine has the lowest risk for peripheral
neuropathy. Similarly, vinblastine has the highest risk of
peripheral neuropathy and the only difference N-methyl group
rather than N-formyl on the vindoline fragment. vincristine
Chemistry 150, Fall 2008
can be an oxidized product from vinblastine. Vinca alkaloids
have various beneficial properties besides being anti-mitotic
and anti-microtuble drugs. Derivatives of vinca alkaloids have
shown to be immunosuppressive drugs and nootropic drugs.
III. Biosynthesis
Vincristine belongs in a group of alkaloids that derive from
tryptophan. The structure of vincristine is derived by coupling
of two alkaloids, catharanthine and vindoline. The
biosynthesis of vincristine is summarized in Figure 4. First,
catharanthine (1) is oxidised by a peroxidise catalyst (2),
which forms a peroxide which acts as a leaving group. When
the peroxide leaves, the carbon-carbon bond is broken and the
intermediate electrophilic ion (3) is attacked by the
nucleophilic vindoline (4). The molecule is then reduced in
the dihydropyridinium ring by NADH-dependent 1,4-addition,
giving the substrate for hydroxylation (7). Finally, reduction
by NADH yields vincristine.
N
N
H
OH
O
peroxidase
CF3CO
N
H
CO2Me
2
O
N
m-chloroperbenzoic
acid
N
N
N
H
CO2Me
charged oxygen to form catharanthine N-oxide (9). When the
carbon-carbon bond is broken by the trifluoroacetic
anhydride, the intermediate electrophilic ion (10) is attacked
by the nucleophilic vindoline (11). The substrate is then
reduced in the dihydropyridinium ring and oxidized by ferric
chloride and oxygen (14). Finally, vincristine is formed by
reduction by sodium borohydride.
There are other methods for the synthesis of vincristine.
The synthesis of (+)-vincristine has been accomplished
through a stereoselective coupling of demethylvindoline and
the eleven-membered carbomethoxyverbanamine precursor.4
The
oxidation
of
17-hydroxy-11-methoxytabersonine,
followed by regioselective acetylation with mixed anhydride
method yielded demethylvindoline.4 Fukuyama’s first de novo
syntheses of these alkaloids was published in 2002 and 2004,
but researchers continue to find new and efficient methods
that allow for the assembly of key substructures of vincristine.
N
H
CO2Me
CO2Me
9
8, catharanthine
1, catharanthine
(CF3CO)2O
N
N
N
5
N
H
N
H
H
CO2Me
N
3
V
CO2Me
OAc
OH
N H CO2Me
MeO
CHO
4, vindoline (V)
H
NADH
N
H
N
H
10
H
N
V
CO2Me
CO2Me
N
OAc
OH
N H CO2Me
MeO
CHO
11, vindoline (V)
H
12
CONH2
N
N
N
H
N
[O]
V
CO2Me
7
6
NaO2C
V
OH
CO2Me
N
H
N
N
H
NADH
N
V
CO2Me
OH
CO2Me
MeO
14
NaBH4
N
H
N
OAc
OH
N H CO2Me
CHO
N
H
OH
CO2Me
Vincristine
Figure 4. Biosynthesis of Vincristine.
V
OH
CO2Me
N
H
13
N
N
H
FeCl3
O2
MeO
8
Vincristine
IV. Synthesis
Like the biosynthesis, the synthesis of vincristine is
composed of catharanthine and vindoline. Catharanthine is
catalyzed by m-chloroperbenzoic acid which adds a negatively
Figure 5. Synthesis of Vincristine.8
N
H
OAc
OH
N H CO2Me
CHO
Chemistry 150, Fall 2008
Conclusion
Vincristine is a very interesting and useful drug. Derived
from catharanthine and vindoline through the alkaloid
pathway, it is used to treat various cancers by disrupting the
formation of microtubules cells, which inhibits the replication
of cancer cells. This drug can only be introduced
intravenously and causes slight nerve damage. Vinca alkaloids
possess beneficial properties such as slow cancer cell growth,
yet they have slight toxic effects and occasionally cause the
patient to be in pain. Since vincristine expresses the lowest
risk of peripheral neuropathy out of the four vinca alkaloids,
the positive effects outweigh the negative. Vincristine is a
useful drug used to treat various lymphomas and sarcomas,
advanced testicular cancer, breast cancer, acute leukemia,
meuroblastoma, and other types of cancers. The development
of an easy synthesis for vincristine is important and
researchers continue to find new and efficient for the
synthesis of vincristine.
References
________________
1
Thibault, K.; Van Steenwinckel, J.; Brisorgueil, M.-J.;
Fischer, J.; Hamon, M.; Calvino, B.; Conrath, M. Serotonin 5HT2A receptor involvement and Fos expression at the spinal
level in vincristine-induced neuropathy in the rat. Pain 2008,
140, 305-322.
2
Harvey, M. J.; Banwell, M. G.; Lupton, D. W. The synthesis
of compounds related to the indole-indoline core of the vinca
alkaloids (+)-vinblastine and (+)-vincristine. Tetrahedron
Lett. 2008, 49, 4780-4783.
3
Chatterjee, K.; Zhang, J.; Honbo, N.; Simonis, U.; Shaw, R.;
Karliner, J. S. Acute vincristine pretreatment protects adult
mouse cardiac myocytes from oxidative stress. J. Mol. Cell.
Cardiol. 2007, 43, 327-336.
4
Kuboyama, T.; Yokoshima, S.; Tokuyama, H.; Fukuyama, T.
Stereocontrolled total synthesis of (+)-vincristine. Proc. Natl.
Acad. Sci. U. S. A. 2004, 101, 11966-11970.
5
Lynch, J. J., III; Wade, C. L.; Zhong, C. M.; Mikusa, J. P.;
Honore, P. Attenuation of mechanical allodynia by clinically
utilized drugs in a rat chemotherapy-induced neuropathic pain
model. Pain 2004, 110, 56-63.
6
Takigawa, N.; Tanimoto, M. Vinca alkaloid and MDR1. Gan
to Kagaku Ryoho 2008, 35, 1086-1089.
7
Jordan, M. A.; Horwitz, S. B.; Lobert, S.; Correia, J. J.
Exploring the mechanisms of action of the novel microtubule
inhibitor vinflunine. Semin. Oncol. 2008, 35, S6-S12.
8
Dewick, P. Medicinal Natural Products:A Biosynthetic
Approach, 2nd ed., Wiley&Sons: West Sussex, England,
2001, p 350-355.