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Chapter: Medicinal Chemistry : Antineoplastic Agents

a. Pyrimidine analogues : Fluorouracil, Fluoxuridine, Cytarabine, Capecitabine (Captabin, Capiibine, Xabine) b. Purine analogues : Mercaptopurine (Purinethol), Thioguanine, Fludarabine c. Folic Acid Analogues : Methotrexate (Amethopterin), Azathioprine, Trimetrexate

Antineoplastic Agents - SYNTHESIS AND DRUG PROFILE


Mode of action: These are analogues that resemble normal compounds of co-enzymes, which participate in the DNA synthesis and competitively inhibit the utilization of normal substrate or incorporates to make dysfunction.

a. Pyrimidine analogues

The structural modification of these metabolites may be on the pyrimidine ring.




Mode of Action: It is converted into 5-flouro-2-deoxy uridine monophosphate, which inhibits thymidilate synthetase and blocks the conversion of deoxy uridic acid to deoxy thymidilic acid. For binding to thymidilate synthetase, this fluorinated pyrimidine prodrug must be converted to its deoxyribonucleotide. The active from of fluorouracil differs from the endogenous substrate only by the presence of the 5-flurogroup, which hold the key to the cytotoxic action of this drugs.

Metabolism: 20% of drug is excreted unchanged in urine and rest undergoes metabolism by polymorphic dihydro pyrimidine dehydrogenase to produce 5-fluoro 5, 6, dihydrouracil, which is converted to α-f luorouridopropionic acid by dihydropyrimidinase and to α-f luoro β-alanine by β-ureidopropionase.

Properties and uses: Fluorouracil is a white crystalline powder, sparingly soluble in water, and slightly soluble in alcohol. It is used topically in the treatment of pancancerous dermatoses, especially actinic keratosis, for which it is the treatment of choice, if the lesions are multiple, even if the lesions that are not clinically discernable respond. For this reason, the drug is applied to the entire affected area. Healing continues for 1 to 2 months after treatment. The drug does not affect nonkeratotic lesion. It is a secondary immuno-suppressive agent, and therefore, is not used in organ transplantation. It is the most active drug available for colorectal cancer. It is effective in the management of the breast, colon, pancreas, rectum, and stomach. It may have devastating bone marrow and gastrointestinal toxicity.

Assay: Dissolve the sample in dimethylformamide by gentle warming, cool and titrate with 0.1 M tetrabutylammonium hydroxide, using thymol blue as indicator.

Dosage forms: Fluorouracil injection I.P., B.P., Fluorouracil cream B.P.




Metabolism: This deoxyribonucleoside prodrug is bioconverted via 2’-deoxyuridine kinase-mediated phosphorylation to the same active 5-fluro-dUMP structure generated in the multistep biotransformation of fluorouracil.

Properties and uses: It is a white to off-white odourless powder, which is soluble in water, alcohol, or chloroform. Fluoxuridine is a prodrug of 5-fluorouracil. It is used for the palliation of gastrointestinal adenocarcinoma metastatic to the liver in patients who are considered incurable by surgery.




Properties and uses: Cytarabine is a white crystalline powder, soluble in water, very slightly soluble in alcohol and methylene chloride. It is used for acute leukaemia, chronic myclocytic leukaemia, meningeal leukaemia, acute lympholytic leukaemia, and chronic lympholytic leukaemia.

Assay: Dissolve the sample in anhydrous acetic acid, warm, if necessary, and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dosage forms: Cytarabine injection I.P., B.P.


Capecitabine (Captabin, Capiibine, Xabine)


Metabolism: The drug is actually another 5-fluoro-deoxy uridine monophosphate prodrug. When given orally, it is extensively metabolized to fluorouracil, which is then converted to the active fluorinated deoxyribonucleotide.

Uses: It is used in acute granulocytic leukaemia of adults and children.

