2. Antineoplastic Agents
Antineoplastic medications: drugs used to treat cancer, also called
cancer drugs ,cytotoxic agents and anticancer drugs.
Cancer
Along with heart disease, cancer is the largest cause of death in the
developed world
Cancer affects 1 in 3 people and is responsible for 25% of all
deaths
Cancer is an unregulated proliferation of cells due to loss of
normal controls, resulting in unregulated growth, lack of
differentiation, local tissue invasion, and, often, metastasis.
Cancer can develop in any tissue or organ at any age. There is
often an immune response to tumor.
Many cancers are curable if detected at an early stage.
2
3. Causes of Cancer:
1. 30 % is due to smoking: lung, mouth, pharynx,
larynx, esophagus, urinary bladder, pancreas, and
kidney cancers.
2. Lifestyle – diet, alcohol consumption, reproductive
behavior, sexual behavior, exposure to sunlight, etc.
3. At least 15% are related to viruses, e.g. cervical
cancer caused by human papilloma virus.
3
5. Characteristics of Cancer Cells
Cancer involves the development and reproduction of abnormal cells
Cancer cells are usually nonfunctional
Cancer cell growth is not subject to normal body control mechanisms
Cancer cells eventually metastasize to other organs via the
circulatory and lymphatic systems
5
9. Cancer chemotherapeutic agents
They are classified into:
Cell-cycle non specific agents(CCNS): are cytotoxic in any phase
of the cycle even on G0 phase and so are more effective against large
slowly growing tumors.
E.G. Bleomycin .
Cell-cycle specific (CCS): are cytotoxic on all phases but not on
cells out of the cycle(at G0 ) and so are more effective against
rapidly growing tumors. Work better in combination than alone
E.G. Mitomycin , doxorubicin,….etc.
Phase specific : act on specific phase of the cycle
E.G.Vinca alkaloids act more in M-phase ,antimetabolites
(mainly act on S-phase.)
9
19. 19
G0 = resting phase
G1 = pre-replicative phase
G2 = post-replicative phase
S = DNA synthesis
M = mitosis or cell division
M
S
G G
2 1 Hydrocortisone
Vincristine,Vinblastine
G0
Cyclophosphamide
Bleomycin
Actinomycin D
Actinomycin D
5-Fluorouracil
Cytosine arabinoside
Methotrexate
6-Mercaptopurine
6-Thioguanine
Purine antagonists
Methotrexate
Cyclophosphamide
5-Fluorouracil
Cytosine arabinoside
Daunomycin
Paclitaxel, Docetaxel
resting
Cell cycle specificity of Anti-Neoplastic Agents
20. I-Alkylating Agents (CCNS)
Mechanism of Alkylating Agents
These drugs work by alkylation with nucleophilic substitution . They alkylate
a variety of cellular constituents, such as cell membranes, proteins, and most
importantly DNA. More specifically, the nitrogenous bases of DNA are what
get alkylated.
The drugs start off as pro-drugs that become activated when a chlorine atom
is extracted. A carbonium ion is thus formed. This “carbonium ion” is very
electrophilic and will then attack any free pair of electrons (i.e. on the N7 of
guanine). This electrophilic attack results in a bond being formed between
the drug and the guanine of DNA. As a result of this “alkylation”, there are a
few consequences:
1) Miscoding (In transcription)
2) Cross linking- this only occurs if the drug is bifunctional
20
23. SAR of alkylating agents
Aryl substituted nitrogen mustard are more stable and
orally available forms, i.e melphalan, uracil mustard,
Electron- withdrawing property of the aromatic rings
decreases the nucleophilicity of the nitrogen atom and
thus reduces the rate of cyclization and rate of carbonium
ion formation
(ClCH2CH2)2N
COOH
NH2
Melphalan
23
24. Mechlorethamine
It is white ,crystalline powder , hygroscopic in nature.
The dry crystals are stable at temperature up to 400C
ClCH2CH2
N
ClCH2CH2
CH3
Mechlorethamine
24
26. Cyclophosphamide
Cyclophosphamide consits of a nitrogen and phosphamide
moiety in its structure .
it is a white crystalline powder , odourless , bitter in taste.
