Anticancer /Antineoplastic

Drugs
Alemu Tadesse
Medicinal Chemistry
Phar 323

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• Antineoplastics are drugs used to treat cancer, also
called cancer drugs, cytotoxic agents and
anticancer drugs.
• Cancer is a disorder of cells in the body
• It begins with a group of cells that fail to respond to
the normal control mechanism and continue to divide
without control
• The new growth is called tumor or neoplasia and may
be either benign or malignant
• A benign tumor is the one that remains localized
whereas a malignant tumor invades neighboring
tissues, enters blood vessels, lymphatic vessels and
other spaces and can be carried to other areas of the
body to form new tumors, “metastasis”
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Causes of Cancer:
 30 % is due to smoking: lung, mouth,
pharynx, larynx, esophagus, urinary bladder,
pancreas, and kidney cancers
 Lifestyle – diet, alcohol consumption,
reproductive behavior, sexual behavior,
etc
 At least 15% are related to viruses, e.g.
cervical cancer caused by human
papillomavirus
 outside exposures to the body such as
chemicals, radiation or even infectious
agents.
• The defective genes are called oncogenes
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• Substances which cause changes that can lead
to cancer are called carcinogens

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• Cancer Therapy
• Surgery
• Radiation
• Immunologican Therapy
• Chemotherapy
– 1. Alkylating agents

– 2. Antimetabolites

– 3. Hormones and Antihormones

– 4. Antibiotics

– 5. Plant products

– 6. Miscellaneous
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1. Alkylating Agents
• Alkylating agents contain chemical groups which
have the ability of forming covalent bonds with
nucleophilic substances in the cell (DNA, RNA and
certain enzymes)
• The alkylating agents are extremely
reactive electrophilic (δ+)
structures.
• Most of the anticancer alkylating agents are
bifunctional; possessing two alkylating
groups
• They are thus able to react with two groups and
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 can cause intra- or inter-chain cross-linking, that
can interfere with transcription and replication of
DNA

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Classification of alkylating agents
A. Nitrogen mustard derivatives B. Nitrosoureas
C. Aziridines D. Sulfonic acid esters
E. Triazines F. Platinum complexes
A. Nitrogen Mustards Derivatives
• Their original use stems from the observation during
world war I, that individuals heavily exposed to
mustard gas suffered damage to bone marrow and
lymphoid tissues.
• Mustard gas: highly toxic, insoluble in water.
• Nitrogen mustard derivatives: less toxic, salts are
solids and water soluble
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 R
N
Cl Cl

Mechanism of Action of Nitrogen Mustards

1. Aliphatic Substituted Nitrogen Mustards
• The molecules undergo neighboring group reactions
in which the nitrogen atoms displaces a chlorine atom
to give strained three-membered aziridinium
intermediates
• The highly strained three-membered ring rearranges by
scission to the carbonium ion, which in turns reacts
with the nucleophilic groups
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• The attack leads to irreversible covalent bond
formation with the substrate

Nu
Cl
- CH2 CH2
CH CH2 + Cl N
H3 Nu H3 N
2
H3 C
N: C CH CH2
C
2 Cl
CH2 CH2 CH2
CH2 Cl
Cl
Aziridinium ion
Nu
CH -
+ Cl
CH2 2 Nu
H3C H3C N
N
CH2 CH
2
N
u CH2 CH2
Nu

Nu = nucleophilic center rich in electrons (OH, NH2, SH, COOH, SO3H ) present

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0
 in enzymes, proteins RNA and DNA

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1
2. Aromatic Substituted Nitrogen Mustards
• Aryl substituted nitrogen mustards are relatively stable
toward aziridinium ion formation, because the
aromatic ring decreases the nucleophilicity of the N
atom.
• The highly reactive carbonium ion species react with
nucleophilic (electron-rich) sites on nucleic acids
and proteins (alkylation occurs via SN1 mechanism)
C + Cl - Nu
CH l CH CH CH CH2
N 2
Ar 2 CH2 Ar 2
2 H3
u N
C
N N
CH2 CH2 CH2 CH2 CH2 CH2
Cl
C Cl
l

Alemu T.
 Nu Nu
CH CH CH CH2
H3C 2 2 Nu H C 2
N N
3
CH CH + -
2 2
CH2 CH2 Cl
8/13/2018 Nu 9

