08:47 PM March, 19 2016 سودانيز اون لاين
سيف اليزل برعي البدوي-
مكتبتى
رابط مختصر
1Authorized in 8/8/2015
بسم هللا الرحمن الرحيم
RESEARCH ABOUT
Synthesis of Uracil and
its Derivatives’ for
Anticancer and Antiviral
Drugs
PREPARED BY ME \
ALI YoUSIF HASAN
TEL: +249123760824
EMAIL:[email protected]
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Authorized in 8/8/2015
TABLE OF CONTENTS
1. preface
2. introduction
3. proliferation of the cell
4. Mechanisms of Antineoplastic Drugs
5. classification of anticancer drugs
6. 5-uracil anticancer drug and its derivatives
7. Uracil derivatives as antiviral drugs
8. syntheses of uracil and 5-uracil
a. The Synthesis of uracil derivatives including 5U
b. The Synthesis of C5-Substituted Uracil
c. The Synthesis of N-Substituted Uracil
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Preface
This research about manufacturing of a drug always demanded
in our country, because it represents the chemotherapy witch comes
on the third degree of treatment of cancer dieses after surgical and
radiotherapy.
After a lot of investigations I found that the drug hasn't produces
in my country despite of the viability of raw materials uses in
production.so I decided to introduce this elaboration to enrich
Sudanese won pharmaceutics library
ALI YOUSIF
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Introduction
The body is made up of trillions of living cells. Normal body
cells grow, divide into new cells, and die in an orderly way.
During the early years of a person’s life when they are still growing,
normal cells divide faster. Once the person becomes an adult, most
cells divide only to replace worn-out, damaged, or dying cells.
Cancer begins when cells in a part of the body start to grow out of
control. There are, many kinds of cancer, but they all start by this outof-control
growth of abnormal cells. Cancer cell growth is different
from normal cell growth. Instead of dying, cancer cells keep on
growing and form new cancer cells. In most cases the cancer cells
form a tumor.
Cancer cells can also grow into (invade) other tissues, something that
normal cells can’t do. So being able to grow out of control and invade
other tissues are what makes every cell a cancerous.
Sometimes cancer cells spread to other parts of the body. There they
begin to grow and form new tumors. This process is called
####stasis.
No matter where a cancer spreads, it is named (and treated) based
on the place where it started. For instance, breast cancer that has
spread to the liver is still breast cancer not liver cancer. Likewise,
prostate cancer that has spread to the bones is still prostate cancer,
not bone cancer.
Different types of cancer can behave very differently. They grow at
different rates and respond to different treatments. That is why people
with cancer need treatment that is aimed at their own kind of cancer.
Not all tumors are cancerous. Tumors that aren’t cancer are
called benign. Benign tumors can cause problems – they can grow
large and press on healthy organs and tissues. But they can’t grow
into other tissues. Because of this, they also can’t spread to other
parts of the body (####stasize). These tumors are rarely life
threatening.
Proliferation of the cell
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Based on the DNA changes in cells, proliferating cycle of tumor
Cells can be divided into 5 phases
Pre-synthetic phase (Gap 1 phase or G1 phase). Cells chiefly
make preparations for the synthesis of DNA.
Synthetic phase (S phase). Cells are synthesizing their DNA.
Post-synthetic phase (Gap 2 phase or G2 phase). DNA
Duplication has been finished and they are equally divided to
the two of future sub-cells.
Mitosis phase (M Phase). Each cell is divided into two sub cells.
Some of these new cells enter the new proliferating cycle, the
others become non-proliferating cells.
Some cell goes on non-proliferating cycle that G0 phase cells
Or (resting-phase cells), G0 phase cells have proliferation
ability but do not divide temporally.
When proliferating cells are suffered heavy casualties, G0
phase cells will get into proliferating cycle and become the reasons of
tumor recurrence. G0 phase cells are usually not sensitive to
antineoplastic drugs, which is the important obstacle to tumor
chemotherapy.
Mechanisms of Antineoplastic Drugs
Most antineoplastic drugs act on the proliferating cycle of cell:
(1) Destruction of DNA or inhibition of DNA duplication:
such as alkylating agents, Mitomycin C
(2) Inhibition of nucleic acid (DNA and RNA) synthesis
such as 5-fluorouracil, 6-mercaptopurine, methotrexate,
cytarabine, etc.
(3) Interfering with the transcription to inhibit RNA synthesis
such as dactinomycin, dauoruicin, and doxorubicin
(4) Inhibition of protein synthesis
such as vinca alkaloids, Epipodophylotoxins, and paclitaxel
(5) Interfering with hormone balance
such as adrenal corticosteroids, estrogens, tamoxifen etc.
Classification of anticancer drugs
There are five kind of anticancer drugs:-
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Alkylating agents,
Anti####bolites,
Natural products,
Hormones and antagonists
Miscellaneous agents.
(Ⅰ) Alkylating Agents
Alkylating agents act via a reactive alkyl ethene (RCH2-CH2 +
-) group that reacts to form covalent bonds with nucleic acids.