It discolored when exposed in light
It is soluble in water
NH
P
O N
O
CH2CH2Cl
CH2CH2Cl
cyclophosphamide 26
27. Synthesis of cyclophosphamide
O
NH2
O
H
NH
P
O N
O
CH2CH2Cl
CH2CH2Cl
P
O N
Cl
CH2CH2Cl
CH2CH2Cl
+
propanolamine
bis-(2-chloroethylphosphoramide cyclophosphamide
Uses
it is frequently used to treat lymphosarcoma and
Hodgkin's diseases as well as in breast, ovarian and lung
cancer
27
28. Thiotepa
It is chemically names phosphothioic acid
triethyleneamide
It is fine white with faint colour and soluble in water.
its becomes active due polymerization.
N
N P N
S
28
29. Synthesis of thiotepa
ClCH2CH2Cl NH3
Ca(OH)2
DMF
N
(C2H5)3N
PSCl3
N
N P N
S
+
H
Uses
it is largely used in the treatment of the bladder cancer
29
30. Busulfan
Chemically ,It is 1,4-butanediol dimethane sulfonate.
It is a white crystalline ,odourless, slightly water soluble ,
powder.
CH3SO2O(CH2)4OSO2CH3
Busulfan
30
31. Synthesis of busulfan
CH3SO2Cl HO(CH2)4OH CH3SO2O(CH2)4OSO2CH3
2 +
Pyridine
methane solfonyl chloride Busulfan
Uses
It is highly effective on granulocyte and is used in
chronic myelocytic leukemia
31
32. Carmustine
It is a low melting point , white powder that changes to
oily liquid
Chemically it is a 1,3bis(2-chloroethyl ) -1-nitrosourea
ClCH2CH2-N-C-NH-CH2-CH2Cl
N=O
O
carmustine
32
33. Synthesis of carmustine
NH COCl2 N
N-C-
O
CLCH2CH2NH-C-NH-CH2-CH2Cl
NaNO2 HCOOH
ClCH2CH2-N-C-NH-CH2-CH2Cl
N=O
O
2
+
HCl
aziridine
sym. bis2-chloroethyl urea
carmustine
Uses
It is used in the treatment of brain tumors and
leukemia
33
34. 34
1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
a. Nitrogen
Mustards
A. Mechlorethamine DNA cross-links,
resulting in
inhibition of DNA
synthesis and
function
Hodgkin’s and non-
Hodgkin’s lymphoma
Must be given
Orally
Nausea and vomiting,
depression, bleeding,
alopecia, skin
pigmentation, pulmonary
fibrosis
B.
Cyclophosphamide
Same as above Breast, ovarian, soft
tissue sarcoma,,
neuroblastoma
Orally and I.V. Same as above
C. Chlorambucil Same as above Chronic lymphocytic
leukemia
Orally
effective
Same as above
D. Melphalan Same as above Multiple myeloma,
breast, ovarian
Orally
effective
Same as above
E. Ifosfamide Same as above Germ cell cancer,
cervical carcinoma, lung,
Hodgkins and non-
Hodgkins lymphoma,
sarcomas
Orally effective Same as above
A. Alkylating agents
35. II-Antimetabolites (CCS)
An antimetabolite is a chemical with a similar structure to a metabolite
required for normal biochemical reactions, yet different enough to
interfere with the normal functions of cells, including cell division.
All antimetabolites are used in cancer treatment, as they interfere with
DNA production and therefore cell division and the growth of tumors
(mainly in S-phase specific).
They are classified into:
1- Folic acid analogues
2- Purine analogues
3- Pyrimidine analogues
Purin and pyrimidine antagonists are phosphorelated inside the body into
nucleotid form in order to be cytotoxic
Uses
leukemia.
non-Hodgkin's lymphoma
inflammatory bowel disease such as Crohn's Disease and ulcerative colitis
It is widely used as immunosuppressant in transplantations to control
rejection reactions.