Alemu T.
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Alkylation of DNA by Nitrogen Mustards
• In DNA, the N7 of guanine, being strongly
nucleophilic, is probably the main molecular target for
alkylation in DNA
• However N1 and N3 of adenine and N3 of cytosine
may also be affected
• The alkylated structure has a positive charge in its
imidazole ring which renders the guanine-ribose
linkage susceptible to cleavage
• Guanine is also implicated in the cross-linking of
double helical DNA, which interferes with separation of
the strands and prevents mitosis

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 Alkylation sites mostly N7 and/or O6 on Guanine and N3 on
Cytosine

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 R
N
O Cl Cl O
N N
HN N NH
N
N NH2 R
H 2N N
R
2 Steps

R
-
Cl Cl
O
- N +
HN + O N
NH
N
NH2
N N
H 2N N N R
R

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Structure-Activity Relationship
1. Aliphatic nitrogen mustards are more soluble in
lipid therefore more bioactive
2. The more localized the unshared pair of electrons on N
the higher is the reactivity
3. Aromatic nitrogen mustards are of low basicity with a
slow rate of C+ formation therefore the molecules can
reach distant sites
4. The presence of an amino acid moiety with nitrogen
mustard may direct the drug to a metabolic site
affecting cancer
5. Monofunctional alkylating agents are less bioactive
6. Iodine or fluorine atoms instead of chlorine decrease
the activity (slow formation of C+ ion); bromine atoms
lead to very reactive molecules but with high toxicity
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i. Mechlorethamine HCl (Mustine HCl)
• Mechlorethamine is only aliphatic nitrogen mustard drug
currently in use in US market.
• Mustine HCl is used in the treatment of Hodgkin’s diseases
and other malignant neoplasm including lung carcinoma,
chronic myelocytic leukemia and brain tumors
• It is administered intravenously and intracavitary
Cl

H+ -
H3 C N Cl

Synthesis
Cl
OH Cl

RN
H + SOCl2 H C + Cl -
2 H3C N 3 N
O

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ii. Mustrone (Mechlorethamine-N-oxide)
• The toxicity of the parent compound is
greatly reduced with only slight reduction
inactivity
• It is active after metabolic reduction
to mechlorethamine

Cl
O
H 3C N

Cl

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iii. Chlorambucil
• Chlorambucil is an alkylating agent used for its
antineoplastic properties in the treatment of
leukemias and lymphomas and various other
malignant neoplasms
• It is the slowest acting and least toxic nitrogen mustard
• It is administered orally

HO

O Cl
N

Cl
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iv. Melphalan
• Melphalan is used for its antineoplastic action in
the treatment of multiple myeloma and in other
malignant neoplasm including tumors of the
breast and ovary
• It is active orally

Cl

O N

HO NH2 Cl

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v. Cyclophosphamide
• Cyclophosphamide is an alkylating antineoplastic
agent, which can be given by mouth or by
intravenous injection:
• Although it is chemically related to the nitrogen
mustards, the nucleophilicity of the mustard
nitrogen is less likely to form an aziridinium ion
than are the alkyl-substituted nitrogen
mustards
• It requires activation in the body to take effect
N
O
P Cl
O
N
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Cl
 Bioactivation of Cyclophosphamide

HO
H H H2 N O
N O N O
P P Cl P
Cl Cl
O N N N
CYP450 O O
(O)
CHO
Cl Cl Cl
Unstable Aldophosphamide
carbinolamine (unstable)

H2N O
P
Cl
HO N
+ CH2 CH CHO
Acrolein
Cl
Phosphoramide
mustard (Active)
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• Cyclophosphamide is used in the treatment of
various malignant diseases including lymphoma,
myeloma, and a variety of solid tumors

Synthesis
Cl
NH2 Cl
- HCl
+ + Cyclophosphamide
OH OP HN
Cl Cl
3-Amino- Phosphorous Cl
1-propanol
oxychloride

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 vi. Mafosamide
• It is a combination between cyclophosphamide
and mesna
NaO3S
S
N H
O
P Cl
O
N

vii. Uracil Cl

• It is a combination of the structural features of N-

mustard and a nucleotide which acts as a carrier for
the
active species H
O N
Cl
HN
N
Cl
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 O

