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

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




Bleomycins

IUPAC nomenclature

(3-{[(2′-{(5S,8S,9S,10R,13S)-15-{6-amino-2- [(1S)-3-amino-1-{[(2S)-2,3-diamino-3-oxopropyl]amino}-3-oxopropyl] -5-methylpyrimidin-4-yl}-13-[{[(2R,3S,4S,5S,6S)-3- {[(2R,3S,4S,5R,6R)-4-(carbamoyloxy)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy} -4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy} (1H-imidazol-5-yl)methyl]-9-hydroxy-5-[(1R)-1-hydroxyethyl]-8,10-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazapentadec-1-yl}-2,4′-bi-1,3-thiazol-4-yl)carbonyl]amino}propyl)(dimethyl)sulfonium.

Classification

Bleomycin falls under the category of antibiotic Antineoplastic cytotoxic drug. [1]

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 1415.6 g/mol
2 Appearance Yellow to colorless powder.

Can appear bluish if copper content is high.

3 Melting point 200-204 °C
4 Solubility Freely soluble in water
5 Presence of ring Bithiazole ring system

Mechanism of Action

i. Bleomycin chelates metal ions and produces pseudoenzymes.

ii. The pseudoenzymes so formed reacts with Oxygen to produce hydroxide and superoxides free radicals.

iii. Cleaving of DNA by the free radicals.[2]

Structural Activity Relationship

  • For the complexation and oxygen activation, N terminal is responsible.
  • Cleaving of DNA and affinity of the drug towards DNA is due to the C-terminal
  • Efficiency of the cleaving property is dependent on the linker moiety.
  • Cell recognition and cellular uptake is controlled by the disaccharide moiety of the drug.
  • Disaccharide moiety is also responsible for the cytotoxic effect of the drug.
  • Deglycosylation of the drug will not change the ability of drug to induce apoptosis.
  • Deglycosyaltion will suppress the ability of drug to induce ROS in laryngeal cancer cells.

Methods of Synthesis

i. Erythro-/3-hydroxy-L-histidine was prepared by condesation of 4-formylimidazole and N-pyruvylideneglycinatocopper(II) by modification of Ishido’s method.

ii. Methyl ester of the above formed compound was treated with MeOH-HCl.

iii. It is then treated with Tert-butyl S-(4,6-dimethylpyrimidine-2-yl)thiocarbonate.

iv. Formed compound will be treated with tosylchloride-Na2CO3 in dioxane water to give tosyl derivative.

v. The compound will be then treated with alpha-bromide of peracetyl in CH2Cl2.

vi. All the protective groups except the Boc-group will be removed by mild alkaline treatemnet.

vii. Then the compound will be treated with DNFB to give N-DNP derivative, then purified using chromatography technique.

viii. The Boc-group is deprotected using trifloroacetic acid and the compound is then coupled with Boc-PBA by DCC-HOBt method in DMF.

ix. The formed compound is then purified using chromatography technique to get the yield of 83%.

x. All the protective groups are removed by using 0.1N NaOH to get the Bleomycin.[3]

Therapeutic Uses

Bleomycins are used for the treatment of:

  • Hodgkin’s lymphoma
  • Non-Hodgkin’s lymphoma
  • Ovarian cancer
  • Testicular cancer
  • Sarcoma
  • Melanoma
  • Squamous cell cancer

Side Effects

  • Common side effects includes hair loss, nail banding, skin reactions, fever and chills.
  • Some people may suffer from side effects like lung problems, inflammation of veins, mouth sores, loss of appetite, loss of weight, nausea and vomiting.

MCQs

Q.1 The term ‘Blenoxan’ is associated with which drug?

a) Prednisolone

b) Ethinylestradiol

c) Toremifene

d) Bleomycin

Q.2 Disaccharide moiety in drug Bleomycin is responsible for?

a) Cellular uptake

b) Cell recognition

c) Cytotoxicity

d) All of the above

Q.3 Which amongst the following are the correct side effects of the drug Bleomycin?

I. Hair loss

II. Arrhythmias

III. Hypertension

IV. Nail banding

a) I, III & IV

b) II, III& IV

c) I & IV

d) I, II & III

Q.4 The microbes required for the synthesis of drug Bleomycin is?

a) Streptomyces caespitosus

b) Streptomyces verticillus

c) Streptomyces peucetius

d) None of these

Q.5 Which pairs of drug and its classification are true

 

I. Bleomycin Antibiotic antineoplastic drug
II. Fosfestrol Glucocorticoids
III. Topotecan Taxanes
IV. Etoposide Camptothecin analogues

a) I & IV only

b) I, II & III only

c) III & IV only

d) I only

Q.6 Correct physical form in which the drug Bleomycin is found?

a) Yellow to colorless powder

b) Bluish when copper concentration is present

c) Red crystalline powder

d) Both a) and b)

 Q.7 Match the following with respect to ring systems of the drug

i. Bleomycin A. Dihydroxyanthraquinone ring system
ii. Mitoxantrone B. Bithiazole ring system
iii. Daunorubicin C. Anthraquinone ring system
iv. Vincristine D. Quinoline ring system

 

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

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

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

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

 

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ANSWERS

1-d

2-d

3-a

4-b

5-d

6-d

7-c

 

REFERENCES

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

[2] Hecht SM. Bleomycin: new perspectives on the mechanism of action. Journal of natural products. 2000 Jan 28;63(1):158-68.

[3] Saito SI, UMEZAWA Y, YOSHIOKA T, TAKITA T, UMEZAWA H, MURAOKA Y. An improved total synthesis of bleomycin. The Journal of antibiotics. 1983;36(1):92-5.

 




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