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Med Chem 3 - Final Exam > Antimetabolites - Purines > Flashcards

Antimetabolites - Purines Flashcards

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1
Q

Which of the following statements is incorrect?

A. THF is required for AMP and GMP biosynthesis
B. Rate limiting step of AMP biosynthesis involves installing amino group from glutamine on a sugar using Mg+2 cofactor
C. Xanthylic acid is the common intermediate for GMP and AMP
D. Both A & C
E. None of the above

A

(C) INOSINIC ACID is the common intermediate for AMP and GMP

*Xanthylic acid is a precursor to only GMP

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2
Q

Which of the following statements is incorrect?

A. In the biosynthesis of AMP and GMP, all substrates are phosphorylated
B. Both mercaptopurine and thioguanine are prodrugs
C. Thiopurine activation involves TPMT installing a pyrophosphorylated ribose on the drug
D. HGPRT requires a free mercapto group to metabolize thiopurine
E. TPMT is polymorphic

A

(C) HGPRT installs the pyrophosphorylated ribose on the drug activating it, NOT TPMT

*TPMT and SAM (cofactor) are involved in further activation and inactivation pathways of thiopurines

D*HGPRT cannot act on a methylated mercapto group. Therefore, after TPMT metabolizes Thiopurine (prodrug) and inactivates it, the inactivated drug with a methylated mercapto group cannot be activated again.

E*10% of caucasians are poor TPMT metabolizers resulting in more active thionucleotide amount per dose

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3
Q

All of the following are required for AMP and GMP biosynthesis, except?

A. Glutamine
B. Amidophosphoribosyl transferase
C. Mg2+
D. THF
E. All of the above are required
A

(E) all of the above are required

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4
Q

Which of the following statements regarding AMP and GMP biosynthesis is incorrect?

A. Guanylic acid and adenylic acid have a common intermediate
B. Conversion of 5-phosphoribosyl pyrophosphate to 5-phosphoribosyl amine is the rate limiting step
C. Methotrexate is an indirect inhibitor of purine biosynthesis
D. All substrates in pathway are phosphorylated
E. Proton extraction by cofactor N10 is a necessary action in biosynthesis of AMP and GMP

A

(E) Proton extraction by cofactor N10 is ONLY REQUIRED in dTMP (pyrimidine) biosynthesis, NOT AMP and GMP biosynthesis

  • A - guanylic acid (GMP) and adenylic acid (AMP)
  • C - Methotrexate is an indirect inhibitor of purine biosynthesis (and pyrimidine!) b/c it inhibits DHFR and depletes THF required in key steps of purine biosynthesis.
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5
Q

What is the common intermediate of GMP and AMP?

A

Inosinic acid

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6
Q

Which of the following statements regarding Thiopurines is incorrect?

A. Mercaptopurine and thioguanine have a double MOA
B. The active thiopurine ribonucleotide can be incorporated into DNA and RNA strands
C. SAM cofactor is a natural methylator
D. Metabolism via TPMT & SAM always results in an inactive metabolite
E. Active S-methythiopurine ribonucleotide metabolite is the main inhibitor of amidophosphoribosyl transferase

A

(D) Active thiopurine ribonucleotide is metabolized by TPMT using SAM as a cofactor. This results in an ACTIVE metabolite S-methythiopurine ribonucleotide. Thiopurine (inactive prodrug) can also be metabolized by TPMT using SAM as a cofactor. This results in an INACTIVE metabolite

  • A - although both thiopurines have their own major active metabolite, they both produce both active metabolites giving (2) MOA each
  • B - Incorporation of thiopurine ribonucleotide into DNA and RNA can result in apoptosis if mutation not repaired
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7
Q

What enzyme installs a pyrophosphorylated ribose on the prodrugs Mercaptopurine and Thioguanine?

A

HGPRT (Hypoxanthine guanine phosphoribosyl transferase)

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8
Q

Name the enzyme involved in the rate limiting step of AMP and GMP biosynthesis? What (2) cofactors are required for this step?

A

Amidophosphoribosyl transferase

  1. Glutamine
  2. Mg2+
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9
Q

All of the following statements are true, except?