There follows either cross-linking of the two strands of DNA,
preventing replication, or DNA breakage. All alkylating agents
are phase-nonspecific. Kill rapidly proliferating cells, also kill
nonproliferation cells.
Examples: Mechlorethamine the first drug used in the treatment
of cancer. At present, it is mainly used for Hodgkin's disease
and non-Hodgkin's lymphomas.
Examples: Cyclophosphamide Most widely used in clinical
therapy for treatment of cancer at present. It has no
antineoplastic action outside the body and must be activated in
the liver
(Ⅱ) Anti####bolites
Anti####bolites are analogues of normal ####bolites and act
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by competition, replacing the natural ####bolite and then
subverting cellular processes.
Examples of anti####bolites include:
Folic acid antagonists (e.g. Methotrexate).
Antipyrimidines (e.g. 5-Fluorouracil, Cytarabine).
Antipurines (e.g. 6-Mercaptopurine)
Example: methotrexate
Mimics folic acid, which is needed for synthesis of DNA, RNA
and some amino acids it acts mainly on the S phase cells. Side
effect a serious myelosuppression
Example: 5-Fluorouracil (5-FU) a fluorine-substituted analogue
of uracil must be ####bolically activated to a nucleotide, in this
case FdUMP. Then its ####bolite inhibits the synthetase of
deoxythymidine monophosphate,blocking DNA synthesis.
Besides, as the fraudulent substance, its ####bolite can also
interfere with the synthesis of RNA.
Example: 6-Mercaptopurine
A structural analogue of hypoxanthin It must be converted
intracellularly to the nucleotide 6-mercaptopurine ribose
phosphate and 6-methylmercaptopurine ribonucleotide, and
then inhibit purine biosynthesis, causing inhibition of
biosynthesis of nucleic acid.
(Ⅲ) Natural Products
This group is determined by the source of the drug
The major classes of natural products include antibiotics, vinca
alkaloids, biologic response modifiers enzymes,
epipodophyllotoxins and taxanes, Antibiotic antineoplastic
agents Damage DNA in cycling and noncycling cells.
Example: Dactinomycin (actinomycin D)
This drug binds noncovalently to double-stranded DNA and
inhibits DNA-directed RNA syntheisis. Dactinomycin is a
phase-nonspecific agent, but it is more active agsinst G1
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phase cells.
Vinca (plant) alkaloids Vincristine and vinblastine are
alkaloids derived from the periwinkle plant. binding to tubulin,
interfere with the assembly of spindle proteins during mitosis..
Act in (M) phase to inhibit mitosis, blocking proliferating cells as
they ####phase. Both can cause bone marrow suppression and
neurotoxicity
(Ⅳ) Hormones and antagonists
The growth of some cancers is hormone dependent. Growth
of such cancers can be inhibited by surgical removal of
hormone glands increasingly, however, administration of
hormones or anti hormones is preferred.
Examples:
Adrenocortical steroids to inhibit the growth of cancers of
lymphoid tissue and blood. Estrogen antagonists (Tamoxifen)
are indicated for breast cancer. Estrogen is used for prostatic
cancers.
(Ⅴ) Miscellaneous agents
Examples: Hydroxyurea
Hydroxyurea inhibits ribonucleotide reductase. Inhibition of
DNA synthesis. It is specific for the cells of S phase .The major
adverse effect of this drug is bone marrow depression.
5-uracil anticancer drug and it derivatives
Mechanism of action
Pyrimidine Drugs
The anticancer drugs based on pyrimidine structure the
pyrimidine derivative 5-fluorouracil (5-FU) was designed to block the
conversion of Uridine to thymidine. The normal biosynthesis of
thymidine involves methylation of the 5-position of the pyrimidine ring
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of uridine. The replacement of the hydrogen at the 5-position of uracil
with a fluorine results in an anti####bolite drug, leading to the
formation of a stable covalent ternary complex composed of 5-FU,
thymidylate synthase (TS), and cofactor (a tetrahydrofolate species).
The normal pathway for the formation of thymidine from uridine
catalyzed by the enzyme TS is shown in Scheme below (No 1).
Anticancer drugs targeting this enzyme should selectively inhibit the
formation of DNA because thymidine is not a normal component of
RNA. TS is responsible for the reductive methylation of deoxyuridine
monophosphate (dUMP) by 5,10-methylenetetrahydrofolate to yield
dTMP and dihydrofolate. Because thymine is unique to DNA, the TS
enzyme system plays an important role in replication and cell division.
The tetrahydrofolate cofactor species serves as both the one-carbon
donor and the hydride source in this system. The initial step of the
process involves the nucleophilic attack by a sulfhydryl group of a
cystine residue at the 6-position of dUMP. The resulting enolate adds
to the methylene of 5,10- CH2-THF perhaps activated via the very
reactive N-5- iminium ion (see Scheme below(1)). The iminium ion
likely forms at N-5 and only after 5,10-CH2-THF binds to TS. The
iminium ion is likely formed at N-5 because it is the more basic of the