Med Chem of Antimetabolites (Dr. Parang)

what class stops the production of the pyrimidine based nucleotides, primarily deoxythmidine monophohspate (dTMP)

pyrimidine antagonists

what class inhibits the synthesis of thee purine based nucleotides adenosine monophosphate (AMP) and guanosine monophosphate (GMP)

purine antagonists

what are the 4 classes of antimetabolites

pyrimidine antagonists

purine antagonists

folate antagonists

DNA chain elongation inhibitors

• stops the de novo synthesis

• rate limiting enzymes of nucleotides

• arrest chain elongation by promoting the incorporation of false nucleotides

MOA of what

pyrimidines antagonists

• anticancer antimetabolites exploit the need for dividing cells to have a constant supply of deoxynucleic acid required for DNA

• deoxythymidine monophosphate (dTMP) is required for DNA synthesis, from deoxyuridine monophosphate (dUTP)

pyrimidine antagonists (5-FU)

dTMP is produced via what of deoxyuridine monophosphate (dUMP)

C5-methylation

the rate limiting enzyme of the dTMP synthetic pathway is the what

thymidylate synthse

all dTMP synthesis inhibitors will inhibit what either directly or indirectly, and this will result in thymineless death

inhibit thymidylate synthase

to bind to the thymidylate synthase, this fluorinated pyrimidine prodrug must be converted to its deoxyribonucleotide form

this deoxyribonucleotide prodrug is biogoverted via 2-deoxyuridine kinase mediated phosphorylation to the same active 5-fluoro dUMP structure generated in the multistep biotransformation

5-Fluorouracil

a carbamylated analog of cytidine, the drug is actually is another 5-fu dUMP prodrug

capecitabine

thymidine phosphorylase enzyme involved in this biotransformation, is much more active in tumors than in normal tissues is what

tumor selectivity (capecitabine)

lower incidence of side effects compared to fluorouracil therapy

capecitabine

Which antimetabolite inhibits the synthesis of thymidine and purine nucleotides, leading to DNA synthesis inhibition?

Methotrexate

5-Fluorouracil

Cytarabine

Gemcitabine

5-Fu

antimetabolites interfere with the availability of normal purine or pyramidine nucleotide precursor (t/f)

true

what are the drugs for antifolates

methotrexate

pralatrexate

pemetrexed

raltitrexed

levels of active drug in the tumor can be up to 3.5 fold higher than in surrounding tissues

capecitabine

5-FU _______________________. (Select all that apply)

• after conversion to 5-FdUMP can irreversibly bind to and inhibit thymidylate synthetase

• is a prodrug.

• its metabolites can be incorporated into DNA.

• its metabolites can be incorporated into RNA.

• is an alkylating agent.

• after conversion to 5-FdUMP can irreversibly bind to and inhibit thymidylate synthetase

• is a prodrug.

• its metabolites can be incorporated into DNA.

• its metabolites can be incorporated into RNA.

e mechanism of action of -----------------------is the inhibition of thymidylate synthase enzyme.

Methotrexate

5-Fluorouracil

Gemcitabine

6-Thioguanine

5-Fluorouracil

3 targets of antimetabolites

• SHMT

• TS

• DHFR

the direct inhibiton of DHFR causes cellular levels of 7,8 DHF to build up is what drug

methotrexate

what generates the folate cofactors needed by DHFR to ensure the continued synthesis of pyrimidine and purine nucleotides in healthy cells is what drug

leucovorin

folinic acid is what drug

• cytoprotectant

• if severe methotrexate toxicity

leucovorin

what is given as prophylaxis after high dose methotrexate therapy

leucovorin

which one is required for the conversion of dUMP to dTMP?

CYP450

5,10-Methylenetetrahydrofolate

Protein kinase

Hypoxanthine guanine phosphoribosyl transferase (HGPRT)

5,10-Methylenetetrahydrofolate

what are the drugs for purine antagonists: inhibitors of AMP and GMP

(meracaptopurine) 6-MP

(thioguanine) 6-TG

what inhibits AMP and GMP biosynthesis

mercaptopurine

what inhibits GMP biosynthesis

Thioguanine

----------------- is an antimetabolite that inhibits DNA synthesis by mimicking the structure of folic acid.

Methotrexate

5-Fluorouracil

Gemcitabine

Cytrabine

Methotrexate

what inhibits the de novo biosynthesis of purine nucleotides, AMP and GMP

purine anatagonists

rate limited enzyme in the synthesis of these purine nucleotides is what

amidophosphoribosyl transferase

since the rate limiting transferase enzyme works on a phosphorylated ribose substrate , no enzyme in the sequence will function without its presence (t/f)

true

prodrugs must be converted to ribonucleotides by what in 6-MP & 6-TG

HGPRT

what are the drugs for DNA polymerase and chain elongation inhibitors

• cytarabine

• gemcitabine

• fludarabine

• cladribine

• clofarabine

Leucovorin ------------.

is used in rescue therapy to prevent toxicity from high-dose methotrexate.

inhibits DNA synthesis by limiting the DeNovo synthesis of thymidine

inhibits dihydrofolate reductase.

A

example of an antifolate is -----------.

Pralatrexate

Fludarabine

5-Fluorouracil

6-Mercaptopurine

pralatrexate

Leucovorin is commonly used in combination with which antimetabolite?

Cytarabine

5-Fluorouracil

Methotrexate

6-Mercaptopurine

Methotrexate

five halogenated or ribose modified DNA nucleosides analogs are marketed for treatment of hematologic cancers and solid tumors is what class

DNA polymerase and chain elongation inhibitors

all nucleotides must be converted to triphosphate nucleotides before tactivity is what class

DNA polymerase and chain elongation inhibitors

what are the drugs for cytidine based anticancer agents undergo initial phosphorylation by deoxycytidine kinase to monophosphate

cytarabine & gemcitabine

gemcitabine has longer half life of 19 hours (t/f)

true

which two drugs are nanoliposome

cytarabine & daunorubicin

what are the 3 halogenated adenosine based nucleosides undergo conversion to active triphosphate nucleotides after active transport into tumor cells

fludarabine, cladribine, clofarabine

arabinoside, marketed as monophosphate nucleotide to enhance water solubility for IV administration

fludarabine

Which of the following is a pyrimidine DNA chain terminator?

Methotrexate

Doxorubicin

Fluorouracil

Cytarabine

None of the above

Cytarabine

Which one of these compounds undergoes initial phosphorylation by a kinase to the monophosphate?

Gemcitabine

Carboplatin

Methotrexate

Dacarbazine

Gemcitabine

ALSO CYTARABINE

topoisomerase ll activity is what drug

daunorubicin

treatment of high risk acute myeloid leukemia

vyxeos (cytarabine & daunorubicin)