A. Metabolism of a thiopurine metabolite by TPMT, after HGPRT metabolism, results in an activated drug
B. Mercaptopurine dose can be cut in half if co-administered with allopurinol
C. Major metabolite of Mercaptopurine is S-methythiopurine ribonucleotide
D. Major metabolite of Mercaptoguanine is thiopurine ribonucleotide
E. Higher risk of secondary cancer is seen with mercaptopurine

A

(E) There is a LOWER risk of secondary cancer seen with mercaptopurine. Its MOA is selective inhibition of the rate-limiting step enzyme. More secondary cancers are seen with Mercaptoguanine since its MOA is incorporation into DNA strands

*B - Yes, b/c allopurinol inhibits xanthine oxidase

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10
Q

Which of the following statements regarding thiopurine metabolism are TRUE?

A. Poor TPMT metabolizers have a lower incidence of SE like life-threatening levels of myelosuppression
B. Poor TPMT metabolizers need to increase dose 10-15 fold
C. Normal TPMT metabolizers have a poor response to thiopurine
D. TPMT genotyping is mandatory before initiating thiopurine therapy
E. None of the above

A

(D) This is the only true statement - TPMT genotyping IS mandatory before initiating thiopurine therapy

  • A - 10% of caucasians are poor TPMT metabolizers resulting in MORE active thionucleotide amount per dose and thus a HIGHER incidence of SE like life-threatening levels of myelosuppression and secondary cancers due to accumulation of false nucleotides in tissues
  • B - Poor TPMT metabolizers need to REDUCE dose 10-15 fold
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11
Q

Which of the following statements is true?

A. Mercaptopurine can be in inactivated by xanthine oxidase
B. Mercaptoguanine can be inactivated by xanthine oxidase
C. Mercaptopurine can be in activated by xanthine oxidase
D. Mercaptoguanine can be activated by xanthine oxidase
E. None of the above

A

(A) ONLY MercaptoPURINE can be inactivated by xanthine oxidase

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12
Q

What is the major metabolite and MOA of mercaptopurine?

A

Mercaptopurine major metabolite is S-methythiopurine ribonucleotide which is responsible for inhibiting Amidophosphoribosyl transferase (enzyme involved in the rate-limiting step of AMP and GMP biosynthesis)

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13
Q

What is the major metabolite and MOA of mercaptoguanine?

A

Mercaptoguanine major metabolite is thiopurine ribonucleotide which is responsible for incorporation into DNA strands

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14
Q

True or False - dose adjustments for mercaptopurine are necessary in patients with hepatic or renal impairments?

A

True

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15
Q

Secondary malignancies are a serious SE for which thiopurine drug?

A

Mercaptoguanine

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16
Q

All of the following statements are true, except?

A. Liposomal formulation of Cytarabine is used for Tx of lymphomatous meningitis
B. It’s relatively easy to substitute F with H in pyrimidine antimetabolites such as Gemcitabine
C. F is much more lipophilic than H
D. Gemcitabine has a longer T1/2 than Cytarabine
E. All of the above are true statements

A

(E) all of the above are true statements

*D - Gemcitabine has a longer T1/2 than Cytarabine b/c it inhibits one of the deaminase enzymes involved in the DNA polymerase/DNA chain elongation inhibitor drugs inactivation pathway

17
Q

Which of the following statements regarding DNA polymerase/DNA chain elongation inhibitors is incorrect?

A. All are prodrugs
B. All are actively transported into the cell
C. All must be converted to nucleotide triphosphate form
D. All have common SE of myelosuppression
E. All drugs are orally available

A

(E) All drugs are administered IV. They are NOT orally available (except Hydroxyurea which is an orally available miscellaneous antimetabolite)

18
Q

Which of the following statements regarding Cytarabine is incorrect?

A. Only the triphosphate metabolite is incorporated into DNA strand
B. Changing amino group to keto group inactivates this drug
C. Can be inactivated by (2) different enzymes
D. Has a dual MOA
E. Has a relatively long T1/2

A

(E) - Has a relatively SHORT T1/2 (~3.6 hours)

  • B - Cytidine deaminase converts the amino group to a keto group that inactivates the drug
  • C - Cytidine deaminase directly inactivates Cytarabine while Deoxycytidylate deaminase inactivates the phosphorylated drug (ara-CMP) both to Uracil arabinose
  • D - causes inhibition of DNA synthesis via dual MOA: incorporates into DNA chain causing conformational changes which cause stacking problems which result in slower DNA synthesis AND by inhibiting DNA polymerase
19
Q

Which antimetabolite is used primarily in the treatment of various leukemias in children and adults?

