Medichem-II, Unit 1

Chapter 3. Anti-Neoplastic Drugs

Syllabus
Alkylating agents: Meclorethamine*, Cyclophosphamide, Melphalan, Chlorambucil,
Busulfan, Thiotepa
Antimetabolites: Mercaptopurine*, Thioguanine, Fluorouracil, Floxuridine,
Cytarabine, Methotrexate*, Azathioprine
Antibiotics: Dactinomycin, Daunorubicin, Doxorubicin, Bleomycin
Plant products: Etoposide, Vinblastin sulphate, Vincristin sulphate
Miscellaneous: Cisplatin, Mitotane.

3.1 ANTI NEOPLASTIC AGENTS/ ANTICANCER DRUGS

These are the drugs used in the treatment of cancer also known as antineoplastic agents.
Cancer cell also known as neoplasm (new growth) is an abnormal and uncontrolled
growth or cell division.
Characteristic Feature of Cancer
➢ Uncontrolled proliferation (decreare apoptpsis, increase telomerase (RNA dependent
DNA polymerase expression).
➢ Uncontrolled differenciation and loss of the function
➢ Invasiveness – Tendency to spread over healthy cell
➢ Metastasis- Spead to different part of body

Etiology
Over expression of growth factor receptor on the cells.
Production of their own extracellular growth factor
Production of cell cycle transducer e.g. cyclin-dependent kinases (cdks), cdk inhibitors
and cyclins
Inhibit apoptosis and tumor suppression gene
Activation of oncogenes
Tumor directed angiogenesis

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Classification of Cancer Cells

1. Carcinoma: Carcinomas are the most common type of cancer formed by epithelial cells.
Most cancers of the breast, colon, and prostate are adenocarcinomas (cancer on glandular
cells).
2. Sarcoma: Sarcomas are cancers that form in bone and soft tissues, including muscle, fat,
blood vessels, lymph vessels, and fibrous tissue. E.g., Osteosarcoma.
3. Leukemia: Cancers that begin in the blood-forming tissue of the bone marrow are called
leukemias. E.g., Blood cancer (Leukemia; increase no. of WBCs)
4. Lymphoma: Lymphoma is cancer that begins in lymphocytes (T cells or B cells). In
lymphoma, abnormal lymphocytes build up in lymph nodes and lymph vessels, as well as
in other organs of the body. There are two main types of lymphoma:
a. Hodgkin lymphoma – People with this disease have abnormal lymphocytes that are
called Reed-Sternberg cells. These cells usually form from B cells.
b. Non-Hodgkin lymphoma – This is a large group of cancers that start in lymphocytes.
The cancers can grow quickly or slowly and can form from B cells or T cells.
5. Multiple Myeloma: Multiple myeloma is cancer that begins in plasma cells, another type
of immune cell. Multiple myeloma is also called plasma cell myeloma and Kahler disease.
6. Melanoma: Melanoma is cancer that begins in cells that become melanocytes, which are
specialized cells that make melanin (the pigment that gives skin its color).
7. Germ Cell Tumors: rise to sperm or eggs.
8. Blastoma: It is common in children. It is the tumor that resemble an immature or
embryonic tissue. E.g., nephroblastoma, medulloblastoma, and retinoblastoma.
9. Neuroendocrine Tumors: Neuroendocrine tumors form from cells that release hormones
into the blood in response to a signal from the nervous system.
10. Carcinoid Tumors: Carcinoid tumors are a type of neuroendocrine tumor. They are slow-
growing tumors that are usually found in the gastrointestinal system (most often in the
rectum and small intestine).

Classification of Antineoplastic or Anticancer Agents

(1) Alkylating agents
(a) Nitrogen mustards : Mechlorethamine, Cyclophosphamide, Chlorambucil, Ifosfamide,
Melphalan
(b) Nitrosoureas : carmustine, lomustine
(c) Alkylsulphonates : Busulfan
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(d) Ethylenimines : Thiotepa

(e) Triazenes : Dacarbazine
(2) Antimetabolites :
(a) Folate antagonists : methotrexate (MTX)
(b) Purine analogues : 6-mercaptopurine, 6-thioguanine, Azathioprim, flutarabine,
pentostatin, cladribine.
(c) Pyrimidine analogues : 5-fluorouracil, floxuridine, cytarabine.
(3) Natural products
(a) Plant products : Vinca alkaloids (vincristine & vinblastine), Podophyllotoxin,
Etoposide & Taxol.
(b) Antibiotics : Actinomycin-D, Doxorubicin, Daunorubicin, Bleomycin, Mithramycin,
Mitomycin-C.
(c) Hormones and antihormones : Prednisone, Diethylstilbesterol, Ethinyl estradiol,
Medroxy progesterone,
Megestrol, Tamoxifen.
(d) Enzymes : L-asparginase
(e) Biologic response modifiers : Interferons (,  and )
(4) Miscellaneous agents : Cisplatin, hydroxyurea, procarbazine

