Anticancer Drugs

( Antineoplastic Drugs )
Cancer is a dangerous disease and happens be greatest killer of mankind The
cancer is a form of abnormal development of normal cells. The abnormal growth
appears as tumor which is due to unlimited and uncontrolled repeated division f
some cells. There are certain substances which causes cancer but it is not fully
understood. These substances are called carcinogenic or carcinogeus. The main
tpe of cancer is in the form of tumor and leukema. There are two types of tumors:
1. A Benign ( Non-malignant ) tumor:- It develop due to slow growth of the
cells but it becomes quite large. It remains restricted to the place of its
origin and does not spread to other areas of the body. It is not canceros
e.g. Adenoma ( caused by glandular tissue ) and Firoma ( caused by
connective tissues ).
2. A Cancerus ( Malignant ) tumor:- It is due to uncontrolled growth of the
cells which at last spread over neighbouring tissues. The cells of tumor
break away and migrate through bloodstream or lymph to the other parts
of the body. The migrated cells accumulate and forms secondary tumors
growth. This stage is called metastasia which is fatal and causes death
e.g. Carcinoma ( malignant due to glandular tissue ), and Sarcoma (
malignant due to connective tissue ).
Like tumor leukaemia (blood cancer) may also be classified as follows:
Leukemia Characteristics
Acute Short duration
Chronic Long duration
Myeloid (myelogenous) Bone marrow involvement
Lymphoid (Lymphogenous monocytic) Glandular involvement
Aplastic leukemia Diminition of both red and white cells,
increase in large atypical leukocytes
Basophilic leukemia Increase in most cells in the blood
Lienomyelogenous leukemia Involvement of spleen bone marrow
Lymphatic anemia Hyperplasia and over activity of the
bone marrow
 In early days some folk medicines were used for the treatment of cancer.
Now attempts have been made to understand, the true cause of cancer and to
offer relief to cancer patients. The drugs used for this purpose are known as
anticancer agents or neoplastic drugs. Some anticancer may be classified in
following types:
( I ) Alkylating Agents
( II ) Antimetabolites
( III ) Antibiotics
( IV ) Plant Products
( V ) Miscellaneous compounds
( VI ) Hormones
( VII ) Immunotherapy

Anticancer drugs may also be classified as follows;

Anticancer Drugs

Acting on DNA Acting on Acting on

Mitotic spindle Steroid Hormone Receptors

Damage DNA Inhibits Synthesis Agonists Antagonists

of Functions

Alkylation Free Radical

Formation Antimetabolites Topoisomerase
Inhibitors

Alkylating Agents
The term alkylating agents is applied for those compound which ‘alkylate’
the substance with which they react, by joining through a covalent or polar bonds.
Any anticancer agents whose activity is explained by such a mechanism is called
an alkylating agents. Alkylating agents acts on DNA and are cell cycle, non-
specific drugs that forms highly reactive electrophilic species ( i.e. electron
deficient ) which covalently bind alkyl groups ( e.g. CH2Cl ) on to nucleophilic
sites of cellular macromolecules ( e.g. bases of DNA and protein ).
Types of alkylating agents
There are mainly two types of alkylating agents:
( A ) Monofunctional alkylating agents :- They have only one reactive group
which cause single strand breaks in DNA or damage bases by inducing abnormal
base pairing.
(B) Bifunctional alkylating agents ;- They have two reactive groups which
can form cross links with cellular macromlecules. Bifunctional alkylating agents
form covalent bonds with adjacent guanine residues, which may act as bridge
between DNA strands, and thus inhibit DNA replication and transcription.
Alkylation at N7 in guanine results in base conformational changes. Thus main
effect of alkylating agents is on DNA synthesis.
Alkylating agents may also be further sub-divided into four catagories,
namely :
( i ) Mustards
( ii ) Methanesulphonates
( iii ) Ethylenimines
( iv ) Nitrosoureas

Mustards :
During second world war, it was found that mustard gas ( Bis-2-chloroethyl
sulphide ) has antileukemic activity.
CH2CH2Cl
S
CH2CH2Cl
Mustard gas
However, mustard gas can not be widely used as anti leukemic compound
due to its high toxicity, its oily nature, low solubility in water and blister-producing
properties. After the discovery and study of the antilekemic activity of mustard
gas it was found that exchange of sulphur with nitrogen ( in mustard gas ) gave
nitrogen mustard. Nitrogen mustards were selected for clinical application for
the treatment of neoplasms because they have fewer problems in handling, their
respective hydrochlorides and other salts are generally stable solids having low
vapour pressure and high solubility in water.
Nitrogen mustard may be synthesised as follows:
1. By reaction of primary amines with an excess of ethylene oxide followed by
treatment of thionyl chloride.
O
SOCl2
RNH2 + 2 H2C CH2 RN(CH2CH2OH)2 RN(CH2CH2Cl)2
Nitrogen mustard
2. By reaction of alkyl halide with diethanolamine followed by treatment of
thionyl chloride.
HCl SOCl2
RCl + HN(CH2CH2OH)2 RN(CH2CH2OH)2 RN(CH2CH2Cl)2
Nitrogen mustard
3. By reaction of alkyl halide with Bis(2-Chloroethyl)amine.
HCl RN(CH2CH2Cl)2
RCl + HN(CH2CH2Cl)2 Nitrogen mustard