35
36. 36
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
1.
Metho
trexate
inhibits
formation of FH4
(tetrahydrofolate)
from folic
acid by inhibiting
the enzyme
dihydrofolate
reductase
(DHFR); since
FH4 transfers
methyl groups
essential to DNA
synthesis and
hence DNA
synthesis
blocked.
Choriocarcinoma,
acute
lymphoblastic
leukemia
(children),
osteogenic
sarcoma, other
non-Hodgkin‘s
lymphomas,
cancer of breast,
ovary, bladder,
head & neck
Orall
y
effect
ive as
well
as
given
I.V.
bone marrow
depression,
intestinal lesions
and interference
with
embryogenesis.
Drug interaction:
aspirin and
sulfonamides
displace
methotrexate
from plasma
proteins.
C. Antimetabolites
37. 37
1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
2 Pyrimidine
Analogs: Cytosine
Arabinoside
inhibits DNA
synthesis
used for induction of remission acute
lymphoblastic leukemia,
non-Hodgkin's lymphomas; usually
used in combination chemotherapy
Orally
effective
bone marrow
depression
1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
2 Purine analogs:
6-Mercaptopurine (6-
MP) and Thioguanine
Blocks DNA
synthesis by
inhibiting
conversion of
IMP to AMPS and to
XMP as well as
blocking conversion
of AMP to
ADP; also blocks
first step in purine
synthesis.
Feedback inhibition
blocks DNA
synthesis by
inhibiting
conversion of IMP
to
XMP as well as GMP
to GDP; also blocks
first step in purine
synthesis by
feedback inhibition
most effective agent for induction of
remission in acute myelocytic
leukemia; also used for induction of
remission acute lymphoblastic
leukemia,
non-Hodgkin's lymphomas; usually
used in combination chemotherapy
Orally
effective
bone marrow
depression,
38. 1-Folic acid analogues
Methotrexate:
-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 (as tetrahydrofolate is also involved in the
synthesis of amino acids as serine and methionine).
It is actively taken up into the cells by the same transport system
for folate
The most common toxicity is nepherotoxicity .
38
39. 1-Methotrexate compete with folic acid for DHFR and inhibits it .
Therefore, it inhibits the synthesis of DNA, RNA and proteins.
2-Also,DHFR catalyses the conversion of dihydrofolate to the active
tetrahydrofolat which is needed for the de novo synthesis of the
deoxynucleoside thymidine mono phosphate DTMP ( required for DNA
synthesis)
39
40. Methotrexate
It is analogue of folic acid.
It is chemically N-(4(2,4-diaminopteridin-6-yl methyl
amino benzoyl) L- glutamic acid.
Its occurs as yellow to orange brown crystalline powder. It
is insoluble in water , freely soluble of alkali and slightly
soluble in dil HCl
N
N N
N
NH2
N
H2
CH2
CH3
NH
CH-COONa
CH2
CH2
COONa
N C
O
Methotrexate
40
41. Synthesis of methotrexate
Uses
it provide great benefit to patients suffering with acute
leukemia's , osteosarcoma.
N
N NH2
NH2
NH2
N
H2
BrCH2CH-C-H H3C-NH-
NH
CH-COONa
CH2
CH2
COONa
N
N N
N
NH2
N
H2
CH2
CH3
NH
CH-COONa
CH2
CH2
COONa
AcOH
NaOH
I2/KI
+
Br
O
C
O
+
N C
O
2,4,5,6-tetramino pyrimidine 2,3- dibromopropioaldehyde
disodium p-(methyl-amibenzoyl glutamate
Methotrexate
41
43. 2-Pyrimidine analogues
5-flurouracil (5-FU)
It act as a uracil analogue, it is transformed inside the cell into 5-
FU deoxynucleotide which compete with deoxyuridine
monophosphate DUMP for thymidylate synthase leading to
inhibition of deoxythymidine monophosphate DTMP synthesis
inhibition of DNA synthesis (Not RNA or protien)
finally inducing cell cycle arrest and apoptosis by inhibiting the
cell's ability to synthesize DNA
It is an S-phase specific drug
5−FU may be used in combination with other chemotherapy agents
to treat cancers of the breast, stomach,colon, rectum, and pancreas.