Medicinal Chemistry of Anticancer Agents

1) Alkylating agents

Mechanism of Action:

✓ Alkylating the DNA stands

✓ Alkylating agents form a highly reactive carbonium ion which react instantaneously with
an electron donor such as an amine, hydroxyl or sulfhydryl group present at the DNA base
pair.
✓ Most of the alkylating agents are the Bifunctional alkylating agents (having two alkylating
groups) can cause intrastrand cross linking of two nucleophilic site such as N7 of guanine,
N1 & N3 of Adenine and N3 of Cytosine in the DNA strand.

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*Nucleophilic Groups

Alkylating agents: Meclorethamine*, Cyclophosphamide, Melphalan, Chlorambucil,

Busulfan, Thiotepa

A) Nitrogen Mustards
1. Mechlorethamine (Mustine)
Cl-CH2-CH2
N − CH3
Cl-CH2-CH2

2,2-dichloro-N-methyldiethylamine
Mechlorethamine rapidly undergoes intramolecular transformation to the active form in
aqueous solution. The solutions lose their activity very rapidly. Hence it is supplied in dry
powder form (supplied in rubber stoppered vials containing a mixture of 10 mg
mechlorethamine hydrochloride and 90 mg of sodium chloride) and a solution is prepared in
10 ml of sterile water immediately prior to injection.

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Synthesis:

CH3-NH2 +
methylamine

SOCl2

Cl-CH2-CH2
N − CH3
Cl-CH2-CH2

Mustin

Uses :
✓ Used in Hodgkin's disease, carcinoma of lung and other solid tumors
✓ Topically used in mycosis fugoides (T-cell lymphoma)

2. Cyclophosphamide
O
O CH2CH2 Cl
P N
NH CH2CH2Cl

2-bis(2-chloroethyl) amino perhydro 1, 3, 2-oxaza-phosphorinane-2-oxide

*Cyclophosphamide, which is activated to give aldophosphamide, then converted to

phosphoramide mustard (cytotoxic molecule) and acrolein which causes bladder damage
that inhibited by Mesna (a cytoprotective agents).

Uses:
✓ Used in Hodgkin's disease, carcinoma of lung and other solid tumors.
✓ Used as immunosuppressant in autoimmune diseases like rheumatoid arthritis, multiple
sclerosis, and wegener’s granulomatosis.
3. Melphalan
NH2
Cl-H2C-H2C
N CH2 −CH−COOH
Cl-H2C-H2C

4-bis (2-chloro ethyl) amino L-phenylalanine

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User:
✓ Used in Hodgkin's disease, carcinoma of lung and other solid tumors.
✓ Multiple myeloma and carcinoma of breast and ovary.
✓ It can be also used in retinoblastoma (Retinal Cancer).
4. Chlorambucil
Cl-H2C-H2C
N CH2-CH2-CH2-COOH
Cl-H2C-H2C

4-[4-bis(2-chloroethyl)-aminophenyl] butyric acid

Uses:
✓ Used in Hodgkin's disease, carcinoma of lung and other solid tumors.
✓ Chronic lymphocytic leukemia.
✓ It can be used for non- Hodgkin's lymphoma, polycythemia, ovarian carcinoma.

Used as immunosuppressantAll alkylating agents have more than one active

alkylating group per molecule. Depending upon this number the compounds are
termed as di or polyfunctional.
The actions of nitrogen mustards resemble to some extent the biological effects
produced by ionising radiation. Hence, nitrogen mustards are also called
radiomimetic drugs.

B) Nitrosoureas
These compound having the nitroso (R-NO) and Urea (NH2-CO-NH2) moiety in the
ring system
They are chloro ethyl nitrosoureas, highly lipid soluble and easily cross the blood
brain barrier, therefore they may be used against tumours of the brain and meninges.