Some important nitrogen mustard are as follows :

Mustargen ( MBA, NM or HN2) , Mechlorethamine Hydrochloride ,USAN

CH 2CH 2Cl
H3C N
CH 2CH 2Cl

Methyl bis(2-chloroethyl)amine

Synthesis : It may be prepared as follows:

CH2CH2OH HCl CH2CH2OH

CH3Cl + HN H3C N
CH2CH2OH CH2CH2OH

SOCl2

CH2CH2Cl
H3C N
CH2CH2Cl
Mustargen
Uses:
Mechloethamine hydrochloride is a bifunctional alkylator and was originally
used for treatment of lymphoma in 1940. It is very hygroscopic and unstable T 1/2
is very short below 10 minutes after IV injection. It is effective in Hodgkin’s
disease and certain leukemias, carcinoma of breast and lung, lymphosarcoma,
neuroblastoma and melanoma. It has no effect in advanced cancers of the
stomach or colon-rectum. Certain antibiotics like penicillin is generally given
along with mustargen to reduce the chances of uncontrolled infections that some
time arise from the administration of mustargen. Usually it is given with other
antineoplastic agents such as Vincristine, Prednisone, Procarbazine. The drug
however, causes vomiting in about 60% of patients. It causes bone marrow
suppression ( leukemia and thrombocytopenia ). It is also mutagenic and
carcinogenic. It causes irritation at injection site. This is widely used in United
States in the treatment of neoplasm.

Mechanism : The 2-Chloroethyl moieties lose chloride ions to generate

carbonium which is very reactive and are capable of alkylating many biologically
vital chemical moieties. It has been observed that in DNA they alkylate guanine
moieties .One arm of mustargen alkylates one guanine group and the second
arm another guanine on opposite strands, thus DNA turns into irreversibly cross
linked. It ultimately gives rise to inhibition of mitosis, besides causing
chromosomal breakage.
O
7
CH2-CH2 Cl CH2-CH2 Cl N 1
Cl 6 NH
H3C N 5
H3C N + + 8
2
CH2-CH2 Cl CH2-CH2 9 N 4 N NH2
Mustargen Reactive intermediate H 3
Guanine
 CH3
CH3
N
N
H2C CH2
H2C CH2 Guanine
H2C CH2 O
O H2C CH2 O
Cl N
N N NH
HN NH
N N NH2
N N N N NH2 H
H2N H H
Guanine alkylated at N7
Guanine cross link

Novembichin, Embichin No 7
CH2-CH2 Cl
CH3 CH CH 2 N
Cl CH2-CH2 Cl

2-Chloropropyl-bis(2-chloroethyl)amine

Synthesis
O CH2-CH2 OH
CH3 CH CH2 N H2 + 2 CH3 CH CH2 N
H2C CH2 CH2-CH2 OH
Cl Cl

H2SO3 SOCl2

CH2-CH2 Cl
CH3 CH CH2 N
Cl CH2-CH2 Cl

Novembichin
It is less toxic than mustargen. It is used against chronic leukaemia,
lymphogranuloma and Hodgkin’s disease
5-Bis(2-chloroethyl)amino-6-methyluracil

CH3
6
1 5
N N(CH2-CH2-Cl)2
2 4
HO N OH
3
It is as effective as Novembichin

Phenylbutyric acid mustard or Chlorambucil (USAN), Leukeran

Cl-CH2-CH2
N CH2-CH2-CH2-COOH
Cl-CH2-CH2

Synthesis
O
H2N CH2-CH2-CH2-COOH + 2
H2C CH2

p-Aminophenylbutyric acid

HO-CH2-CH2
N CH2-CH2-CH2-COOH
HO-CH2-CH2

SOCl2

Cl-CH2-CH2
N CH2-CH2-CH2-COOH
Cl-CH2-CH2

Chlorambucil

It is used in the treatment of a number of human tumours, including

lymphocytic leukaemia, chronic granulocytic leukaemia, multiple myeloma,
Hodgkin’s disease, carcinoma of breast and ovarian cancer. It has an edge over
other nitrogen mustard because of its least toxicity and slowest activity.
Phenylalanine mustard or Melphalan (USAN) or Alkeran