Cl
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 B. Nitrosoureas
i. Carmustine
• Carmustine is a neutral molecule that is highly
lipophilic and poorly soluble in water
• These properties allow for efficient crossing of
blood- brain barrier
• Although carmustine administration is thought to
alkylate DNA and RNA as a mechanism of action,
and alternate mechanisms of action involving
enzyme inhibition by carbamoylation of proteins
• Carmustine is used in the treatment of leukemia,
lymphomas, malignant melanoma and brain
tumors
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 Cl
HN

O C
N

N Cl

Carmustine

Synthesis
O
N N
2 + COCl2 C

NH

Carnustine

H
N

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NaNO2 Cl
O C HCl

HCOOH
N
H Cl

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ii. Lomustine
• It is a nitrosourea antineoplastic agent similar
to carmustine
• It is formulated as capsules

H
N
O C
N Cl
NO

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C. Aziridines (Ethyleneimines)
• Aziridine is a 3 membered nitrogen heterocycle
that reacts with nucleophiles in order to relief ring
strain
• At acidic pH, the aziridine group is protonated to
provide a reactive aziridinium ion that is known
to alkylate DNA
i. Triethylenemelamine (TEM)
• It is an aziridine contaning compound

N
N

N N

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 N

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ii. Thiotepa
• An aziridine containing drug, used in
carcinoma of breast, bladder, Hodgkin’s and
non Hodgkin’s lymphoma
• It is administered intravenously,
Intracavitary and intravesical
• Metabolic desulfuration leads to a
toxic metabolite
S O
N PN N P
NN
N
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Toxic metabolite 27
 Synthesis
H S
N Base
3 + Cl P Thiotepa
-3
HCl
Cl Cl
D. Sulphonic Acid Esters
Busulphan (Myleran)
• Busulphan is an alkylating agent with a
methane sulfonic acid acting as a leaving group
• It is used to treat chronic myelocytic leukemia
• It is formulated as tablets
O
O
H3 C
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 O S
S CH
3
O O

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 E. Triazines
Dacarbazine
• Dacarbazine is a cell-cycle nonspecific
antineoplastic agent which may function as an
alkylating agent after its activation in the liver
although other hypotheses, including inhibition of
DNA synthesis by acting as a purine analogue, and
interaction with sulfhydryl groups, have been
proposed for its activity
• It is used mainly in the treatment of metastatic
malignant melanoma and Hodgkin’s lymphoma

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 CONH
2 CH
N
3N

N CH3
N NH

Mechanism of action
CONH2 CONH2
N N
Demethylation
In liver N
N + N CH CH2O
3
N H
N N NH
N CH3 H
H
:
C
+ +
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 Diazomethane
CONH2
N

NH2
N

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F. Platinum compounds
i. Cisplatin
• It is a platin complex containing two
ammonia molecules and two chlorine atoms
in a cis configuration
• It reacts with nitrogen atoms of DNA
preferentially with N7 of deoxyguanylic acid
forming intra-strand and inter-strand cross-links
 It is active against testicular cancer,
lymphoma, carcinoma of the head and neck,
ovarian cancer and bladder cancer
• Trans platin is inactive as it lacks the
stereochemistry required for cross linking
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Mechanism of action
NH3
Pt O
+ O

H 3N N
H3 N N
Cl H 3N OH2 N Cl
N H O NH
2 7
Pt Pt
H 3N N NH N NH2
H 3N Cl Cl
2
Suga
N
r
Sugar

NH3 O N
O
H3
NH3
Pt
DNA
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link
 H 2O O N N
O H3N Pt N H O
N N N 2 7
N 7 +
7 7 NN NH2

H 2N H 2N N
N N N Sugar
Suga
N Suga Suga N
NH2 r
r r

DNA
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link
ii. Carboplatin
• It is less toxic than cis platin and used in
ovarian cancer

O
O
Pt
O
O

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 2. Antimetabolites
• Antimetabolites are compounds that prevent
the biosynthesis or utilization of normal cellular
metabolites
• They are closely related in structure to the
metabolite being antagonized
• Many antimetabolites are enzyme
inhibitors ex. PABA / sulfonamides

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A. Folic acid Antagonists
• Folic acid is essential for the synthesis of nucleic acids
• It is reduced to dihydrofolic acid (DHFA) then
to tetrahydrofolic acid (THFA) by folate
reductase
Methotrexate (MTX)
• A folic acid analogue, prevents the formation of
tetrahydrofolate, essential for purine and pyrimidine
synthesis, by inhibiting dihydrofolate reductase. This leads
to inhibition of production of DNA, RNA and proteins
• It is actively taken up into the cells by the same
transport system for folate
• The most common toxicity is nepherotoxicity
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 1
H2N N N
2
N 4 R O CH CH COOH
2 2
N CH2
N C N CH
5
1 10 H
R COOH

