Anticancer Extracts or Hemi-Synthesized Starting From

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Turkish Journal of Agricultural and Natural Sciences
Special Issue: 1, 2014
TÜRK
TARIM ve DOĞA BİLİMLERİ
DERGİSİ
TURKISH
JOURNAL of AGRICULTURAL
and NATURAL SCIENCES
www.turkjans.com
Anticancer Extracts or Hemi-Synthesized Starting From Medicinal Herbs.
Wafa Soudani a, Rachid Djafer b, Fatma/Z Hadjadj -Aoul a ,Mohamed Abdaoui c
Chemistry Laboratory Therapeutic, Department of Pharmacy, Annaba Medical College and Algiers Medical
College, Annaba and Alger - Algeria.
b:
Service of Toxicology CHU Annaba and Head of Department of Pharmacy, Annaba Medical College, Annaba,
Algeria.
c:
Chemistry Laboratory applied, University of Guelma -Algeria.
Corresponding author: [email protected]
Abstract
For much of cancer the adequate biodisponibility at the tumoral level, without over-exposure of healthy
fabrics, remains a major limitation for an effective chemotherapy and not very toxic, the improvement of the
specificity of action and the prevention of toxicity represent the main axes of research under full development. The
greatest challenge in cancerology is to improve specificity of action of the anti-cancer drugs by detection of the
cancer cells and treatment selective of these sick cells. The anti-cancer ones discovered during first decades of
chemotherapy interacted mainly with the DNA or its precursors inhibiting the synthesis again material genetics, or
causing irrevocable damage with
the DNA itself. These last years, the discovery of new agents
extended from the natural products most conventional, these substances are themselves a source for the
synthesis or the hemisynthesis of other anti-cancer molecules. In this context, the objectives of our work were to
give a chemical and therapeutic study of anti-cancer derived from medicinal herbs and to demonstrate the
principals methods of obtaining of these anti-cancer derivatives.
a:
Keywords: cancer, natural anticancer, synthesis, medicinal herbs.
promising results in the treatment of various types
of cancers.
Introduction
The DNA plays a key role in the life and the
division of the cells, it constitutes the target most
exploited in antitumor chemotherapy; therefore it is
obvious that the sought-after goal in the use of the
antitumor agents is to reach the tumoral cells in
order to destroy them. All this explains the
multiplicity of the research undertaken in the field of
the cancerology; several processes can be used for
the eradication of a tumor: the surgical exérèse, the
radiotherapy and chemotherapy which are the
average classics employed and intended to cause
cellular death.
Progress of anticancer means allowed the
emergence of different therapeutic approaches: the
anticancer resulting ones from molecular biology
and the anticancer ones of natural origin. Today, this
therapeutic innovation has allows a better control of
the side effects and toxic effects, and to note
Anticancer extracts of Camptothécine:
Chemical structure: The compound
pentacyclic comprises a cycle pyrrolo [3,4b] quinoline (cycles A, B, C), a
cycle indolizine (cycle C, D) and a d-lactonic cycle
(E) with a chiral center (in C4) of configuration S,
carrying a tertiary hydroxyl.
Structural modifications were
carried out by
substitution into 10 of (S) - camptothécine
natural or of (S) - 9-hydroxycamptothécine
1343
Turkish Journal of Agricultural and Natural Sciences
Special Issue: 1, 2014
9
10
11
A
B
8
O
12
N
C
14
6
7
D
N
1
5
E
2
4
H 3C
O
3
O
HO
Fig.1: Chemical structure of Camptothécine.
Irinotécan,
comprising OH phenolic into 9
(carbamate) and a chain ethyl in 11.
The sequence pipéridinopipéridine carried by
carbamic ester makes it possible to increase the
hydrosolubility of éthylhydroxycamptothécine. Le
Topotécan is (+)-(4S)-10-[(diméthylamino) méthyl]4-éthyl-4,9-dihydroxy-1Hpyranol[3’,4’ :6,7]indolizino[1,2-b]quinoléine3,14(4H,12H)-dione.