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5. Carmustine O
CH2CH2 Cl
Cl.H2C.H2C − NH − C − N
NO
1, 3-bis(2-chloroethyl) 1-nitrosousea
Uses : Brain tumours (because of its ability to cross blood-brain-barrier) Hodgkin's disease,
multiple myeloma and non-Hodgkin's lymphomas.
6. Lomustine
O
CH2CH2Cl
NH − C − N
NO

1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea
Uses : Brain tumors, Hodgkin's disease, malignant melanoma,lung cancer and various solid
tumours.
C) Alkylsulphonates
7. Busulfan (Busulphan)
It has a selective effect on the bone marrow, depressing the formation of granulocytes and
platelets.
H3C-SO2-O-CH2-CH2-CH2-CH2-O-SO2-CH3
1, 4-butanediol dimethanesulphonate
Uses
✓ Used in the treatment of chronic granulocytic leukemia.
✓ Immunosupressant
D) Ethylenimines (Aziridines)
8. Thiotepa
S
N − P − N
N

tris-(1-aziridinyl) phosphine sulphide

It is supplied in vials containing 15 mg of thiotepa, 80 mg of sodium chloride and 50 mg of
sodium bicarbonate. It is stored at 2 to 8 C.
Dose : 15 - 30 mg by parenteral route.
Uses : Used in the treatment of breast cancer, ovarian cancer and various lymphomas.

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E) Triazenes
9. Dacarbazine
H3C H
N−N=N N
H3C
N
H2NC
O
5-(3, 3-dimethyl-1-triazeno)-imidazole-4-carboxamide
Uses: Used in the treatment of malignant melanoma, Hodgkin's disease and sarcomas.

2) Antimetabolites

General Mechanism of action: Antimetabolites are drugs that block vital cellular metabolic
reactions by virtue of its close structural similarity to the metabolite (i.e., antimetabolites
prevent the biosynthesis or utilisation of normal cellular metabolites).
A) Folate Antagonists:
Mechanism of action: Folic acid is essential for the production of the co-enzyme
tetrahydrofolic acid. The conversion of folate to tetrahydrofolic acid is carried out by folate
reductase. Folate antagonists block folate reductase irreversibly and prevent the production
of tetrahydrofolic acid.
Folic acid
Folate antagonists folate reductase

indicate inhibition
Tetrahydrofolic acid

Lack of tetrahydrofolic acid leads to inhibition of DNA synthesis and cell replication.

10. Methotrexate

N N NH2
CH2 N
N
H3C − N NH2

COOH

CONH − C − H
CH2 CH2COOH

N-{4-[(2,4-diaminopteridin-6 yl methyl) methylamino] benzoyl} L-glutamic acid

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It has low lipid solubility and dose not cross blood brain barrier. It has actively taken
up into cell by the folate transport system and is metabolized to polyglutamate derivetives.
Synthesis:

Uses:
✓ Used in the treatment of acute lymphoblastic leukemia & choriocarcinoma.
✓ In combination with other anticancer drugs it is used in the treatment of
lymphosarcoma, Burkitt’s lymphoma, carcinoma of testes, bladder, breast, pharynx
and tongue.
✓ Also used as immunosupressant
B) Purine Analogues
11. 6-Mercaptopurine (6-MP)
SH
H
N N

N N

Purine –6-thiol
MOA:
✓ 6-Mercaptopurine is converted by hypoxanthine-guanine phosphoribosyl transferase
(HGPRT) to 6-thioinosinic acid (TIMP) which inhibits some enzymes involved in
purine synthesis and hence of DNA.
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✓ 6-mercaptopurine is metabolised to 6-methylmercaptopurine ribotide (MMPR) and

thioguanylic acid in human body are responsible for its cytotoxic effects.
Synthesis:

Uses: Used in the treatment of leukemia.

12. 6-Thioguanine (6-TG)
S
I H
HN N

H2N N N
2-aminopurine-6 (1H)-thione
MOA:
✓ It inhibits purine nucleotide interconversion.
✓ It’s incorporation into DNA leads to strand breaks.
✓ It decreases intracellular level of guanine nucleotides resulting in inhibition of
glycoprotein synthesis.
Uses: Used in the treatment of non-lymphoblastic leukemia.

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13. Azathioprine

6-(3-methyl-5-nitroimidazol-4-yl)sulfanyl-7H-purine

MOA: Purine synthesis inhibitors

Use: Mainly used as immunosuppressant for facilitating the survival of organ and tissue
transplantation.