A

Cytarabine

20
Q

Why does Gemcitabine have a much longer T1/2 than Cytarabine?

A

Gemcitabine inhibits one of the deaminase enzymes that normally inactivates these type of cancer drugs leading to a longer T1/2 (19hrs vs 3.6 hrs for Cytarabine)

21
Q

Which of the following statements is incorrect?

A. Cytarabine is quickly metabolized through deamination to inactive uracil derivative
B. Gemcitabine is not a prodrug
C. Fludarabine is an analog of dAMP
D. Similar SE are seen with some DNA polymerase/DNA chain elongation inhibitors and pyrimidine antimetabolites
E. Pentostatin and Hydroxyurea SE are mild

A

(B) ALL DNA polymerase/DNA chain elongation inhibitors, including Gemcitabine, are prodrugs

  • C - Fludarabine is administered as a monophosphate resembling dAMP
  • D - the same SE are seen b/c they both contain F (SE include tumor lysis syndrome, neurologic effects, pulmonary toxicity)
  • E - mild SE b/c both drugs are more hydrophilic and not halogenated
22
Q

Which antimetabolite is used as first line Tx for advanced or metastatic pancreatic cancer?

A

Gemcitabine

23
Q

Which antimetabolite, used in Tx of chronic lymphocytic leukemia (CLL), has SE’s of pulmonary toxicity, tumor lysis syndrome, and hemolytic anemia?

A

Fludarabine phosphate (Fludara ®)

24
Q

Which antimetabolite has a triple MOA and is used in the Tx of hairy cell leukemia and refractory CLL?

A

Cladribine

  1. inhibits DNA polymerase
  2. inhibits ribonucleotide reductase
  3. resistant to adenosine deaminase
25
Q

Which antimetabolite, used in the Tx of acute lymphoblastic leukemia, requires permanent hydration during drug administration, and has a serious SE of cardiac toxicity?

A

Clofarabine

26
Q

All of the following statements are true, except?

A. GI disturbances are seen in >90% of patients taking Cytarabine
B. Pentostatin inhibits both adenosine deaminase and DNA polymerase
C. Myelosuppression SE of Fludarabine is exploited in stem cell transplants
D. Clofarabine inhibits both DNA polymerase and ribonucleotide reductase
E. All of the above are true

A

(B) Pentostatin is one of the few antimetabolites that does NOT inhibit DNA polymerase. Its MOA is inhibition of adenosine deaminase AND ribonucleotide reductase

27
Q

Which antimetabolite used in the Tx of hairy cell leukemia, CLL, and lymphomas, does NOT inhibit DNA polymerase, but instead inhibits adenosine deaminase and ribonucleotide reductase?

A

Pentostatin

28
Q

Which antimetabolite has excellent oral bioavailability and is used in the Tx of melanoma, resistant chronic myelocytic leukemia, and an adjunct to the radiation Tx of head and neck cancers?

A

Hydroxyurea

29
Q

True or False - inhibition of ribonucleotide reductase will result in no deoxyribonucleotides for DNA synthesis?

A

True

30
Q

Which (2) antimetabolites inhibit DNA elongation via incorporation into DNA causing conformational changes?

A
  1. Cytarabine

2. Fludarabine

31
Q

Which of the following antimetabolites is NOT used to treat some kind of leukemia?

A. Fludarabine
B. Cytarabine
C. Clofarabine
D. Gemcitabine
E. Cladribine
A

(D) Gemcitabine is only used to treat advanced or metastatic pancreatic cancer (also breast and non-small cell lung cancer)

32
Q

Which antimetabolite used in the Tx of acute lymphoblastic leukemia has severe SE’s (b/c presence of (2) halogens in structure) such as cardiac toxicity, tumor lysis syndrome, and organ failure

A

Clofarabine

33
Q

Which antimetabolite used in the Tx of hairy cell leukemia, CLL, and lymphomas is a natural product derived from Streptomyces?

A

Pentostatin

Med Chem 3 - Final Exam (5 decks)

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