C H
CH3
N
10
9
O
C H
H O
O
N
A
8
7
11
B
O
12
C
N
6
9
14
11
A
B
3
O
12
N
C
14
6
7
D
N
1
5
1
5
E
4
H 3C
10
8
D
N
, H C l , 3 H 2O
3
N
2
E
O
4
3
HO
, H C l
H
3
O
Fig. 2: Chemical structure of Irinotecan
C
2
O
3
O
H O
Fig.3: Chemical structure of Topotécan
he
o Preparation:
The camptothécine is an alkaloid extracted f
or the first time from the bark
from a Chinese tree,
Camptotheca acuminata, then of a tree of t
south
of
India
and
Taiwan, Nothapodytes faetida
Fig.4: Tree of Camptotheca acuminata
o
Mode of action:
The Camptothecine and its derivatives act o
n the replication of the DNA; the cut of one
of the chains by a topoisomérase allows
désenroulement
and
the
the relieving of the propeller of the DNA. Th
ese initial stages of the process of
replication are normally followed of a
welding of the chain broken with formation
of a fork of replication and a complete
duplication of the molecule of DNA. The
Camptothecine and its derivatives cause a
stabilization of the cleavable complex
normally formed between the DNA and the
topoisomérase I, this action induced of the
lesions simple-bit of the DNA which block
the replication.
1344
Turkish Journal of Agricultural and Natural Sciences
Special Issue: 1, 2014
o
Fig.5: Site of action of Irinotecan and Topotécan.
o
Therapeutic use: Irinotécan is used for
treatment
of
colorectaux
cancers
metastasic after failure of a former
treatment by the 5-fluorouracile, while
Topotécan is used for treatment of cancer
of the repeating ovary.
Anticancer synthesized starting from Podophyllotoxine:
o Chemical structure:
O
O
O
H
3
C
O
S
O
O
HO
O H
H O
O H
O
O
4
5
7
O
B
C
8
2
1
O
11
3
6
A
O
O
D
10
O
O
9
O
O
H
3
OCH
CO
H
3
3
CO
OR
R
= H
R
= H O
OCH
OCH
3
3
E t o p o s id e
P
+
O H
T é n ip o s id e
P h o s p h a t e d 'é t o p o s id e
O
Fig.6: Chemical structure of Etoposide and Teniposide
Chemical synthesis:
Podophyllotoxine is one of the components
of podophylline extracts alcoholic coniferous tree
from the roots and the rhizomes of various
species of podophylle: Podophyllum peltatum .The
chemical synthesis of Etoposide is done by use of
o
Epipodophyllotoxine like a raw material, the
chemical synthesis of Teniposide is carried out by
substitution of methy group of Etoposide by a
thiophene group.
1345
Turkish Journal of Agricultural and Natural Sciences
Special Issue: 1, 2014
Etoposide
Fig.7: Chemical synthesis of Etoposide.
o Relation structure-activity:
Influence of the nature of the chain in positi
on 4: simple glycosylée chain: D-glucose in
position 4 of podophyllotoxine increases
the
hydrosolubility,
the replacement of a β, D-glucose by β.D
galactopyranose decreases the activity in
vivo and in vitro, it is with the steric
obstruction, which
prevented
the
connection with report- isomérase II.
The best results have summers obtained af
ter
condensation with the ethanal which
make Etoposide or condensation by 2thiénylcarboxaldéhyde
which
make Téniposide.
o
Influence of the modification of the cycle
lactone: Trans stereophony- isomerism is
fundamental for the stabilization of the
cleavable complex with the topo-isomérase
II,
the complexes cis are inactive. The replace
ment of lactone by a lactam of the
o
Etoposide
increases the activity of 10%, the reduction
of lactonic group(CO) in (CH2 ) decreases
the cytotoxicity on various tumoral lines.
The opening of the cycle lactone of
Etoposide and Teniposide leads to the
inactive acid cis- hydroxy.
Anticancer extracts of Taxane :
o Chemical structure: Structure complexes class of Taxane.
1346
Influence of the modification of cycle a: The
grouping méthylènedioxy of cycle
A is
essential for the activity, its replacement by
2groupings methoxyl, hydroxyl or by a func
tion
thiocarbonyle led to molecules of
low toxicity in vitro, inactive on L1210 in
vivo.
Influence of the nature of the substituents
of the cycle E: Derivatives 4'-demethylated
are slightly more active
that the not demethylated compounds, the
cytotoxic activity of the inhibitors of the
topoisomerase II seems dependent the
presence of hydroxyl into 4’.
Mode of action: Inhibition of reportisomérase II, enzyme allowing
the
transcription and the replication of the
DNA, the blocking of the cellular division is
carried out at a stage earlier than for the
poisons of the spindle.
Therapeutic use : Etoposide is used for
treatment of disease of Hodgkin and
lymphomas
not
Hodgkin, solid tumors, acute myeloid and
lymphoblastic leukemia, while Teniposide is
used for treatment of cancers of the
testicule, the bronchi with small cells,
breast cancer.
