TOPOTECAN Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

TOPOTECAN Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

Topotecan

IUPAC nomenclature

(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride.

Classification

Toptecan falls under the category of camptothecin cytotoxic drug. [1]

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 421.4 g/mol
2 Appearance Present in solid form
3 Melting point Range between 213-218°C
4 Solubility 2350 mg per liter in water
5 Octanol water partition coefficient 0.8
6 Presence of ring Ring systems like quinoline and pyridine are present.

Mechanism of Action

i. During the S phase of the DNA synthesis, topotecan binds with the topoisomerase I-DNA complex. This prevents the relegation of the DNA strands. Topotecan binds at the site of the DNA cleavage by intercalating between the upstream and downstream base pairs by mimicking a DNA base pair.

ii. The ternary complex so formed interferes with the moving replication fork.

iii. The lethal double-stranded breaks in the mammalian cells cannot be repaired by the cells and thus apoptosis takes place. [2]

Structural Activity Relationship

  • The E ring in a lactone form is much more potent than the E-ring in the caboxylate form.
  • For the activity of the drug, chiral center at position 20 is necessary.
  • R-configuration is inactive form.
  • Drug without the A and B rings shows less potency for the DNA synthesis inhibition.
  • A and B rings are important for the activity of the drug. [3]

Methods of Synthesis                                                                       

i. Reduction and selective oxidation of the quinoline moiety of the camptothecin.

ii. Introduction of the N,N-dimethylaminomethyl side chain.

 

Therapeutic Uses

  • when other treatments fails during the cure of ovary cancer, this drug is prescribed.
  • Topotecan is also used for the treatment of certain lung cancers like small cell lung cancer.

Side Effects

  • Common side effects includes low blood counts, nausea,vomiting, hair loss and diarrhea.
  • Some people may suffer from side effects like constipation, fatigue, fever, abdominal pain, bone pain, weakness, mouth sores, loss of appetite, skin reactions like rashes, shortness of breath, cough and headache.

 MCQs

Q.1 Which term is NOT associated with the drug Topotecan?

a) Topotel

b) Duanocin

c) Oncotron

d) Both b) and c)

Q.2 Match the following with respect to the physical forms of drugs

i. Tinidazole A. White to pale yellow crystalline powder
ii. Metronidazole B. present in solid form at room temperature
iii. Topotecan C. colorless crystals
iv. Morphine D. White crystalline solid

a) i-A, ii-D, iii-C, iv-B

b) i-B, ii-A, iii-C, iv-D

c) i-C, ii-A, iii-B, iv-D

d) i-C, ii-D, iii-B, iv-A

Q.3 The drug Topotecan shows its action through-

a) Inhibiting the pyrimidine synthesis within the cell

b) Inhibiting the purine synthesis within the cell

c) Inducing radiosensitization in the cells

d) Binding with topoisomerase I-DNA complex

Q.4 The correct order for the synthesis of the drug Topotecan can be

I. Selective oxidation of the quinoline moiety.

II. Extraction of camptothecin from its natural source

III. Extraction of Epipodophyllotoxin from its natural source

IV. Introduction of N,N-dimethylaminomethyl side chain

a) III – I – IV

b) II – I – IV

c) III – IV – I

d) II –IV – I

Q.5 Predict the incorrect statements from the following with respect to the classification of the drugs.

I. Chlorambucil belongs to class Nitrogen mustard alkylating agent

II. Dacarbazine belongs to class Nitrosoureas

III. 6-Mercaptopurine belongs to pyrimidine antagonist

IV. Topotecan belongs to class Camptothecin analogues

a) All of the above

b) Only III & IV

c) Only II & III

d) Only I, II & III

Q.6 The correct sequence of True and False for the given statements with respect to the side effects of drug Topotecan is-

I. RBC and WBC counts may increase

II. RBC and WBC counts may decrease, platelet counts may increase

III. Hair loss is a common side effect of this drug

IV. Fatigue and fever may occur in the patient taking topotecan drug.

a) FTTT

b) FFTT

c) TFTT

d) FFFT

Q.7 Which amongst the following drugs is having highest number of ring system in its structure-

a) Etoposide

b) Tinidazol

c) Metronidazol

d) Topotecan

 

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ANSWERS

1-d

2-c

3-d

4-b

5-c

6-b

7-a

 

REFERENCES

[1] Tripathi KD. Essentials of Medical Pharmacology, 6thEdn. Jaypee Brothers Medical Publishers (P) Ltd. 2008: 820.

[2] Kelner MJ, McMorris TC, Estes L, Samson KM, Trani NA, MacDonald JR. Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action with topotecan. Leukemia. 2000 Jan;14(1):136-41.

[3] Li F, Jiang T, Li Q, Ling X. Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer?. American journal of cancer research. 2017;7(12):2350. cx

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