Dose: The dose for colorectal cancer and breast cancer for adults is 1.25 g per m2 two times a day for 2 weeks followed by a 1-week rest period. Therapy is to be given in 3-week cycles. Recommended treatment duration for colorectal cancer is 6 months. May be used in combination with docetaxel at 75 mg per m2 given as a 1 h IV infusion, once in every 3 weeks for the treatment of breast cancer.

Gastric cancer: The dose for adults , used in combination with platinum-based compound, 1 g per m2 two times a day for 14 days followed by a 7-day rest period. First dose is given on the evening of day 1 and the last dose on the morning of day 15.


b. Purine analogues

Mode of action: These drugs are converted into appropriate mono-ribonucleotides, which inhibit the conversion of inosine monophosphate to adenine and guanine nucleotides.


Mercaptopurine (Purinethol)

Properties and uses: Mercaptopurine is a yellow crystalline powder, practically insoluble in water, slightly soluble in alcohol, and dissolves in solutions of alkali hydroxides. It is used in the treatment of acute monocytic leukaemia.

Assay: Dissolve the sample in dimethylformamide and titrate with 0.1 M tetrabutylammonium hydroxide. Determine the end point potentiometrically.

Dose: The usual initial oral dose for children and adults is 2.5 mg per kg body weight daily, but the dose varies as per individual response and tolerance.


Route-I. From: 7H-Purin-6-ol

Route-II. From: 6-Chloropyrimidine-4,5-diamine

Route III. From: Hypoxanthine

Dosage forms: Mercaptopurine tablets I.P., B.P, Mercaptopurine oral suspension B.P.




Properties and uses: It is used in treating acute leukaemia, especially in combination with cytarabine. The adverse effects are bone marrow depression, leucopenia, thrombocytopenia, and bleeding.




Metabolism: This is a 3-halogenated adenosine based nucleoside, which undergoes conversion to active triphosphate nucleotides after active transport into the tumour cells.

Properties and uses: Fludarabine phosphate is a white crystalline hygroscopic powder, slightly soluble in water, soluble in dimethylformamide, and very slightly soluble in anhydrous ethanol. It shows activity against low-grade lymphoma and mycosis fungoides.

Assay: It is assayed by adopting liquid chromatography technique.

c. Folic Acid Analogues

Mode of action: These drugs inhibit dihydrofolate reductase (DHFRase), which converts the dihydrofolic acid to tetrahydro folicacid, the co-enzyme required for one carbon transfer reaction in de novo purine synthesis and amino acid interconversion.


Methotrexate (Amethopterin)


Route-I. From: Pyrimidine-2,4,5,6-tetraamine

Route-II. From: Pyrimidine-2,4,5,6-tetraamine

Properties and uses: Methotrexate is a yellow or orange crystalline hygroscopic powder, practically insoluble in water, ethanol, and methylene chloride. It dissolves in dilute mineral acids and dilute solutions of alkali hydroxides and carbonates. It is used for the treatment of acute lymphocytic leukaemia, acute lymphoblastic leukaemia, breast cancer, and epidermoid cancer of the head, neck, and lung cancer.

Assay: It is assayed by adopting liquid chromatography technique.

Dose: For the maintenance therapy of acute lymphoblastic leukaemia, the dose is 15–30 mg per m2 body surface once or twice weekly either orally or intramuscularly, with other agents, such as mercaptopurine.

Dosage forms: Methotrexate injection I.P., B.P., Methotrexate tablets I.P., B.P.




Properties and uses: Azathioprine is a pale-yellow powder, practically insoluble in water and alcohol. It is soluble in dilute solutions of alkali hydroxides and sparingly soluble in dilute mineral acids. It is used as an immuno-suppressant.

Assay: Dissolve the sample in dimethylformamide and titrate with 0.1 M tetrabutylammonium hydroxide. Determine the end point potentiometrically.

Dosage forms: Azathioprine tablets B.P.




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