Turkish Journal of Agricultural and Natural Sciences
Special Issue: 1, 2014
2
R
O
-O
O H
C H
10
9
3
11
H
R
1
3
C
3'
1'
3
3
1
3
17
2
O
H
H O
O H
5
4
14
O
6
8
16
C H
15
13
2'
7
C H
12
O
-NH
O
O
C H
3
O
O
O
O
P a c lit a x e l :
R
1
=
R
2
=
C H
O
D o c é ta x e l :
R
1
=
H
3
C
O
C H
C H
3
R
2
=
3
H
3
Fig.8: Chemical structure of Paclitaxel and Docétaxel.
o
Relation structureactivity: complex of the class of the taxane
whose activity depends on the presence of
a skeleton taxene of the type polyoxygéné
methanobenzocyclodecene, coupled cycle
oxétane in position 4 and 5 and one site
chain carrying the function ester out of
carbon 13.
o
Preparation: Paclitaxel was isolated from
the barks of the Yew of the pacific (Taxus
brevifolia).Currently, these derivatives are
obtained by hemisynthesis starting from the
baccatine III or the 10-désacétylbaccatine III
after extraction of the needles of the yew of
various origins (Taxus
baccata) more
available than the barks necessary
to the extraction.
The paclitaxel is the derivative of the yew of
the Pacific whereas the Docetaxel is the
derivative of the European yew.
Fig.9: Yew of the pacific (Taxus brevifolia).
o
o
Mode of action: Block the cellular replicatio
n by inhibing the depolymerisation of the
tubuline
and
by
increasing
its
polymerization, which would
make
it
possible to
decrease the resistance of
certain cancers the other anti-cancer ones.
Therapeutic use: Paclitaxel is used for
treatment of ovarian cancers metastases, in
the
event
of failure
of derived from platinum, while Docetaxel is
used
for
treatment
of
breast
cancer metastases in the patients
pretreated with the anthracyclines.
o
o
1347
Anticancer Alkaloids of the Periwinkle:
Chemical Structure:
dimerous alkaloids indolic,comprising fragm
ent velbénamine and a fragment vindoline.
Turkish Journal of Agricultural and Natural Sciences
Special Issue: 1, 2014
Vinblastine
Vincristine
Fig.10: Chemical structure of Alkaloids of Periwinkle.
o
Mode of action: They act by connection
o
Preparation:
Drugs
extracted from
with
dimerous
tubuline
by
inhibiting
the plant Periwinkle of Madagasca,
Cataranthus
Polymerization, the assembly of the microtubules is
roseus,
this
plant
blocked and consequently the cellular division.
belonged to the family of Apocynacées.
Fig.11: Periwinkle of Madagasca (Cataranthus roseus)
References :
o
Therapeutic use: Vinblastine is used for
1. F. Pieri, S. Kirkiacharian. Pharmacologie et
treatment of disease of Hodgkin, lymphomas not
thérapeutique. 2ème Edition Ellipse, Paris,
Hodgkin, breast cancers, cancer of the ovary, cancer
of
the testicle,
syndrome
of
Kaposi,
(1992).
choriocarcinomists, while Vincristine is used for
2. J.D. Brion, J. Couquelet .Traité de Chimie
treatment of leukemia acute, disease of Hodgkin,
thérapeutique. Edition Lavoisier Paris
lymphoma not Hodgkin, neuroblastome, tumor of
(2003).
3. G .L. Patrick. Chimie pharmaceutique .Edition De
Wilms, sarcoma of Ewing.
Boeck, Paris, Bruxelles, (2003).
Conclusion:
4. L. Brunton, K.L. Parke. Goodman and Gilman’s
Significant number of anticancer drugs
Manuel Of Pharmacology and
available with various mechanisms of action and
Therapeutics. Edition Mc Graw-Hill, New York,
multiple possible therapeutic methods; used only or
(2008).
in combination according to the histological type, of
5. M. Schorderet et coll. Pharmacologie des
the stage and the condition of the patient. Choice of
concepts fondamentaux aux applications
the therapeutic strategies is based on a primary
Thérapeutiques. 3éme Edition Frison Roche,
empirical advance, the evolution towards a greater
(1998).
specificity and a less great toxicity is based on
6. R.S. Vardanyan, V.J. Hruby. Synthesis of essential
elements of natural origin.
drugs. Edition Elsevier, Paris (2006).
The contribution of recent discovered the 25
7. Serge Kirkiacharian. Guide de Chimie médicinale
last years results in new specific drugs of cancer
et médicaments. Edition Lavoisier Paris
(more than 100 ),for a great part; those are of
(2010).
natural origin, they are especially active in
8. www.eurocancer.com.
partnership with the cytotoxic classics of chemical
9. www.inrs.fr .
origin. Large field of investigation remains open in
10. www.sciencedirect.com
biological and botanical fields, little explored in
associations of targeted drugs, ignored by
pharmaceutical industry.
1348
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