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Part 3 – PM3A > (PM3A) Chemistry of Immunosuppressants > Flashcards

(PM3A) Chemistry of Immunosuppressants Flashcards

1
Q

What are immunosuppressant drugs?

A

Class of drugs

Suppress/ reduce

Strength of body’s immune system

‘Anti-rejection’ drugs if used after a transplant

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2
Q

Name some autoimmune diseases.

A

(1) Systemic lupus erythematosus (SLE)
(2) Rheumatoid arthritis
(3) Crohn’s disease
(4) Multiple sclerosis
(5) Psoriasis
(6) Alopecia areata

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3
Q

What is FK506?

A

Tacrolimus

Immunosuppressant

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4
Q

What is azathioprine?

A

Purine analogue

Imidazolyl prodrug of mercaptopurine

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

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5
Q

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

A

6-mercaptopurine

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6
Q

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

A

Affects proliferation of all rapidly dividing cells

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7
Q

What is mycophenolate mofetil?

A

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

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8
Q

What is ciclosporin A?

A

First discovered natural immunosuppressant
– from a Norwegian soil fungus

Cyclic peptide

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9
Q

What is the mechanism of action of ciclosporin A?

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

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10
Q

In which treatment is ciclosporin A widely used?

A

(1) Organ and tissue transplant surgery
–Rejection prevention

(2) Severe resistant psoriasis
(3) Severe eczema

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11
Q

What is voclosporin?

A

Semi-synthetic derivative of ciclosporin A (CsA)

More potent + less toxic

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12
Q

For which clinical use has voclosporin been used?

A

Treatment of uveitis

An inflammatory disease of the iris + focusing muscle

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13
Q

What is rapamycin?

A

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

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14
Q

How can natural products be diversified into therapeutic medicines?

A

(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

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15
Q

What is everolimus?

A

Semi-synthetic derivative of rapamycin

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16
Q

What is SAR?

A

Structure-activity relationships

17
Q

What is semi-synthesis?

A

– Application of synthetic chemistry
– To modify compounds which are extracted from natural sources
– To improve pharmacological properties/ improve supply issues

18
Q

What is total chemical synthesis?

A

– Can be used to synthesise a wide range of analogues
– Can advance understanding of structure-activity relationships
– Built from simple chemical compounds

19
Q

What are combinatorial biosynthesis technologies?

A

Normal starting materials to assemble natural product are given to organism

20
Q

What is mutasynthesis?

A

– utilises mutant microorganisms

– can lead to new derivatives of the natural product

21
Q

What is FK506 (tacrolimus)?

A

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

22
Q

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

A

(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

23
Q

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

A

About 100 times more potent

24
Q

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

A

Topical treatment of moderate-severe atopic eczema

25
Q

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

A

> 61 steps

26
Q

What are corticosteroids primarily used for?

A

(1) Anti-rheumatic and anti-inflammatory conditions

(2) Hayfever/ asthma

27
Q

What is the mechanism of action of corticosteroids?

A

(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

28
Q

What are some long-term side effects of corticosteroids?

A

(1) Adrenal suppression
(2) Osteoporosis
(3) Ulcers
(4) Fluid retention
(5) Increased susceptibility to infections

29
Q

How are corticosteroids synthesised?

A

Majority via total chemical synthesis

Can also be made via biosynthesis/ fermentation

30
Q

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

A

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

31
Q

(1) How are prednisone and prednisolone made from cortisone and hydrocortisone respectively?
(2) What microbe catalyses this?

A

(1) Microbial introduction of 1,2 double bond

(2) Arthrobacter simplex

32
Q

Why is there urgent need for development of new immunosuppressants?

A

Current immunosuppressants are effective

BUT

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

Part 3 – PM3A (28 decks)

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