C) Pyrimidine Analogues
14. 5-fluorouracil (5-FU) O
F
HN

O N
H

5-fluoropyrimidine-2, 4(1H, 3H) dione

MOA:
✓ This a fluorinated analogue of pyrimidine.
✓ 5-fluorouracil is metabolised to 5-fluoro 2' deoxyuridine 5' phosphate (FdUMP)
which competitively inhbits thymidylate synthetase (an enzyme that converts 2'-
deoxyuridylic acid to thymidylic acid for DNA synthesis).
✓ Inhibition of DNA synthesis results in “thymineless death” of cells.
Uses :
✓ Used in the carcinoma of stomach, colon, rectum, breast and ovaries.
✓ Also given topically for skin cencer, actinic keratoses, and Bowen’s disease.
✓ It is also used as eye drop for treatment of ocular surface squamous neoplasia.

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15. Floxuridine O
F
HN

O N
HOH2C
O
H H H

OH H
1-(2-deoxy--D-ribofuranosyl)-5-fluorouracil
MOA: Similar to 5-fluorouracil (thymidylate synthetase inhibitor)
Uses:
✓ Used in the treatment of malignant neoplasms of the liver and GIT.
✓ Mainly in colon cencer.
16. Cytarabine (Cytosine arabinoside, Ara C)

NH2

O N
HOH2C
O
H H
H H
O H

4-amino-1 -D-arabinofuranosyl pyrimidin-2(1H)-one

1--D-arabino-furanosyl cytosine
MOA: Cytarabine is converted in the body to Ara-cytosine triphosphate which competitively
inhibits DNA polymerase resulting in blockade of DNA synthesis.
Uses :
✓ Used in the treatment of acute non-lymphoblastic leukemia.
✓ Cytarabine is used as an antiviral agent in the treatment of Herpes infection and
encephalitis.

Raltitrexed inhibit thymidylate synthetase. Pemetrexed inhibit thymidylate transferase.

Gemcitabine, a new analouge of cytarabine.

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Antibiotics: Dactinomycin, Daunorubicin, Doxorubicin, Bleomycin

3) Antibiotics

17. Actinomycin-D (Dactinomycin)

CH(CH3)2 CH(CH3)2
O C CH HC C O
NCH3 NCH3
MeGly MeGly
O L−Pro L-Pro O

D-Val D-Val
C=O C=O
CH3CH CH HC CHCH3

NH NH

C=O C=O
10
9 1
N NH2
8 2
7 3
O O
6 4
CH3 5 CH3

Actinomycin-D is produced by Streptomyces chrysomallus and other species of Streptomyces.

It is made up of amino acids.
MOA: It binds to double helical DNA, intercalates in the minor groove of DNA between
adjacent guanosine-cytosine pairs, block DNA dependent RNA polymerase and hence
transcription of DNA molecule is blocked.
Uses : Used in the treatment of carcinoma of uterus, testis, Kaposi's sarcoma, osteogenic
sarcoma, Wilm's tumour and Ewing's sarcoma.

18. Doxorubicin and Daunorubicin

O
OH 14
O CCH2R
7 6 5 4
13
8 3
9
OH
10 11 12 2
1 Daunorubicin R = H
H3CO O OH
H
O O
Doxorubicin R = OH
H
CH3
O H
HO H
NH2 H
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Doxorubicin and Daunorubicin are anthracycline antibiotic obtained from Streptomyces

coeruleorubidus and S. peucetius.
MOA: It intercalate DNA and produce DNA strand breakage. They also interfere on
topoisomerase II (DNA gyrase) enzyme.
Uses: Used in acute lymphoblastic & myeloblastic leukemias, Hodgkin’s & non-Hodgkin’s
lymphomas breast & ovarian cancers and Wilm’s tumour.
19. Bleomycin:
O
H3N O NH2
H C−R
NH2
N

O CH3 O N S
N N H
O HO
O N
H3N NH N
CH3 HN N O
H CH3 OH CH3 S
HO O N
N
OH O H
O OH
OH O
OH
O
OH
O NH2 CH3
Bleomycin A2 R = −NHCH2CH2CH2 − S+
CH3
Bleomycin B2
NH
R = −NHCH2CH2CH2CH2NHC
NH2

It is a glycopeptide antibiotic. Commercially it is obtained from Streptomyces verticillus and

it is a mixture of bleomycin A2 (main component) and bleomycin B2. Bleomycin is inactivated
by bleomycin hydrolase.
MOA: It produce DNA strand breakage [breakage is due to DNA-bloemycin-Fe(II) complex].
Inhibition of DNA biosynthesis is also reported.
Uses : It is used in Hodgkin's disease, testicular cancer, malignant neoplasm and other
malignancies.
20. Mithramycin (Chromomycin, Plicamycin)
It is isolated from Streptomyces plicatus, S. argillaceus and S. tanashiensis.
MOA: It inhibits DNA-dependent RNA synthesis by binding to DNA through Plicamycin
Mg++ complex.

