MedChem of Antimetabolites

How is dTMP produced via?

• C5-methylation of dUMP

What is rate limiting enzyme of dTMP pathway?

• TS

• all dTMP synthesis inhibitors will inhibit TS either directly or indirectly (5-FU) to cause thymine less death

What does 5-FU bind to?

• TS

• It is a prodrug to 5-fluro-dUMP

What is capecitabine?

• Another 5-fluro-dUMP prodrug

• Extensively metabolized to flurouracil then converted to the DUMP

What is known about the selectivity of thymidine phosphorylase enzyme?

• Thymidine phosphorylase enzyme is involved in biotransformation so more active in tumors vs normal cells

Explain SHMT, TS, DHFR?

• SHMT → catalyze reaction of serine with tetrahydrofolate to form glycine and ___

• TS → dUTP to form dTMP

• DHFR → reduction of dihydrofolate to tetrahdyrofoate using NADPH to NADp+

MTX MOA?

• Direct inhibition of DHFR causes inhibition of TS

• Thymineless death

What is Leucovorin rescue therapy?

• Cytoprotectant

• Folinic acid

• It regenerates folate cofactors needed by DHFR in healthy cells

What are the purine antagonists (inhibit AMP and GMP)?

• 6-MP → inhibit AMP and GMP

• 6-TG → inhibit GMP

What is the rate limiting enzyme of the purine antagonists?

• Amidophosphoribosyl transferase

  • This works on a phosphorylated ribose so no enzyme will function without its presence

• Target for both 6-MP and 6-TG

What is known about thiopurine metabolism?

• The 6-MP and 6-TG need to be converted to ribomuceolides by HGPRT before exerting cytotoxic actions

The DNA polymerase inhibitors (Pyrimidine and purine analogs) all need to be what before activity?

• Converted to triphosphate nucleotides

What is Cytarabine and Gemcitabine?

• Cytidine based anticancer agents undergo initial phosphorylation to monophosphate with subsequent phosphorylations

• Gemcitabine longer half life

What is Vexes?

• Nanoliposome of both Cytarabine and Daunorubicin

  • Cytarabine → antimetabolite of pyrimidine

  • Daunorubicin → inhibit topo II

  • Tx of AML

What is Fludarabine, Cladribine, and Clofarabine?

• Adenosine based nucleosides → undergo conversion to active triphosphate nucleotides after active transport to tumor cells

  • Fludarabine → enhance water solubility for IV