chemistry dyal singh karnal

1. Dyal Singh College
,Karnal
Topic - Synthesis ,General Mode of action
and medicinal uses of Antineoplastic
Agents -Carmustine , Aminopretin , 6 –
Mercaptopurine
Submitted By-
Garima
MSc chemistry

2. Antineoplastic agents -
• Antineoplastic agents are a group of specialized drugs used
primarily to treat cancer (the term "neoplastic" refers to cancer
cells).
• The first antineoplastic agents, used in the 1940s, were made from
either synthetic chemicals or natural plants. Antineoplastic agents
are classified by origin and by how they work to destroy cancer
cells.
• Antineoplastic agents travel the body and destroy cancer cells. Side
effects are expected to occur when treated with these agents, and
can include nausea, mouth sores, hair loss, and lowering of the
blood counts. Many of the side effects associated with antineoplastic
agents occur because chemotherapy treatment destroys the body's
normal cells in addition to cancerous cells

7. Nitrosaureas
• Alkylating agents
Nitrosoureas: A group of cancer drugs called alkylating agents
because they act by the process of alkylation to inhibit DNA repair.
The nitrosoureas can cross the blood-brain barrier and are used to
treat brain tumors. The nitrosoureas include carmustine (BCNU),
lomustine (CCNU) and semustine.They produce alkylating agents
which then alkylate DNA and prevent their replication .

8. How alkylating agents work ?
• Cell division takes place with the help of
karyokinesis and cytokinesis .
• Karyokinesis is division of nucleus which in turn
is processed by DNA replication (These
alkylating agents stop DNA replication )
• Alkylating agents binds with these nitrogenous
bases ( DNA base pairs ) through covalent
bonding this causing structural changes and
base pair mismatch which stops dna replication
and further cell division.
• Each DNA has 10 base pairs and these
alkylating agents binds at 7th position at
Guanine

9. • Carmustine is an orange-yellow solid medication used mainly for chemotherapy. It is
a nitrogen mustard β-chloro-nitrosourea compound.
Carmustine.
IUPAC name1,3-Bis(2-chloroethyl)-1-

10. Properties
Chemical formula C5H9Cl2N3O2
Molar mass 214.05 g·mol
−1
Appearance Orange crystals
Odor Odourless
Melting point 30 °C (86 °F; 303 K)
log P 1.375
Acidity (pKa) 10.194
Basicity (pKb) 3.803

12. Carmustine can also be synthesized by
taking phosgene and aziridine in dilute HCL .

13. Mode of action -
Mode of action
These drug metabolise first and generate
carbonium ion that can alkylate our DNA
.

14. Mechanism of Action
•Carmustine cross links the DNA strands through alkylation. This
results in the disruption of DNA function and it leads to apoptosis of
cell.
•Along with alkylation, Carmustine also carbomylates the proteins,
which also includes the enzymes like DNA repair enzymes.
•It is highly lipophillic and can cross the blood brain barrier very
easily .
•It is a mustard gas related beta chloro nitroso urea .
Uses-
• It is used treatment of several types of brain cancers , multiple myeloma( cancer of
plasma cells , Hodgkin diseases (cancer of part of immune system )etc .
• It is also used during bone marrow transplantation to reduce WBCs .

15. • Antimetabolites
-
Antimetabolites are compounds which are similar to metabolites
but are not metabolites (have different chemical group , when
Antimetabolites are used dna synthesis is inhibited.
Purine antagonists
Antimetabolites are group of anticancer agentsthat exert their
cytotoxic effects by interfering with the DNA synthesis
These molecules are pyrimidine or purine analogues with altered
chemical groups [20] and induce cell death during the S phase of cell
growth when incorporated into RNA and DNA or inhibit enzymes
needed for nucleic acid production
The inhibition of enzymes involved in DNA synthesis or misincorporation of
antimetabolites in DNA prevents mitosis and induces apoptosis in dividing
cells.
They trick cancer cells into using the drug instead of the molecules
it needs to make the genetic material to replicate, or DNA
Metabolites used for dna
synthesis- purine ,
pyramidine and folic acid .

16. 6 – Mercaptopurine -
Itisapurineanalogueclassofantineoplasticdrugs.Ithasthiolgroupat6thpositionof
purinering.
IUPAC name
•3,7-dihydropurine-6-thione

18. Methods of synthesis -
 From hypoxanthine –mercaptopurine can be prepared by
treating hypoxanthine with phosphorus pentasulphide.

19. • From 4 amino 6 chloro-5 nitro pyramidine-

20. Mechanism of Action -
•Mercaptopurine is an antimetabolite antineoplastic, as such it interferes with
normal metabolic processes within cells, typically by combining with enzymes,
to disrupt DNA and RNA synthesis (cell-cycle S phase-specific) leading to
death of rapidly proliferating cells, especially malignant ones. Specifically,
Mercaptopurine is a purine antimetabolite or purine antagonist as such inhibits
DNA synthesis by inhibiting the production of the purine containing
nucleotides, adenine and guanine thus halting DNA
synthesis.[18]Mercaptopurine also acts as an immunomodulator by inhibiting of
several pathways in nucleic acid biosynthesis preventing proliferation of cells
involved in the determination and amplification of the immune response.[19]
• In body , mercaptopurine is converted into an active form nucleotide 6
thiosin 5 phosphate by enzyme hypoxanthine quinine phosphoribosyl
transferase (HGPRT)
• It inhibits 1st step in synthesis of ionisin 5- phosphate by negative
feedback.
• It will prevent its transformation to adenosine or guanine nucleotides ,
which are necessary for DNA synthesis.
• Thus mercaptopurine inhibits and inter conversion of purine nucleotides
Inosin 5 phosphate

21. • Uses -
Mercaptopurine is used alone or with other chemotherapy drugs to
treat acute lymphocytic leukemia (ALL; also called acute
lymphoblastic leukemia and acute lymphatic leukemia; a type of
cancer that begins in the white blood cells).

22.  Aminopterin -
Aminopterin (or 4-aminopteroic acid), the 4–amino derivative
of folic acid, is an antineoplastic drug
with immunosuppressiveproperties often used in chemotherapy.
Aminopterin is a synthetic derivative of pterin. Aminopterin
works as an enzyme inhibitor by competing for the folate binding
site of the enzyme dihydrofolate reductase. Its binding affinity for
dihydrofolate reductase effectively
blocks tetrahydrofolate synthesis. This results in the depletion
of nucleotide precursors and inhibition of DNA, RNA, and protein
synthesis.
IUPAC nameN-(4-{[(2,4-Diaminopteridin-6-yl)methyl]amino}benzoyl)-L-
glutamic acid

23. Method of synthesis-

24. Mode of action
Most important event which takes
place during cell division is DNA
replication. DNA is made up of
nucleotides-A,G,T,C

25. • THF required , without this pathway will not
proceed further . THF is made from dihydrofolate
with the help of enzyme dihydrofolate reductase . If
synthesis of THF is blocked synthesis of
nucleotides by Denovo pathway will automatically
stops . One such enzyme is aminopterin it
competes for folic binding site of the enzyme
dihydrofolate reductase thus blocks
tetrahydrofolate synthesis.
• Aminopterin blocks the de novo synthesis pathway
of nucleotides synthesis.

26.  Uses -
It is used in treatment of leukaemia, lung cancer and breast
cancer.