INTRODUCTION,MOA,STRUCTIRES,SAR,USES OF ANTINEOPLASTIC AGENTS

1. ANTI NEOPLASTIC
AGENTS
Mrs. Sandhya Sujeetkumar Ahire
Pharmaceutical chemistry
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2. TOPICS TO BE COVERED
 What is antineoplastic agents
 Examples
 Classification
 MOA
 SAR
 Uses
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3. DEFINATION
CANCER:
• Abnormal and uncontrolled division and
growth of cells, which forms tumors and
invades adjacent normal tissues.
• Neoplasm means “relatively autonoumous
growth of tissue”
• The agents which are used in treatments are
known as anti cancer agents.
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6. Antineoplastic agents
• Used in management of maligant
disease
• Also known as cytotoxic agents.
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7. CLASSIFICATON
I. CYTOTOXIC DRUGS (directly act on cells)
a) ALKYLATING AGENTS
i. Nitrogen mustards- mustine
ii. Ethyleneimine - thiopeta
iii. Alkyl sulfonate - buslfan
iv. Nitrosoureas - carmustine
v. Triazine - dacarbazine
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8. b) ANTIMETABOLITES (act on metabolic pathway
involved in DNA synthesis)
i. Folate antagonist - methotrexate
ii. Purine antagonist - 6 mercaptopurine
iii. Pyrimidine antagonist - 5-flurouracil
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9. C) PLANT DERIVATIVE
1. Vinca alkaloids – vinblastin ,vincristin
2. Taxanes – paclitxel
3. Epipodophyllotoxin – etoposide
4. Camptothecin analogue - topotecan
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10. D) ANTIBIOTICS
I. Hormones (mainly steroids which suppress
hormone secretion or antagonize hormone
action)
a) Glucocorticoids
b) Estrogen
c) Progestins
d) Antiandrogens
II. Miscellaneous (include
• Hydroxyurea, Cisplatin, Monoclonal
antibodies and L.Asparginase)
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11. ALKYLATING AGENTS
 Contain chemical groups that can form covalent
bonds with particular nucleophilic substances in
the cell.
 Produce highly reactive carbonium
ion intermediates.
 Forms covalent bond with electron donors like
amine, hydroxyl and sulfhydryl groups.
 Alkylating agents are bifunctional i.e They have
two alkylating groups .
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12.  The nitrogen at position 7 (N7) of guanine, being
strongly nucleophilic, is probably the main
molecular target for alkylation in DNA.
 N1 and N3 of adenine and N3 of cytosine may
also be affected.
 Being bifunctional they can cause intra- or
interchain cross-linking, abnormal base
pairing or chain scission.
 Interferes not only with transcription but also
with replication
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13. • Main impact is seen during replication (S
phase) when some zones of the DNA are
unpaired and more susceptible to
alkylation.
• Results in a block at G2 and
subsequent apoptotic cell death.
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16. Types of Alkylating agents
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CATEGORY DRUGS
Nitrogen mustards Cyclophosphamide,
Meclorethamine,
Chlorambucil
Ethyleneimine Thiotepa
Alkyl sulfonate Busulfan
Nitrosoureas Carmustine, Lomustine
Triazine Dacarbazine
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17. MECHLOETHAMINE
MOA
1. Attachement of alky gr to DNA bases, resulting in
the DNA being fragmented by repair enzymes in
their attempts to replace the alkylated bases,
preventing DNA synthesis and RNA transcription
from the affected DNA OR
2. DNA damage via the formation of cross links
which prevents DNA from being separated for
synthesis or transcription. OR
3. Induction of mispairing of the nucleotides leading
to mutation.
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18. Clinical uses
• Treatment of hodgkin’s disease
• mycosis fungoides and lymphomas
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19. CYCLOPHOSPHAMIDES
MOA
• It prevents cell division by cross linking DNA
strands
Clinical uses
• Multiple myeloma chronic leukaemias,acute
leukaemia of children,hodgkins disease,lung
cancer
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20. MEPHALAN
• It alters the DNA nucleotide guanine through
alkylation,causes linkages between strands of
DNA. This chemical alteration inhibite and
RNA synthesis function necessary for cells to
survive.
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CLINICAL USES
• Multiple myeloma
• Testicular CANCER
• ovarian cancer
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22. BUSULFAN
MOA
• It contain 2 labile methanesulfonate
groups.On hydrolysis the methenesulfonate
gr are released and carbonium ions
produced.
• This carbonium ions alkylate DNA which
results in the interference of DNA replication
and RNA transcription ultimately leading to
the disruption of nucleic acid function.
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23. Clinical uses
• Granulocytic leukaemia
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24. CHLORAMBUCIL
MOA
• induction of mispairing of the nucleoties
leading to mutation.
CLINICAL USES
• chronic lymphocytic
leukaemia,macroglobulinaemia disease.
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25. THIOPETA
MOA
• Alkyl gr of thiopeta is attached to guanine base of DNA
at the number 7 nitogen atom of the imidazole ring.
• They stop tumor growth by crosslinking guanine
nucleobases in DNA double helix strands,directly
attacking DNA.