Cl-CH2-CH2
N CH2-CH--COOH
Cl-CH2-CH2
NH2

Synthesis
O
O
N CH2-CH-COOC2H5 + 2
H2C CH2
O NH2

L-N-Phthalimido-p-aminophenlethylester

HO-CH2-CH2
N CH2-CH-COOC2H5
HO-CH2-CH2
NH2

POCl3

Cl-CH2-CH2
N CH2-CH-COOC2H5
Cl-CH2-CH2
NH2

Hydrolysis

Cl-CH2-CH2
N CH2-CH--COOH
Cl-CH2-CH2
NH2
Melphalan
It is used in the treatment of wide variety of tumours, also used in palliative
therapy of multiple myeloma, malignant melanoma and carcinoma of the ovary
and breast. However reports on the efficiency are conflicting. Its antitumor activity
is different from mustargen. It shows slower rate of ionization of chloride.
Antimalarial nitrogen mustards
Since the quinoline antimalarials are selectively absorbed in certain body
tissues thus it was planned to incorporate the N-mustard in the basic side chain
of a quinoline antimalarials. Many compounds of this type were prepared. Some
of this class are chloroquine mustard and quinacrine mustard.
It is believed that the quinoline nucleus might transport the nitrogen
mustard function into certain tumors.
CH3
CH2-CH2 Cl
NH-CH-(CH2)3 N
CH2-CH2 Cl

Cl N
Chloroquine mustard

CH3
CH2-CH2 Cl
NH-CH-(CH2)3 N
CH2-CH2 Cl
OMe

Cl N
Quinacrine mustard

Nitrogen Mustard N-oxides or Mustron, HN2 oxide

R-N-(CH2-CH2Cl)2

O
R = CH3 , Mustron
It was found that conversion of nitrogen mustard to its N-oxide greatly
reduces its toxicity with less reduction in anticancer activity. Most important N-
oxide of this type is mustron which is used in the treatment of chronic leukaemia
and breast cancers.
Antimetabolites in cancer chemotherapy
Antimetabolites are structurally related to naturally occurring compounds
i.e. vitamins, amino acid or nucleotides and they interfere with the production of
nucleic acids by preventing synthesis of normal nucleoside triphosphates by
inhibiting key enzymes. They may be substitute of normal purine and pyrimidine.
Thus by use of antimetabolites the synthesis of DNA and RNA decreases and
they interfere with cell growth and proliferation.
In general, following are the various classes of antimetabolites usually
employed in the treatment of cancer. They are namely,
(a) Antifolic acid compounds
(b) Analogues of pyrimidines
(c) Analogues of purines
(d) Sugar modified analogues

(a) Antifolic acid compounds

Antifolic acid compounds are also referred to as ‘antifolics’ or
‘Folate Antagonists’. Drugs belonging to this category act by preventing the
synthesis of folic acid which is required by the tissues. They bind strongly to
dihydrofolate reductase (DHFR) thereby inhibiting the conversion of dihydrofolic
acid to tetrahydrofolic acid and thus inhibit the synthesis of purines and
thymdines. Antifolics kill cells by inhibiting DNA synthesis. Therefore they act as
effective antimetabolites in long growth phase.

1 8
H2N 2 N N
7
9 10
3N 6
CH2-NH- CO-NH-CH-CH2-CH2-COOH
4 N
5
OH COOH
Folic acid or PGA (Pteroylglutamic acid)

It is observed that some analogues of folic acid have antineoplastic or

anticancer activity. It was further observed that folic acid promotes the production
of blood corpsules. It was therefore presumed that compounds related to folic
acid in structure might functions as antagonists to the cells concerned with
neoplastic disease.this will be specially true in conditions such as leukaemia
where retardation of the production of certain types of blood cells is desirable.
Among the analogues of folic acid which has shown to have antifolic activity , the
following modifications in the structure of folic acid have been affected.

( i ) Replacement of 4-OH group by an amino group

The most important compound of this type is aminopterin in which 4-OH
group is replaced by amino group in pteridine ring. It has been found to exhibit
inhibitory effect on human cancer.
1 8
H2N 2 N N
7
9 10
3N 6
CH2-NH- CO-NH-CH-CH2-CH2-COOH
4 N
5
NH2 COOH

Aminopterin
( ii ) Substitution at 9, or 10 positions
The most important compound of this series is
4-Amino-N10-methylpteroylglutamic acid amethopterin or Methotrexate, BAN,
USAN, INN. It is extensively used for the treatment of acute lymphoblastic
leukaemia, lung cancer, breast cancer and epidermoid cancers of the head. It is
also used for the treatment of prophylaxis of meningeal leukaemia.