43
44. Activation pathways for 5-Fluorouracil
5-Fluorouracil-riboside (FUR)
Fluorodeoxyuridine-monophosphate
FdUMP
5-Fluorouracil-deoxy-riboside(FUdR)
F
O
HOH2C
O
H
O
N
H
N
O
OH
F
O
O
N
H
N
O
HO
CH2
O
P
OH
HO O
F
O
HOH2C
O
H
O
N
H
N
O
1. Uridine phosphorylase
2. Thymidine phosphorylase
3. Phosphoribosyl transferase
4. Thymidine kinase
5. Uridine kinase
6. Ribonucleotide reductase
7. Dihydropyrimidine
dehydrogenase
5-FU
FUR
FUdR FdUMP
FUMP FUDP FUTP RNA
FdUDP FdUTP DNA
Dihydro 5-FU
1
2
3
4
5
6
7
Inhibitor of thymidylate synthetase
44
46. 5-fluorouracil
• It is a pyrimidine analogue .
• Chemically it is 5- fluopyrimidine 2,4(1H, 3H) dione .
• It occurs as white ,odorless crystalline water soluble
powder which may darken in presence of light.
N
H
N
F
O
O
H
5-fluorouracil
46
47. Side effect
1- Most unwanted effect is GIT epithelial damage,
diarrhea and mouth ulcers.
2-the most dangerous side effect is bone marrow
suppression
Cytarabine
It is analogue to 2-deoxycytidine and in the body it
is converted into cytosine triphosphate and inhibit
DNA polymerase thus inhibiting DNA synthesis.
47
49. 3-Purine analogues
Mercaptopurine (6−mercaptopurine, or 6−MP) :
-It is immunosuppressive cytotoxic substance. It is
widely used in transplantations to control rejection reactions.
Adverse reactions
Diarrhea, nausea, vomiting, loss of appetite,
Allergic reaction include rash, itching, swelling, dizziness,
trouble breathing.
Mercaptopurine cause myelosuppression.
49
50. 6- mercaptopurine
It is a analogue of naturally occurring purine , which is an
essential component of DNA called adenine.
Chemically it is purine 6-thiol
It is yellow ,crystalline ,odorless, tasteless powder and is
insoluble in water
N
N
N
N
SH H
50
51. PURINE ANTIMETABOLITES:-
Sometimes, the antimetabolite must be transformed
biosynthetically in to the active inhibitor.
Eg:- 6-mercaptopurine ribonucleotide (activeform)
Potent inhibitor
5-phosphoribosylpyrophosphate 5-phosphoribosylamine
Rate limiting
step in the de-novo
synthesis of purines.
1. 6- Mercaptopurine:-
MECHANISM
52. Synthesis of 6-mercaptopurine
N
N
N
N
OH H
P2S5
N
N
N
N
SH H
N
N
NH
SH
NH2
C
H
O
Con HCOOH
N
N
NH2
NH2
SH
N
N
Cl
NO2
NH2
NaOH
KSH
Hypoxanthine 6-MP
4-amino-6-chloro-5-nitro pyrimidine 4,5-amino-6-thiopyrimidine
Uses
It is useful in the treatment of leukemias and chronic
myelocytic leukemia
5,6-Diamino-pyrimidine-4-thiol-
52
53. III-Antitumor antibiotics (CCNS) :
1-Dactinomycin
is isolated from soil bacteria of the genus Streptomyces.
It was the first antibiotic shown to have anti-cancer activity and used in
treatment of a variety of cancers.
It inhibits transcription by binding to DNA at the transcription initiation
complex and preventing elongation by RNA polymerase.
As it can bind DNA duplexes, it can also interfere with DNA replication
2-Doxorubicin (adriamycin)
Mechanism of action
its antitumor effect is related to its inhibition of topoisomerase II enzyme
(responsipole for DNA repair).
