IMMUNOSUPPRESANT

AGENTS
MEDICINAL CHEMISTRY
IMMUNOSUPPRESANTS
• Immunosuppression involves an act that reduces the activation or efficacy of the
immune system.
• Some portions of the immune system itself have immunosuppressive effects on other
parts of the immune system, and immunosuppression may occur as an adverse
reaction to treatment of other conditions.
• Immunosuppressants are used to control severe manifestations of allergic, autoimmune
and transplant-related diseases.
IMMUNOSUPPRESANTS
SELECTIVE INHIBITORS
OF CYTOKINE
PRODUCTION
MEDICINAL CHEMISTRY
SEELECTIVE INHIBITOR OF CYTOKINE
PRODUCTION:
•CYCLOSPORIN: is an immunosuppressant medication and
natural product. It was isolated in1971 from the fungus and came
into medical use in 1983. It was first immunosuppressant that
acted selectivity to supress T- cell immunity.
• Cyclosporin is a calcineurin inhibitor. Calcineurin is an enzyme
that activates T-cells of the immune system. T-cells (also called T-
lymphocytes) are a type of white blood cell that play a key role
in cell-mediated immunity. Because calcineurin inhibitors
suppress the immune system they are known as
immunosuppressants.
Structural characteristics of cyclosporine A. Cyclosporin A is an 11 amino-acid residue
and macrocyclic peptide. Seven peptide bonds are N- methylated (highlighted in
blue). Two residues possess non-proteinogenic sidechains (highlighted in pink) and a
single D -alanine
MECHANISM OF ACTION:
• Cyclosporin is thought to bind to the cytosolic protein cyclophilin
(an immunophilin) of immunocompetent lymphocytes, especially
T-lymphocytes. This complex of cyclosporin and cyclophilin
inhibits calcineurin, which under normal circumstances induces
the transcription of interleukin-2. The drug also inhibits lymphokine
production and interleukin release, leading to a reduced
function of effector T-cells.
• Cyclosporin is believed to work by decreasing the function of
lymphocytes. It does this by forming complex which leads to
blockade of phosphatase activity in turn decreases the
production of inflammatory cytokines by T-lymphocytes.
THERAPEUTIC APPLICATIONS:
• It is used in Rheumatoid Arthritis
• In rheumatoid arthritis, cyclosporine is used in cases of severe
disease that have not responded to methotrexate
• Soriasis, Crohn’s disease, nephrotic syndrome, organ transplants
and prevent rejections.
• It is used in eye drops for keratoconjunctivitis sicca (dry eyes).
ADVERSE DRUG REACTIONS:
• Hypertension
• Headache
• Kidney problems
• Vomiting
• Increase risk of infection
• Liver problems
• Increase risk of Lymphoma
IMMUNOSUPPRESSIVE
ANTIMETABOLITES
MEDICINAL CHEMISTRY
IMMUNOSUPPRESIVE
ANTIMETABOLITES:
• Antimetabolites interfere with the synthesis of nucleic acids. These
include:
• folic acid analogues, such as methotrexate;
• purine analogues such as azathioprine and mercaptopurine
• pyrimidine analogues; protein synthesis inhibitors.
PURINE ANALOUGES:
•AZATHIOPRINE: (6-MERCAPTOPURINE)
• It is a purine analogue and is a synthetic derivative of 6-
mercaptopurine. It was first made in 1957.
• It is a prodrug of mercaptopurine that is used as an
immunosuppressive agent in organ transplantation to prevent
rejection and in autoimmune diseases as a corticosteroid sparing
agent
STRUCTURE:
IMIDAZOLE RING

1
1
1
1
PURINE RING
1
1

6-(1-methyl-4-nitroimidazole-5yl)sulfanyl-7-H-purine
Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine
in dimethyl sulfoxide (DMSO). The synthesis of the former starts with an amide from methylamine and
diethyl oxalate, which is then cyclizised and chlorinated with phosphorus pentachloride; the nitro
group is introduced with nitric and sulfuric acid.
MECHANISM OF ACTION:
• Azathioprine is a prodrug that is converted by hepatic xanthine oxidase to its active
metabolite 6-mercaptopurine (6-MP). 6-MP is further metabolized by hypoxanthine-
guanine phosphoribosyltransferase (HGPRT) into 6-thioguanosine-5'-phosphate (6-thio-
GMP) and 6-thioinosine monophosphate (6-thio-IMP), both inhibit nucleotide
conversions and de novo purine synthesis. This leads to inhibition of DNA, RNA, and
protein synthesis. As a result, cell proliferation may be inhibited, particularly in
lymphocytes and leukocytes.
THERAPEUTIC APPLICATIONS:
• It is used to treat autoimmune diseases.
• It is used in rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease,
• Ulcerative colitis, and for multiple sclerosis.
• Kidney transplant to prevent rejections
CLASS ACTIVITY:
•HOW AZATHIOPRINE IS CONVERTED TO 6-
MERCAPTOPURINE ?