Synthesis of Uracil and its Derivatives’ for Anticancer and Antiviral Drugs PREPARED BY ME \ ALI Yo

سودانيز اون لاين
سيف اليزل برعي البدوي-
مكتبتى
رابط مختصر

Authorized 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]

2

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

3

Authorized in 8/8/2015

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

4

Authorized in 8/8/2015

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

5

Authorized in 8/8/2015

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:-

6

Authorized in 8/8/2015

 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

7

Authorized in 8/8/2015

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

8

Authorized in 8/8/2015

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

9

Authorized in 8/8/2015

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