(PM3A) Chemistry of Immunosuppressants Flashcards
What are immunosuppressant drugs?
Class of drugs
Suppress/ reduce
Strength of body’s immune system
‘Anti-rejection’ drugs if used after a transplant
Name some autoimmune diseases.
(1) Systemic lupus erythematosus (SLE)
(2) Rheumatoid arthritis
(3) Crohn’s disease
(4) Multiple sclerosis
(5) Psoriasis
(6) Alopecia areata
What is FK506?
Tacrolimus
Immunosuppressant
What is azathioprine?
Purine analogue
Imidazolyl prodrug of mercaptopurine
Mercaptopurine metabolites are incorporated into the replication of DNA
– Blocks the pathway for purine synthesis
If a patient is unable to take azathioprine due to side effects but still requires a purine analogue, what may they take instead?
6-mercaptopurine
What feature of azathioprine accounts for the prevalence of its side effects?
Affects proliferation of all rapidly dividing cells
What is mycophenolate mofetil?
CellCept
Semi-synthetic derivative of mycophenolic acid
Inhibits B + T lymphocyte action
Inhibits inosine monophosphate dehydrogenase
– Which is essential for catalyses purine synthesis in lymphocytes
– Has a more specific effect in lymphocytes than other cell types
What is ciclosporin A?
First discovered natural immunosuppressant
– from a Norwegian soil fungus
Cyclic peptide
What is the mechanism of action of ciclosporin A?
(1) Binds to cyclophilin to form a complex
(2) Complex inhibits calcineurin
– Responsible for desphosphorylation of transcription factor: NFAT
(3) NFAT normally increases activity of genes coding for IL-2
– Which regulates growth of T helper cells
(4) Ciclosporin A (CsA) inhibits formation of T cells
(5) Inhibition of T cells inhibits immune response
In which treatment is ciclosporin A widely used?
(1) Organ and tissue transplant surgery
–Rejection prevention
(2) Severe resistant psoriasis
(3) Severe eczema
What is voclosporin?
Semi-synthetic derivative of ciclosporin A (CsA)
More potent + less toxic
For which clinical use has voclosporin been used?
Treatment of uveitis
An inflammatory disease of the iris + focusing muscle
What is rapamycin?
Isolated from soil samples on Easter island
Originally for prevention of allograft rejection following liver tranplantation
31-membered macrocyclic polyketide
Inhibits activity of mTOR
Has a central role in cell growth and proliferation
How can natural products be diversified into therapeutic medicines?
(1) Semi-synthesis
– Application of synthetic chemistry
– To modify compounds which are extracted from natural sources
– To improve pharmacological properties/ improve supply issues
(2) Total chemical synthesis
– Can be used to synthesise a wide range of analogues
– Can advance understanding of structure-activity relationships
– Built from simple chemical compounds
(3) Combinatorial biosynthesis technologies
– normal starting materials to assemble natural product are given to organism
(4) Mutasynthesis
– utilises mutant microorganisms
– can lead to new derivatives of the natural product
What is everolimus?
Semi-synthetic derivative of rapamycin
What is SAR?
Structure-activity relationships
What is semi-synthesis?
– Application of synthetic chemistry
– To modify compounds which are extracted from natural sources
– To improve pharmacological properties/ improve supply issues
What is total chemical synthesis?
– Can be used to synthesise a wide range of analogues
– Can advance understanding of structure-activity relationships
– Built from simple chemical compounds
What are combinatorial biosynthesis technologies?
Normal starting materials to assemble natural product are given to organism
What is mutasynthesis?
– utilises mutant microorganisms
– can lead to new derivatives of the natural product
What is FK506 (tacrolimus)?
Natural product
Has a common structural unit with rapamycin
Inhibits T cell activation
Achieves T cell activation inhibition by a DIFFERENT mechanism than that of rapamycin
What is the mechanism of action of FK506 (tacrolimus)?
(1) Binds to FKBP-12 (protein) to form a complex with calcium + calmodulin (another cellular protein)
(2) This complex blocks the entry of resting immune cells into the reproductive section of the cell cycle
– G0 to G1
How does the potency of FK506 (tacrolimus) compare to that of ciclosporin A?
About 100 times more potent
What is a less common therapeutic implementation of FK506 (tacrolimus)?
Topical treatment of moderate-severe atopic eczema
How many synthetic steps does it take to produce FK506 (tacrolimus) by total chemical synthesis?
> 61 steps
What are corticosteroids primarily used for?
(1) Anti-rheumatic and anti-inflammatory conditions
(2) Hayfever/ asthma
What is the mechanism of action of corticosteroids?
(1) Interfere with the cell cycle of lymphoid cells
(2) Impairs process of chemotaxis
(3) Toxic to specific subsets of T cells
(4) Decrease the number of circulating lymphocytes
(5) Partially inhibit IL-1, IL-2, and INF-gamma
What are some long-term side effects of corticosteroids?
(1) Adrenal suppression
(2) Osteoporosis
(3) Ulcers
(4) Fluid retention
(5) Increased susceptibility to infections
How are corticosteroids synthesised?
Majority via total chemical synthesis
Can also be made via biosynthesis/ fermentation
When is biosynthesis of corticosteroids used ahead of total chemical synthesis?
To achieve transformations which are more difficult to achieve in the laboratory
(1) How are prednisone and prednisolone made from cortisone and hydrocortisone respectively?
(2) What microbe catalyses this?
(1) Microbial introduction of 1,2 double bond
(2) Arthrobacter simplex
Why is there urgent need for development of new immunosuppressants?
Current immunosuppressants are effective
BUT
Possess serious side effects, e.g. – nephrotoxicity – neurotoxicity – risk of infection – risk of cancer –risk of hypertension
