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 disease

      4. Ulcerative colitis

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).

• 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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