H2 N N NH2 O

+ Br-CH2-CH-C-H + H3C-NH- CO-NH-CH-CH2-CH2-COONa

N
NH2
Br COONa
NH2 2,3-Dibromopropanaldehyde Disodium-p-(methylaminobenzoyl) glutamate
2,4,5,6-Tetraaminopyrimidine
I2
lime water
1 8 KI
H2 N 2 N N
7
9 10
3 N CH2-N CO-NH-CH-CH2-CH2-COOH
N 6
4
5
NH2 CH3 COOH

Amethopterin or Methotrexate

( iii ) Modification of glutamic acid part or replacement of glutamic acid by other

amino acid.
( b ) Analogues of Pyrimidine
A large number of purines, pyrimidines and related compound have been
tested for anticancer activity. These compounds interfere in some way with
normal growth. However these compounds lack in specificity i.e. their major effect
will be on rapidly growing cancer tissues. Cancer cells are often deficient in some
vitamins and related coenzymes. Therefore these cells are more susceptible to
the antagonistic compounds affecting the metabolic process. Some important
pyrimidine derivatives as anticancer agents are:
O O
O
HN HN CH3
HN F

O N O N
H H O N
H
Uracil Thymine 5-Fluoro uracil

5-Fluorouracil ( 5-FU ), Fluorouracil, Efudex or Fluoroplex ( Allergan )

O

HN F

O N
H
5-Fluorouracil
Synthesis : It is prepared as follows:
O
O
HN F
+ CF3OF HN
O N
H O N
H
Uracil Fluroxytrifluoromethane 5-Fluoro uracil

It resembles pyrimidine bases uracil and thymine. It is given IV T 1/2 few

min. It is used in palliative treatment nof the breast, pancreas, prostate, colon and
hepatoma for which surgery or irradiation is not possible. It has profound activity
against ten different transplanted tumours. It possess toxicity to bone marrow and
mucous membranes.
5-Fluorourotic acid
H
O N O

HN
F
COOH
It is less active except against leukaemia.
( C ) Analogues of Purine
OH SH SH
H H H
N N N
N N N

H2N N N H2N N N N
N

Guanine 6-Thioguanine 6-Mercaptopurine

6-Mercaptopurine ( 6-Purinethiol, 6MP, Mercaptopurinium)
It is prepared as follows:
OH SH
H H
N N
N N
+ P2S5
N N N N

5-Mercaptopurine
Hypoxanthine
It is analogue of purine / guanine in which OH group is replaced by SH.
This is more toxic, used in acute leukaemia. It has not been found effective
against chronic leukaemia, multiple myelomaq etc. It inhibits the synthesis of
purine nucleotide. It has side effect and causes bone marrow suppression,
nausea and vomiting.

2,6-Diaminopurine

NH 2
H
N
N

H 2N N N

It is used in acute leukaemia or chronic myelocytic leukaemia.

Sugar modified analogues
NH2 NH2 NH2

N N N

O N O N O N
HOCH2
O HO O HO O

H HO H HO H H
H H H H H H
OH H OH H OH H
Cytidine Cytosine arabinoside Deoxycytosine arabinoside

These are analogues of cytidine and 2-deoxycytidine in which arabinose

sugar moiety replaces ribose or deoxyribose sugar. These are activated by
pyrimidine nucleoside kinase to ara-cytosinetriphosphate (ara-CTP). Ara-CTP is
a competitive inhibitor of DNA polymerase. It is also substrate for DNA
polymerases and anlog of dCTP. If it is incorporated into DNA it alter DNA
function. It has poor oral absorptiobn and hence given intravenous IV. Its T 1/2 is
10 min. and hence given frequently IV. It is used in treatment of acute
myelogenous leukemia. It is toxic and possesses toxicity to severe bone marrow
hypoplasia and gastrointestinal tract toxicity.

6-Mercaptopurine riboside
SH
H
N
N

N N
HOCH2
O

H HO
H H

OH H
Its activity is same as 6-MP
Hormones in cancer chemotherapy
Treatment of cancer with hormone is based on the principle that neoplastic
tissues is not necessarily autonomous, but it retains some of the characteristics
of the tissue from which it derived. It has been observed that the majority of
metabolic pathways in normal and cancer cells are similar. It has been found that
the tumours can be controlled by hormonal imbalances caused by surgical
attractions. The use of estrogens in prostate cancer and androgens in breast
cancer have been used. Testosterone has benificial effects in advanced breast
cancer. Cortisone, cortisole and halogenated corticoid hormones have been used
as anticancer agents. The acetylated thyroid stimulating hormone (TSH) reduces
the size of the tumours.