R1 R2
Folic acid OH H Metabolite
Aminopterin NH2 H Antimetabolite
Methotrexate NH2 CH3 Antimetabolite

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 O

OH NH
CO2H
N
N
N

H
H 2N N N
Antibact. sulfonamide CO2H
O R O Folic acid
H2 S NH
N OH
O OH
N
N
From diet, humans
O N H
H 2N H 2N N N
OH H
PABA Dehydropteridinsyre

O O

NH OH NH
OH
H CO2H Folate- CO2H
N reduktas N N
N N N
H
H e
H 2N N N H 2N N N
H H
CO2H CO2H
Tetrahydrofolic acide ssenti processes bacteria and animals
E al

(Me8t/ Alemu T. 40
a13b/.20C18H3O
 H2 Trimetoprim Dihydrofolic acid
N
NH2
OCH3
N

N OCH3
ex. Thymin synthesis OCH3

(Me8t/ Alemu T. 41
a13b/.20C18H3O
 Synthesis of methotrexate

H 2N NH O H H 2N N
2 C
N
N CH
+ +
Br N CH2Br
N NH N
CH2Br
2
NH2 H
2,3- NH2
Dibromopropionaldehyde
2,4,5,6- N
Tetraaminopyrimidine (O)
H
H
NH H 2N N N
3
2
C
+ N
HOOC N
+ N
COO H
H 2
COOH

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 C H2Br

Methotrexate

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B. Purine Antagonists
• 6-Mercaptopurine (6MP) and 6-thioguanine (6TG)
are examples of purine antimetabolites
• Possible mechanisms:
• Incorporation DNA or RNA; misreading
• Inhibition of DNA polymerase
• Inhibition of Kinases
• Inhib. of enzymes involved in pyrimidine /
purine biosynthesis
NH2 H

N
N

N
Natural
 O H2N N
N N
HN
H

Adenine Guanine
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Natural
 S-Analog hypoxanthine
SH S
Metabolic
S S Me

N N activation N N N
N
HN HN

N N N N N N
H H N
P O
N
O
P O
6-MPMP O
Inhib. several steps
HO OH in purine biosynth
HO OH
also antimetabolite

HN N

N N
PP P O
O

HO OH
Incorp . DNA / RNA instead og guanine

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C. Pyrimidine Antagonists
O NH2
NH2 O N
HN
DNA HN N N
N N
N
O N O N
N N H2 Guanine O O
Adenine N
O
Thymin Cytosin P
O Base
O
O R=H in DNA

RNA HN O R
R=OH in RNA

Cytosin Adenine Guanine

O N

Uracil

i. 5-Fluorouracil (5FU)
O
F
O HN
F
O HN in vivo
O O Inhibitor
F O O
N HO Thymidylate synthetase
N
P O
HN H
OH
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 O N HO
H

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ii. Floxuridine (5-Fluorodeoxyuridine)
• It is easier to be activated than 5FU since it needs
only the phosphate group to be added
• Cancerous cells may undergo mutation and develop
resistance upon prolonged treatment with purine
and pyrimidine antimetabolites
• The formation of alkaline phosphatase enzyme
would break 6-mercaptopurine
O
F
HN

O N
HO-H 2C O

OH
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3. Hormones and Antihormones
• Hormone based therapies are used for cancers which are
hormone dependent.
• Their growth can be inhibited by hormones of opposing
actions, by hormone antagonists or by agents that inhibit the
synthesis of these hormones
• Hormones essential for reproduction are also responsible for
development and growth of breast, prostate and uterine
cancer
• If the cancer cell requires a specific hormone, then a hormone
can be administered which has a opposing effect----like
hormone antagonists.
• Several types of hormone-dependent cancer (especially
breast, prostate, and endometrial cancer) respond to
treatment with their corresponding hormone antagonists.
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Antiestrogens (Breast Cancer )
• The female hormone estrogen is a growth factor for
some types of breast cancer.
• Estrogens inhibit the effects of endogenous
androgens and androgen-dependent metastatic
prostatic carcinoma. Diethylstilbestrol is usually the
agent of choice.
• Tamoxifen and raloxifene are synthetic drugs
which are estrogen receptor blocker that inhibits the
growth of breast cancer cells.
• Tamoxifen is the drug of choice in postmenopausal
women with or recovering from metastatic breast
cancer. It is most effective in patients who have
estrogen receptor-positive tumors.
• Tamoxifen is also used as adjunvctive therapy to
oophorectomy to leuprolide or goserelin in
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premenopausal women with estrogen receptor-
positive tumors.