• This makes the strands unable to uncoil and separate.
• As this is necessary in DNA replication the cells can no
longer divide.
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26. Clinical uses
• Chronic lymphatic leukaemia,
• lymphosarcomatosis,
• carcinoma of breast
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27. ANTIMETABOLITES
 Folate Antagonist: - Methotrexate
 Folates are essential for the synthesis of
purine nucleotides and thymidylate which in
turn are essential for DNA synthesis and cell
division.
 The main action of the folate antagonists is
to interfere with thymidylate synthesis
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28. MERCAPTOPURINE
MOA
Inhibite synthesis and interconversion of purine
nucleotides which leads to a halt in DNA synthesis
in proliferating cells during the cell cycle.
CLINICAL USES:
• Acute monocytic leukaemia
• Lymphobastomas,
• Neuroleukemia
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29. METHOTREXATE
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30. CLINICAL USES:
• Acute lymphoblastic leukaemia
• Acute lymphocytic leukaemia
• Lung cancer
• Neck cancer
• Breast cancer
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31. THIOGUANINE
MOA
Interfere the synthesis of guanine nucleotides in
the presence of enzyme inosine monophosphate
dehydrogenase (IMP DEHYDROGENASE)
Clinical uses
• Acute leukaemia
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32. FLUROURACIL
MOA
Inhibition of the formation of thymidylate from
uracil which leads to the inhibition of DNA and
RNA synthesis and cell death.
CLINICAL USES:
used for the palliation of gastrointestinal
adenocarcinoma metastatic to the liver in patients
who are considerd incurable by surgery
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34. AZATHIOPRINE
MOA
• It interfere nucleic acid synthesis.
CLINICAL USES
• primary drug used for transplants,especially for
kidney transplants
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35. CYTARABINE
MOA
• Inhibits DNA synthesis by blocking DNA
polymerase enzyme
CLINICAL USES
• Acute leukaemia
• Acute lympholytic leukaemia
• Chronic myclocyctic leukaemia
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36. FLOXURIDINE
MOA
• Catabolized to 5 flurouracil which is the active
form of the drug.
• Primary effect is interference with DNA synthesis
CLINICAL USE
Palliation of gastrointestinal adenocarcinoma
metastatic to the liver in patients
Who are considered incurable
By surgery.
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37. ANTIBIOTICS
DACTINOMYCIN
MOA
It forms a complex with DNA due to binding with
guanine cytosin segments and as result DNA
requiring synthesis of RNA is blocked.
CLINICAL USES
• Wilms tumors
• Kaposi
• Edwins sarcomas
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38. DOXORUBICIN
MOA
Inhibite topoisomerase II activity by stabilizing the
DNA –topoisomerase II complex preventing the
DNA double helix from being resealed and therby
stopping the process of replication.
CLINICAL USE
Acute lymphocytic leukaemia, lung cancer, gastric
carcinoma
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39. DAUNORUBICIN
MOA
Binds with DNA and inhibite nucleic acid
synthesis , mitosis and promotes chromosomal
aberration.
CLINICAL USES
Acute myclocytic leukaemia,
ovarian endometrial carcinoma
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40. BLEOMYCIN
MOA
It chelates copper or iron produces superoxide
ions and intercalates between DNA strand causes
chain scission and inhibite repair
CLINICAL USES
• Lymphomas
• Carcinomas
• Sarcomas
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41. PLANT PRODUCTS
ETOPOSIDE
MOA
• It arrest cells in G2 phase and causes DNA breaks by
affecting the DNA topoisomerase –II function and
subsequent resealing of the strant is prevented.
CLINICAL USES
• Treatment of germinogenic tumor ovarian,
stomach, testicular and lung cancer
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42. VINBLASTIN SULPHATE
MOA
• Binds to microtubular protein tubulin, prevents
polymerization and assembly of microtubules and
cause mitotic spindle destruction.
CLINICAL USE
• Lymphoblastic leukaemia,
• neuroblastoma,sarcoma
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43. VINCRISTIN SULPHATE
MOA
• Binds to microtubular protein tubulin, and
prevents polymerization and assembly of
microtubules and causes mitotic spindle
destruction.
CLINICAL USE
• Treatment of acute leukaemia in children
• Neuroblastomas
• Wilm’s tumor and
• Rhabdomyosarcoma
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44. MISCELLANEOUS
CISPLASTIN
MOA
• Prevents cell division by binding to DNA , nuclear
and cytoplasmic proteins causing cross linking
CLINICAL USES
• Highly reactive with carcinomas of the testicles,
ovaries,heat ,neck, lungs
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45. MITOTANE
MOA
It modifies the peripheral metabolism of steroids as
well as directly suppressing the adrenal cortex
CLINICAL USE
Treatment of adrenal cortex carcinoma
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46. QUESTIONED ASK IN EXAMS
 Give bioactivation of any one
alkylating agents
 Give classification of anticancer
drugs.Explain the mechamism of action
of anticancer antibiotics.
 Comment on naturally obtained
anticancer agents.
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47. THANK YOU
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