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
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.
The
structural modification of these metabolites may be on the pyrimidine ring.
Synthesis
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.
Synthesis
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.
Synthesis
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.
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.
Mode of action: These drugs are converted into appropriate
mono-ribonucleotides, which inhibit the conversion of inosine monophosphate to
adenine and guanine nucleotides.
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.
Synthesis
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.
Synthesis
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.
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.
Synthesis
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.
Synthesis
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.
Trimetrexate
Synthesis
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