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• Tamoxifen is a nonsteroidal antiestrogen used in
the treatment of the advanced breast cancer
• In breast tissues, tamoxifen competes with
endogenous estrogen for the estrogen receptor and
inhibits the transcription of estrogen-responsive genes
• It is bioactivated first to produce the
active hydroxylated derivative

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 CH3 CH3
N N
O O CH3

CH3

Bioactivation

HO

Synthesis tamoxifen
CH3
N
O O
CH3
OH
C
+

C
2-Ethyldeoxybenzoin MgB
r O H CH
2
4- [(2-N,N- C
Dimethylamino)ethoxy]-
phenylmagnesium bromide H3 N CH3
 CH O
3
2

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Tamoxifen
Antiandrogens (Prostatic Cancer )
• Most of prostatic tumors are androgen-dependent
• The action of androgens in prostate involves metabolic activation of
circulatory androgens to a derivative with high binding affinity for
androgen receptors
• Androgen antagonists are used for the treatment of metastatic prostate
cancer
• They block the action of testosterone and dihydrotestosterone
• Flutamide and cyproterone acetate are used to treat prostate cancer and
work by blocking the androgens at their receptors.
• At present prostatic cancer is treated with a combined therapy of an
luteinizing hormone-releasing hormone agonist and an antiandrogen.
• They inhibit androgen formation by inhibiting a metabolic enzyme called
cytochrome p450, which is involved in the formation of androgens.

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Antiandrogens may be classified into :
a. Steroidal compounds as cyprotone, chlormadinone
and megesterol
b. Nonsteroidal compounds as flutamide which is
bioactivated first
Flutamide (Eulexin)

O O
CH3 CH3
HN CH C OH
HN
CH3 CH3
Bioactivatio
n
CF 3 CF 3
NO2 NO
2

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4. Antibiotics
• Several compounds that were originally evaluated
for their antibiotic activity have been clinically useful
anticancer agents
• However, they were rejected as antibiotics because
of their toxicity
• This property was subsequently turned into asset
with their application as anticancer agents
• The source of most antitumor antibiotics is
from microbial fermentation

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Antracyclines Antibacterial Tetracyclines
OH
Isolated Streptomyces sp, several semisynth analogs OH O HO OO

NHR2
O O
OH
R2
Doxorubicin HH
OH
N
OH Doxorubicin® Adriamycin® R6 R5

R1
Caelyx® R1 = OMe, R2 = OH, R3 = H;
OH
O R4 = OH
CH3
O
Daunorubicin
R3
R4
NH2 Cerubidin® R1 = OMe, R2 = H, R3 = H; R4 = OH

Idarubicin Epirubicin
Zavedos® R1 Farmorubicin®
= H, R2 = H, R3 = H; R4 = OH
R1 = OMe, R2 = OH, R3 = OH; R4 = H

Valrubicin
Mitoxantrone
O OH O
OCOC4H9 Novantrone®
OH H
N
OH O HN OH
OCH3O OH
O
 CH3
HO OH O HN OH
HN N
H
COCF
3
Mechanism ≈ Actinomycins (Intercalation)

Also interact aminosugar - phosphate

Antraquinone - red/ox react:

prod. reactive oxygen radicals

DNA-Daunomycin Complex
Bleomycins
Isolated from Streptomyces
verticillius Naturally occuring as Cu-
chelates 1) Binds Fe(II) inside cells

H2N O
H 2N O

O NH2 NH
O
NH OH N O2
H2N NH N NH
OH H 2N
N N Fe
N O N N
H N
H2N N
O
O O OH H 2N
NH O OH O
O
HO O NH
OH O 2 2) Bleomycin complexed Fe(II) reduce O2
OH
NH 3) .OH radicals produced
HN O Bleomycine A: R =
S(CH3)3
NH
4) Cleavage of DNA
2
H
Bleomycibe -CH2 N
B: NH2
N
S
N
O S DNA binding
Interact heterocycl. bases
HN
Electrostat. interact. with phosphates Bleomycin
R
Bleomycin Baxter®
Mitomycins
Isolated Streptomyces sp,