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CH3O HO
CH3
O O
O O OH
HO CH3 O
CH3 OH OH O
CH3 CH3
O O
OH O
HO HO

CH3 OH
O O O
CH3 CH3
HO
OH
Mithramycin
Uses : Used in chronic myelocytic leukemia and malignant hypercalcemia.
21. Mitomycin-C
Mitomycin C is obtained from Streptomyces caespitosus.
MOA: It inhibit DNA synthesis by crosslinking double stranded DNA through guanine and
cytosine.

OCONH2
O
H2N OCH3

H3C N NH
O
Mitomycin C
Uses: It is used for the treatment of gastric adenocarcinoma, carcinoma of cervix, colon,
rectum, pancreas breast and lung.

4) Plant Products :
22. Vinca alkaloids
OH
N CH2CH3

N
CO2CH3
H
N

H CH2CH3
N OAC
CH3O H CO2CH3 Vincristine: R = CHO
R HO
Vinblastine: R = CH3
Vinca alkaloids are derived from plant Vinca rosea, these are vincristine and vinblastine.
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MOA: Vinca alkaloids are "spindle poisons". They bind to the microtubule protein "tubulin"
and causes depolymerisation of microtubules, which are essential for formation of mitotic
spindle*.
* The mitotic spindle is essential for cell division in which DNA divides into genetically
identical daughter cells.

Dose : Vincristine- 0.5 – 2 mg/m2/weekly by i.v. route.

Vinblastine- 0.1 – 0.2 mg/kg weekly by i.v. route.
Uses:
✓ Vincristine: Used in the treatment of acute lymphoblastic leukemia in children,
Hodgkin’s & non-Hodgkin's lymphomas, Ewing’s soft-tissue sarcoma and Wilm’s
tumour.
✓ Vinblastine: Used along with bleomycin and cisplatin for the treatment of metastatic
testicular carcinoma, Also used in the treatment of systemic Hodgkin's and non-
Hodgkin's lymphomas.
*Vindesine and Vinorelbin is a semisynthetic vinka alkaloid with similar properties and
that mainly used to breast cancer.
23. Etoposide: Etoposide is a semisynthetic derivative of podophyllotoxin.

O
CH3 O O
OH
O
EtoposideO OH O
O
O

CH3O OCH3
CH3O

MOA: Etoposide induce strand breaks in DNA via topoisomerare II cleavage, inhibition of
nucleoside transport and inhibition of mitochondrial transport.
Uses: Used in refractory testicular tumours, Kaposi’s sarcoma, non-Hodgkin lymphoma,
small cell lung cancer, Wilm’s tumour & hepatocellular carcinoma.
24. Podophyllotoxin: Podophyllotoxin is obtained from root of the May apple (Podophyllum
OH
peltatum). H
O
O
O
O H

CH3O OCH3
OCH3

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25. Campothecins: Irinotecan and Topotecan.

They are isolated from the stem of the tree Camptotheca acuminata, bind to and inhibit
topoisomerase I, high levels of which occur throughout the cell cycle.
26. Taxol: Paclitaxel and Docetaxel.
Taxol was isolated from Pacific Yew tree bark. It is an antimitotic agent (act on microtubules
& stabilises them in polymerised state).
O
OAC O OH
H CH3
NH CH3 H
O
CH3
H
O
CH3 O
OH H H
OAC
OH H
OH
O

Taxol

4) Miscellaneous agents

27. Cisplatin
Cl− NH3
2+
Pt
Cl − NH3

cis-diamine dichloro platinum

MOA: When it enters the cells, chloride ions dissociate leaving a reactive
diamineplatinum complex which reacts with water and then interacts with DNA and cause
denaturation of DNA chain. It is not absorbed orally, therefore must be given intravenously.
Uses: It is used in the treatment of metastatic testicular and ovarian tumours and bladder cancer.
28. Mitotane

1-chloro-2-[2,2-dichloro-1-(4-chloro phenyl) ethyl] benzene

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MOA: Modulate the peripheral metabolism of steroids as well as directly suppressing the
adrenal cortex. Derivative of DDT with anti-adrenal cortex property
Uses: Used in the treatment of adrenocortical carcinoma and cushing’s syndrome.

****

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