Anti-Cancer Drugs

Introduction
Definition of Cancer:
Diseases in which a group of body cells multiply
without apparent control, destroying healthy
tissues and organs and sometimes undergo
metastasis.
Cancer [Tumor] is type of Neoplasm:[Neoplasm :
autonomous growth of tissues]
Tumor may be :
Benign : no metastasis.
Malignant : metastasized into other organs.
 Treatment Strategies of Cancer
[1] Surgery:
For localized tumors [NOT disseminated forms as
Leukemia].
By removal of the tumor & part of certain healthy
tissues around it [to prevent further spread].
[2] Radiotherapy: killing the cancer cell by
ionizing radiations.
[3] Chemotherapy:
Using of anti-cancer drugs.
Used even if metastasis occurs.
 Chemotherapeutic Agents
[Antineoplastic, Anticancer, Antitumor or
Cytotoxic Drugs]
Ideal anti-cancer should eradicate cancer cells without
harming normal cells.
Anticancer drugs act on cells in the process of division, so
as tumor cells divide more rapidly than normal cells, they
are most affected.
That's why normal cells with high rate of division are also
affected causing many side effects :for e.g.
Hair follicles: hair loss.
Lymphatic system: decrease in immunity & increased
susceptibility to infection.
Bone marrow: aplastic anemia.
Mucous membrane of the stomach nausea &
vomiting.
 Alkylating agents
[A] Nitrogen mustard [Bis (chloroethylamines)]
History:
In World War: Usage of Sulphur mustard as a war gas it was
found to have sever atrophy of lymphoid tissue &bone marrow.
So, trials were carried out to find related but less toxic derivative.
M.O.A:
By alkylation [covalent binding] of important molecules in cells [as
DNA, Proteins] cell death.
Example: alkylation of 7-position on guanine base in each of
double strands of DNA CROSS LINKAGE.
This cross-linkage interfere with separation of DNA strands
prevents miosis.
CH2 CH2 Cl
Cl S bis(2-chloroethyl) sulphide
HN CH2 CH2 Cl
Cl
 R
Nucleophilic site O CH2 CH2 N CH2 CH2 O
O
6 .. N N
1 5 N 7 CH2 CH2 Cl HN NH
HN R N
8 +
CH2 CH2 Cl H2N N N N N NH2
H2 N 2 4 N 9
3 DNA Srand A DNA Srand B
DNA Srand A
Cross-linked Product
 Mechlorethamine [Mustine HCl]
Cl
N CH3
Cl
Methyl-2,2'-dichloro diethyl amine
In solution fast intramolecular cylcization aziridinium cation
(immonium ion) [highly strained & very reactive] rapid alkylation on
nucleophilic sites of important protein or nucleic acid.
Nu
Cl Nu
N CH3 N CH3 N CH3
Cl Cl
Cl
cylic immonium ion
[Aziridinium Cation]

Used in combination therapy of Hodgkin's disease & non-Hodgkin's

lymphomas. But of low safety so, replaced by other drugs.

Synthesis: HO Cl
O SOCl2
H3C NH2 + 2 N CH3 N CH3
methyl amine ethylene oxide
HO Cl

assay : boil with alc.KOH (or by O2 reflux or double crucible ) KCl carry out
Volhards (What is Volhards method??).
 Chlorambucil [Leukeran]
Cl

N COOH

Cl

Introduction of terminal carboxylic group water soluble Na

form.
Aromatic ring formation of cyclic immonium ion
[aziridinium cation] due to electron density on N
selectivity.
Assay : Acid-base titration by titration with std. NaOH (
Ph.Ph.).
Used in chronic lymphocytic leukemia [orally].
Synthesis: O HO
2 SOCl2
N COOH
Chlorambucil
H2N COOH

HO
P-amino phenyl butyric acid
 Melphalan [Alkeran ]

Cl
NH2
N CH2 CH COOH

Cl
Phenyl alanine moeity
Phenyl alanine is a natural substrate assist in active
transport of N-mustard to active site [act as carrier].
 Cyclophosphamide [Endoxan ]

6 1 Cl
O O
5 2 P N
NH
4 3
Cl

The drug was designed based on an assumption that cancer

cells contains phosphoamidase enzyme that will break the
P-N bond & this will increase selectively towards cancer
cells.
But found to be a prodrug metabolized in the liver initially.
Drug undergoes hydroxylation by cyt.P450 mono-
oxygenase in liver.
 Biotransformation of cyclophosphamide
M
O O O O
O CH 2CH2Cl Cyt.P450 O
P P M P M
N
N CH2CH 2Cl liver N CH H N
H 2
H
HO O
4-hydroxycyclophospamide aldophosphamide

Normal cells Cancer cells

further oxidation(enzymatically) (non-enzymatically)

due to low pH

O O
P M CH 2=CH-CHO HO
O
N + P
O H acrolein H 2N M
inactive
phosphoramide
O O mustard
P M (alkylating agent)
H2 N active
O OH

Acrolein formed is nephrotoxic co-administered with N-Acetyl cysteine or mesna

to overcome its toxicity by forming non-toxic conjugate with it.

HS-CH2CH2SO3Na + CH2=CH-CHO OHC-CH2CH2 S-CH2CH2SO3Na

mesna acrolein safe addition product

 [B] sulfonate esters
Busulfan [ Myleran ]
O O

H3C S O O S CH3

O O
tetramethylene-bis-(methane sulfonate)
NOT N-mustard act by nucleophilic displacement of
methanesulfonate by nucleophilic group in biomolecules
alkylation & cytotoxicity.
O O O
H3C S O O S CH3 H3C S O Nu
- CH3SO 3H
O .. O
Nu ..
Nu - CH3 SO3 H

Nu Nu

Assay : hydrolysis with H2O CH3SO3H methanesufonic

acid titrated against Std. alkali(ph.ph).
 [C] Nitrosoureas
Carmustine [BCNU: bis-chloronitrosourea] Lomustine [CCNU]
O
NO
H
Cl Cl N N
N N Cl
H
NO O

Uses: Due to its high lipophilicity it passes B.B.B. used in brain

carcinoma.
NH R
O C
N CH2 CH2 Cl
N O
Cleavage at aqueous solution

N CH2 CH2 Cl
N R
N OH
O C
Chloroethyl azohydroxide Isocyanate

-
OH + N2 + CH2 CH2 Cl Carbamoylation
chloroethyl of protein
carbonium ion

alkylate DNA