immunosuppressants medicinal chemistry

Question 1

define anti-metabolites

Answer 1

• Molecules that disrupt metabolic functions within the body - Affect biochemical synthesis of functional molecules and metabolism and recycling

Question 2

which immunosuppressants alter pyrimidine and purine biosynthesis and metabolism

Answer 2

Methotrexate, azathioprine, allopurinol, leflunomide

Question 3

what role does folic acid play in the body

Answer 3

Involved in de novo synthesis of purines and pyrimidines in DNA/RNA

Question 4

folic acids role in de novo synthesis

Answer 4

1. folic acid + dihydrofolate reductase = dihydrofolate
2. dihydrofolate + dihydrofolate reductase = tetrahydrofolate 3.
3. Pyroxidal enzyme uses serine turns it to N5,N10-methylenetetrahydrofolic acid 4. Thiol group attacks double bond on dUMP (alpha beta unsaturated ketone - carbon is electron deficient)
4. Forms a bond between N5, N10 - methylenetetrahydrofolic acid and dUMP6. transfer of CH2 unit to dUMP to give dTMP

Question 5

MOA methotrexate

Answer 5

• Competitive, reversible inhibitor of dihydrofolate reductase - Reduces formation of dihydrofolate and tetrahydrofolate and therefore N5, N10 - methylenetetrahydrofolic acid and purines and pyrimidines - more effect on purine synthesis

Question 6

rescue therapy for methotrexate OD

Answer 6

• Alternative CH2 donor molecule must be provided - leucovorin * Metabolised to N10-formyltetrahydrofolic acid and can be further changed to N5, N10-methylenetetrahydrofolic acid

Question 7

name 3 other dihydrofolate reductase inhibitors

Answer 7

• Trimethoprim: antibacterial - exploits differences between mammalian and bacterial dihydrofolate - Co-trimoxazole: Trimethoprim and sulfamethoxazole, Attacks synthesis pathway in two places in bacteria - Synthesis of folic acid, synthesis of di and tetrahydrofolate- Pyrimethamine: Malaria, Exploits differences between active sites of dihydrofolate reductase in mammals and plasmodium

Question 8

azathioprine activation

Answer 8

• Activated by glutathione conjugation to give mercaptopurine - Thiol group attacks double bond on imidazole ring making it electron deficient - Leaving group loss due to aromaticity

Question 9

further metabolism of azathioprine

Answer 9

○ Xanthine oxidase metabolises it to thiouric acid - inactive ○ Thiopurine S-methyl transferase adds a methyl group - inactive methyl mercaptopurine

Question 10

MOA of azathioprine

Answer 10

1. Gains a ribose ring to give thioinosine monophosphate (TIMP)
2. This can be further transformed to the guanine derivative
3. This is further phosphorylated to give a modified guanine DNA building block (tdGTP) - This acts as a substrate for DNA polymerase and becomes incorporated into DNA/RNA

Question 11

other xanthine oxidase inhibitors

Answer 11

febuxostat - 2008, not resembling a purine ○ Binds to channel leading to active site in xanthine oxidase - blocking substrate entry

Question 12

how is leflunomide made active

Answer 12

• Majority of activity comes from the metabolites Z form - Z-teriflunomide

Question 13

MOA of leflunomide

Answer 13

1. ATP is converted to 2 building blocks (carbamyl phosphate and aspartate)
2. Cyclised to Dihydroorate
3. Di hydro orate dehydrogenase converts dihydroorotate to orotate - this requires ubiquitin as a cofactor
4. Orotate will then be converted to OMP 5. OMP is a precursor of UMP and pyrimidines - leflunomide inhibits Dihydroorate dehydrogenase

Question 14

leflunomide SAR

Answer 14

• Cyano group essential
• Limited options to change methyl substituent on alkene - cyclopropyl group also works
• Amide is essential (ester/ketone = loss of activity) (crucial H bond)
• Aromatic group is best
• Substituent needs to be para!
  -lipophilic group