SAR and Mechanism of Action of 6-MERCAPTOPURINE –


SAR of 6-Mercaptopurine

• 6-Mercaptopurine is a Purine Analogue with a Sulphur atom
substituted at the 6th position of the purine nucleus.

• Structure of the basic purine nucleus with numbering:

• 6-Mercaptopurine falls under the anti-metabolite class of
cytotoxic anti-cancer drugs.

• Apart from being an anti-cancer drug, it is also used for
the treatment of autoimmune diseases.

• It is used in the treatment of –

      1. Acute
lymphocytic leukemia

      2. Chronic
myeloid leukemia

      3. Crohn’s

      4. Ulcerative

Mechanism of Action of 6-Mercaptopurine

Salvage Pathway
for the synthesis of Purine nucleotides

De Novo synthesis
of Purine Nucleotides

Conversion of IMP
to AMP and GMP

• 6-Mercaptopurine acts by competing with purine derivatives
Hypoxanthine and Guanine in order to bind to the enzyme Hypoxanthine-Guanine
Phosphoribosyl Transferase (HGPRT) (involved in the Salvage Pathway).

• It itself gets converted to Thio inosine monophosphate

• TIMP inhibits several reactions involving Inosine
Monophosphate (IMP), including the conversion of IMP to AMP and XMP.

• TIMP can further get converted to Thioguanosine
Monophosphate (TGMP).

• On incorporation of TGMP, a faulty nucleotide into DNA,
the cell cycle gets arrested and apoptosis takes place.

• Further methylation of TIMP produces methyl thio inosine
monophosphate (MTIMP).

• TIMP and MTIMP inhibit the enzyme
Phosphoribosylpyrophosphate Amidotransferase (PRPPAT), which is the first
enzyme involved in the de-novo synthesis of purine nucleotides.

• Since this enzyme is the rate-limiting factor for purine
synthesis, inhibition of the enzyme alters the synthesis and function of DNA
and RNA, eventually inhibiting the cell from undergoing division and promoting
cell death.

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