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Pharm Decks > Lecture 9 - Antimetabolites > Flashcards

Lecture 9 - Antimetabolites Flashcards

1
Q

What hallmark of cancer do antimetabolites target?

A

Limitless replicative potential

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2
Q

How do antimetabolites work as anticancer agents?

A
  • usually via enzyme inhibition of enzymes involved in DNA biosynthesis
  • inhibiting cellular processes
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3
Q

What are the 4 groups of antimetabolite drugs?

A
  1. Folate antagonists
  2. Pyrimidine antagonists
  3. Purine antagonists
  4. Sugar-modified nucleosides
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4
Q

What was Dr Sidney Farbers thinking process behind folates?

A
  • Realised rapidly dividing cells needed folate, so treated them with a folate antagonist
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5
Q

What is the differences between folic acid, dihydrofolate and tetrahydrofolate?

A
  • Folic acid –> reduced to dihydrofolate by addition of an H atom
  • Tetrahydrofolate –> doubly reduced and contains two H’s
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6
Q

What is folic acid converted to in the body?

A

Folate
- which is vitamin B9, required for DNA synthesis

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7
Q

What are the 3 important enzymes in the folate cycle?

A
  • Dihydrofolate reductase (DHFR)
  • Serine hydroxymethyltransferase (SHMT)
  • Thymidylate synthetase (TS)
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8
Q

Of the 3 enzymes of the folate cycle, which are rate limiting and which is not?

A

Rate limiting -
TS and DHFR

Not -
SHMT

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9
Q

3 examples of folate antagonists

A
  • Analogues of Folate
  • Lipophilic antifolates
  • Inhibitors of thymidylate synthetase
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10
Q

Example of an analogues of folate

A

Methotrexate

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11
Q

Example of lipophilic antifolates

A
  • Pyrimethamine
  • Nolatrexed
  • Piritrexim
  • Methylbenzoprim
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12
Q

Inhibitors of thymidylate synthetases examples

A
  • Pemetrexed
  • Raltitrexed
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13
Q

What is the mode of action of methotrexate?

A
  • Binds to DHFR at folate binding site
  • Potent competitive inhibitor of DHFR
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14
Q

What are some of the issues with methotrexate?

A
  • Too polar for passive diffusion into cell, taken up through reduced folate carrier
  • Must be polyglutamylated to be retained in cells
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15
Q

What are the structure features of Methrotrexate?

A
  • Analogue of Dihydrofolate
  • Methyl and NH2 instead of carbonyl in dihydrofolate
  • Polar
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16
Q

What are the mechanisms of resistance to methotrexate?

A
  • Mutations to DHFR enzyme
  • Mutations to RFC, reducing the uptake
  • Active efflux of the drug
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17
Q

Difference between lipophilic antifolates and methotrexate

A

Lipophilic can enter cells by passive diffusion – don’t need RFC

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18
Q

What are inhibitors of thymidylate synthetase analogues of?

A

5,10-CH2-tetrahydrofolate

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19
Q

What are lipophilic antifolates analogues of?

A

Dihydrofolate

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20
Q

Example of pyrimidine antagonists

A

5FU - Mechanism based inhibitor of Thymidylate synthetase
FdURD
Azacytidine - Competitive binding inhibitor of TS

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21
Q

What is important to remember about Mechansism of Thymidylate synthetase?

A
  • Ternary complex breaking apart is triggered by the loss of a proton
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22
Q

Overview of the Thymidylate Synthase reaction

A
  • dUMP –> dTMP
  1. TS sulphur attacks dUMP in a 1,4 fashion
  2. forming dUMP-TS intermediate
  3. At same time 5,10-CH2-THF exists in an equilibrium
  4. Intermediate unwinds and attacks carbon of 5,10-CH2-THF forming ternary intermediate molecule
  5. BREAKDOWN of ternary intermediate by loss of proton liberating TS and binary complex
  6. Binary complex breaksdown –> dTMP and DHF
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23
Q

What happens to the TS mechanism with 5-FU and FdURD?

A
  • 5-FU –> FdURD –> FdUMP
  • FdUMP instead of dUMP which goes into TS mechanism
  • In ternary complex there is fluorine instead of proton and TS cannot be eliminated
  • Ternary complex gets stuck and process stops
24
Q

What is the mechanism of action of Azacytidine?

A
  • Gets phosphorylated to form azacytidine triphosphate, then incorporated into RNA
  • causing RNA damage as is unstable
  • inhibits methyltransferases
25
Q

Is Azacytidine weak or strong inhibitor of TS?

A

Weak

26
Q

Examples of purine antagonists

A
  • 6-Mercaptopurine
  • 6-thioguanine
  • tiazofurin
27
Q

Mechanism of action of tiazofuran

A
  • Mimics NAD+ as it is converted to tiazofurin adenosine disphosphate (TAD)
  • mimics with an azofurin ring
  • TAD can inhibit IMP dehydrogenase in the NAD+ binding site –> no IMP –> no purines
28
Q

How does TAD inhibit as a purine antagonist

A

TAD (from tiazofurin) inhibits the NAD+ binding site blocking IMP dehydrogenase

29
Q

Examples of sugar-modified nucleosides

A
  • Ara-C
  • fludarabine
  • gemcitabine
30
Q

As a general, how do sugar-modified nucleosides work?

