(PM3A) Chemistry of Immunosuppressants

Question 1

What are immunosuppressant drugs?

Answer 1

Class of drugs

Suppress/ reduce

Strength of body’s immune system

‘Anti-rejection’ drugs if used after a transplant

Question 2

Name some autoimmune diseases.

Answer 2

(1) Systemic lupus erythematosus (SLE)

(2) Rheumatoid arthritis

(3) Crohn’s disease

(4) Multiple sclerosis

(5) Psoriasis

(6) Alopecia areata

Question 3

What is FK506?

Answer 3

Tacrolimus

Immunosuppressant

Question 4

What is azathioprine?

Answer 4

Purine analogue

Imidazolyl prodrug of mercaptopurine

Mercaptopurine metabolites are incorporated into the replication of DNA
– Blocks the pathway for purine synthesis

Question 5

If a patient is unable to take azathioprine due to side effects but still requires a purine analogue, what may they take instead?

Answer 5

6-mercaptopurine

Question 6

What feature of azathioprine accounts for the prevalence of its side effects?

Answer 6

Affects proliferation of all rapidly dividing cells

Question 7

What is mycophenolate mofetil?

Answer 7

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

Question 8

What is ciclosporin A?

Answer 8

First discovered natural immunosuppressant
– from a Norwegian soil fungus

Cyclic peptide

Question 9

What is the mechanism of action of ciclosporin A?

Answer 9

(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

Question 10

In which treatment is ciclosporin A widely used?

Answer 10

(1) Organ and tissue transplant surgery
–Rejection prevention

(2) Severe resistant psoriasis

(3) Severe eczema

Question 11

What is voclosporin?

Answer 11

Semi-synthetic derivative of ciclosporin A (CsA)

More potent + less toxic

Question 12

For which clinical use has voclosporin been used?

Answer 12

Treatment of uveitis

An inflammatory disease of the iris + focusing muscle

Question 13

What is rapamycin?

Answer 13

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

Question 14

How can natural products be diversified into therapeutic medicines?

Answer 14

(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

Question 15

What is FK506 (tacrolimus)?

Answer 15

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

Question 16

What is the mechanism of action of FK506 (tacrolimus)?

Answer 16

(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

Question 17

How does the potency of FK506 (tacrolimus) compare to that of ciclosporin A?

Answer 17

About 100 times more potent

Question 18

What is a less common therapeutic implementation of FK506 (tacrolimus)?

Answer 18

Topical treatment of moderate-severe atopic eczema

Question 19

How many synthetic steps does it take to produce FK506 (tacrolimus) by total chemical synthesis?

Answer 19

> 61 steps

Question 20

What are corticosteroids primarily used for?

Answer 20

(1) Anti-rheumatic and anti-inflammatory conditions

(2) Hayfever/ asthma

Question 21

What is the mechanism of action of corticosteroids?

Answer 21

(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

Question 22

What are some long-term side effects of corticosteroids?

Answer 22

(1) Adrenal suppression

(2) Osteoporosis

(3) Ulcers

(4) Fluid retention

(5) Increased susceptibility to infections

Question 23

How are corticosteroids synthesised?

Answer 23

Majority via total chemical synthesis

Can also be made via biosynthesis/ fermentation

Question 24

When is biosynthesis of corticosteroids used ahead of total chemical synthesis?

Answer 24

To achieve transformations which are more difficult to achieve in the laboratory

Question 25

(1) How are prednisone and prednisolone made from cortisone and hydrocortisone respectively?

(2) What microbe catalyses this?

Answer 25

(1) Microbial introduction of 1,2 double bond

(2) Arthrobacter simplex

Question 26

Why is there urgent need for development of new immunosuppressants?

Answer 26

Current immunosuppressants are effective

BUT

Possess serious side effects, e.g.
– nephrotoxicity
– neurotoxicity
– risk of infection
– risk of cancer
–risk of hypertension