Mitomycin C
Mutamycin®
In vivo:
H B
O OCONH OCONH2 O OCONH2 O OCONH2
H2N H2N H H H2
2 OCH3 re OCH3 B
H2N N
d
H3C N H3C N H3C N
H3C N NH
NH O NH OH NH OH OH H

quinone

Hydroquinone O H
NH2
OH Nu OH O Nu O OCONH2 Nu
H2 H2N
Nu DNA NuDNA NuDNA
H2 N N N H3C N
OH NH2 OH NH OH NH2
N H3C
2
H3C

Active drug

N
OH OH Nu
H2N
Nu NH2
H3C
DNA
Actinomycins

Isolated from Streptomyces sp.

Dactinomycin (Actinomycin D)
Cosmegen®

O
O
N Planar, aromatic rings
N
Intercalate between G-C base
N
N N pairs ( stacking interact)
O N
O O
O O
O
NH O
NH O
O
O
HNOO NH
NH2
N

O O - Affects DNA topoisomerase II (Unwinding)

- May also promote DNA cleavage (nucleases)

5-Plant Products (Antimitotic Agents)
• These agents prevent cellular mitosis, and in
particular, interfere with the formation of the mitotic
spindle
• During mitosis; the protein tubulin
undergoes polymerization to form mitotic
spindle
• Antimitotic agents interfere with this either by
depolymerization of the microtubules or by causing
structures other than the normal mitotic spindle to
be formed
• In the absence of a properly formed mitotic spindle,
the chromosomes cannot correctly segregate and
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 this ultimately leads to cellular death

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i. Vinca Alkaloids
e.g. Vincristine, Vinblastin and Vinorelbine
SAR
 Methyl instead of formyl has greater activity
 Acetyl at C4 very important
 Acetylation of free hydroxyl group leads to lose of activity
 Hydrogenation or reductive formulation of C6,7 double bond leads to
lose of activity
OH N
N CH -CH H
2 3

of microtubuli dynamics-
COOH
HO C
.
. HO C COOH

Binds to microtubuli-

Depolymerization of
H2SO4 N COOCH3
N HH

Metaphase arrest
COOCH3 H N
N

CH -CH H CH2-CH3

Supression
CH3O H 2 3 CH3
OCOCH O N OCOCH3
N H CO CH 3 H OHCO2CH3
OH 2 3 CH3
R
Vincristine: R = = CH3
CHO Vinblastin: R
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 Venorelbine

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8/13/2018 Alemu T. 59
ii. Taxans
• Paclitaxel and docetaxel are taxan
derivatives of yew tree black
1 O R2-O O OH
R
H 3C CH3
6
NH
3'
CH3
2' 1' O 3
4
5 H
1 CH3
2 O
HO O HO OCOCH
3
O

1 2
Paclitaxel: R=C H ;R =
6 5
1
Acetyl Docetaxal: R =
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 (CH3)3C-O; R2 = H

Mecanism ≈ Vinca alkaloids, different binding sites

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6. Miscellaneous Anticancer Agents
i. Podophyllotoxins
• They are obtained as extracts of the May apple
plant, used to treat small cell carcinomas of
the lung and Hodgkin’s diseases
• They cause DNA linkages or DNA strand breaks
by inhibiting topoisomerase II
ii. Hydroxyurea, H2N-CO-NH-OH
• It inhibits ribonucleotide diphosphate reductase,
thus interferes with the conversion of
ribonucleotides to deoxyribonucleotides
required for DNA synthesis
2+
• The action may be due to chelation of Fe cofactor
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iii. Mitotane
• It is related in structure to the insecticide DDT
• It is used in adrenal cortex carcinoma and
administered as tablets
Cl
CHCl2

CH

Cl

iv. Procarbazine (Matulane)

• It is an alkylating agent
O CH3

H
H 3C N
N H

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 N
CH3 H

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v. Pipobromane
• It is used for the treatment of polycithemia
Br
O
N N
O
Br

vi. Mitobronitol (Dibromomannitol)

• It is a sugar derivative that can penetrate the
blood- brain barrier
• It acts as busulphan (alkylating agent) CH2Br
HO C H
HO C H
H C
OH
8/13/2018 Alemu T. CH2Br 65
 H C OH

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 Thank You!!
8/13/2018 Alemu T. 6