A
  • They are converted to triphosphates and inhibit DNA polymerases making DNA non functional
31
Q

Which is the most effective sugar modified nuceloside?

A

Gemcitabine

32
Q

Overview of Gemcitabine mode of action

A

Gemcitabine (F2dc) to F2dCMP is rate limiting step –

Drug taken into cells by same molecular transporters as nucleosides

CTP synthase converts UTP to CTP

F2dCDP inhibits CTP synthase and ribonucleotide reductase = therefore less dCTP is produced.

Depletion of dCTP activates cCK, and thus MORE F2dCTP is made – FEEDBACK!!!!
SELF POTENTIATION

33
Q

Applications of methotrexate in the clinic

A
  • Widely used against many cancers
  • Used in high dose regimen with leucovorin
34
Q

What is the mode of action of Pyrimethamine?

A
  • Inhibits DHFR as an analogue of dihydrofolate
35
Q

What is the mode of action of Nolatrexed?

A

Inhibits DHFR and TS

36
Q

What is the mode of action of Piritrexim?

A

Lipophilic inhibitor of DHFR

37
Q

What is the mode of action of Methylbenzoprim?

A

Lipophilic inhibitor of DHFR

38
Q

Example of cancer Nolatrexed used for

A

Liver carcinoma

39
Q

What is the structure of Inhibitors of Thymidine Synthetase, drugs Pemetrexed and Raltitrexed?

A
  • Analogues/similar to 5-10-Ch2-tetrahydrofolate
40
Q

What is the mode of action of Inhibitors of Thymidine Synthetase, drugs Pemetrexed and Raltitrexed?

A
  • Competitive inhibitors of TS
  • Binding in the 5, 10-Ch2-tetrahydrofolate binding site
41
Q

What are the structural features of 5-FU?

A
  • Analogue of uracil
  • Fluorine atom at the C-5 position in place of hydrogen
42
Q

Resistance mechanisms against 5-FU

A
  • DPD overexpression –> DPD mediated degradation of 5-FU
  • Increased levels of TS
  • LOF of p53 –> reduced sensitivity
43
Q

What markers can indicate response to 5-FU?

A
  • DPD and TS levels can indicate response to 5-FU
44
Q

Structural features of Azacytidine

A
  • Mimics C in RNA
  • however it is unstable and causes RNA damage
45
Q

Structural features of 6-mercaptopurine

A
  • Hypoxanthine analogue
  • competes with Hypoxanthine for HPRT
46
Q

What is HPRT?

A
  • Hypoxanthine phosphoribosyl transferase
  • catalyses guanine –> guanosine monophosphate which is used as a nucleotide for DNA or RNA equivalent
47
Q

Mechanism of action of 6-mecaptopurine

A
  • 6-MP via HPRT –> Thio-IMP
    -Thio-IMP –> thio-GMP (sometimes 6-MP end up as nucleotide derivatives of 6-TP)
  • Thio-GMP –> thio-GTP or thio-dGTP
  • inhibits de novo purine synthesis
  • Incorporated into RNA or DNA (respectively) mimic guanine
  • Act as poisions for RNA and DNA via incorporation and inhibit GTP-binding protein
48
Q

Mechanism of action of 6-thioguanine

A
  • 6-TG via HPRT to Thio-GMP
  • Thio-GMP –> Thio-GTP or ThiodGTP
  • Incorporated into RNA or DNA (respectively) to mimic G
  • Act as poisions for RNA and DNA via incorporation and inhibit GTP-binding protein
49
Q

Structural features of 6-thioguanine

A
  • Guanine analogue
50
Q

Structure of Cytarabine (Ara-C)

A
  • analogue of dCTP
  • OH groups on carbon
51
Q

Structure of Fludarabine

A
  • Analogue of dATP
  • OH group on carbon
52
Q

What structural feature about gemcitabine makes it most efficient?

A
  • fluorine’s on carbon
53
Q

What does Gemcitabine need which the other two sugar-modified nucleosides don’t need

A
  • Transporters to get into the cell
54
Q

What ways can a cell become resistant to gemcitabine?

A
  • Downregulation of rate limiting enzyme dCk
55
Q

Clinical application of gemcitabine

A
  • first line treatment for pancreatic cancer
  • as a combo or monotherapy
  • better to treat PDAC than 5-FU –> better overall survival
56
Q

What is the importance of the products of gemcitabine in the mode of action of Gemcitabine?

A
  • F2dCTP competes with dCTP as an inhibitor of DNA polymerase
  • DNA polymerase usually uses energy from hydrolysis of dCTP for DNA synthesis
  • F2dCDP is a potent inhibitor of ribonucleoside reductase, resulting in depletion of dCTP which inhibits dCK and is necessary for DNA synthesis
  • SELF POTENTITATION
57
Q

What do the purine antagonists 6-MP and 6-TG inhibit?

A

formation of AMP and GMP
- either encorpoorated into DNA or blocking synthesis of GMP and AMP

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