53
54. Uses
Multiple cancers including breast, bone, ovarian & leukemia.
Acute lymphocytic leukemia (ALL).
Non−Hodgkin's lymphoma
Side effects
A major problem with the use of doxorubicin is that it cause irreversible
heart problems specially heart failure
Hypersensitivity, myelosuppression
Nausea, vomiting & diarrhea
Urine and tears may take on a red color.
3-Mitomycin−C
Mitomycin−C is an antitumor antibiotic. Mechanistically however, it
belongs to DNA alkylating agents.
Upon bioactivation inside the cell ,it preferentially alkylates O6 of
guanine base in DNA leading to cross linking of DNA.
It also degrade DNA through formation of free radicals.
Side effects
-mitomycin−C may cause bone marrow suppression. 54
55. 4-Bleomycin
It is cytotoxic in any phase of the cycle even on G0 phase
Bleomycin degrade performed DNA causing chain fragmentation and
release of free bases through the formation of free radicals (superoxide
and hydroxyl radicals).
Uses
-Bleomycin is used in the treatment of a number of different cancers,
including cancer of the head and neck, skin, esophagus, lung, testis, and
genitourinary tract.
-In addition, it is used in the treatment of Hodgkin's disease and
non−Hodgkin's lymphomas.
Side effects
Pulmonary fibrosis
Raynaud's phenomenon (which affects the fingers and toes, may involve
pain, pale color, and abnormal sensation as burning)
In addition, headache, and nausea and vomiting may occur.
55
56. IV-Plant alkaloids (Phase specific)
1-The vinca alkaloids
Vincristine & vinblastine (M-phase)
Mechanism of action
Tubulin is a structural protein which polymerises to form microtubules. The cell
cytoskeleton and mitotic spindle, amongst other things, are made of microtubules.
Vincristine binds to tubulin inhibiting polymerization of microtubule structures.
Disruption of the microtubules arrests mitosis in metaphase. The vinca alkaloids
therefore affect all rapidly dividing cell types including cancer cells, but also
intestinal epithelium and bone marrow.
Side effects
peripheral neuropathy.
Accidental injection of vinca alkaloids into the spinal canal (intrathecal
administration) is highly dangerous, with a mortality rate approaching 100%.
(vinblastin is less neurotoxic)
Uses
Non Hodgkin's& Hodgkin's disease, malignant lymphomas and leukemia.
56
57. 2-Taxanes
Paclitaxel & docetaxel
it is used for treatment of lung, ovarian and breast cancer.
Mechanism of action
paclitaxel hyper-stabilizes microtubule structure (freez them). Paclitaxel
binds to the β subunit of tubulin ,the resulting microtubule/paclitaxel
complex does not have the ability to disassemble. This adversely affects
cell function because the shortening and lengthening of microtubules is
necessary for their function.
Side effects
Bone marrow suppression and neurotoxicity
57
58. References:
. William’s DA, Lemke TL. Foye’s principle’s of Medicinal
chemistry; 15 th ed: 924-49.
John HB, John MB. Wilson and Gisvold’s textbook of Organic,
Medicinal and Pharmaceutical Chemistry; 11th ed: 403-14.
Pandeya SN. A Text Book Of Medicinal chemistry. Vol -2, 3rd ed:
668-686.
Abraham DJ. Burger’s Medicinal Chemistry and Drug Discovery;
Vol-5: 075-95.
Joel GH, Lee EL. Goodman & Gilman’s The Pharmacological basis
of therapeutics; 10th ed. 1404-17.
Rang and Dale’s Pharmacology; 6th ed .718-729
58
Editor's Notes
In next slides we are going to look at mechanism of action of alkylating agents.
Methotrexate (MTX) is a folic acid analog that binds with active site of DHFR, interfering with synthesis of tetrahydrofolate (THF), which serves as the key one-carbon carrier for enzymatic processes for involved in de novo synthesis of thymidylate, purine nucleotides, and amino acid serine and methionine.
