N

In the body, mercaptopurine is converted into an active form of the drug, nucleotide 6-thioinosin-5-phosphate. Nucleotide 6-thioinosin-5-phosphate inhibits the first step in the synthesis of inosin-5-phosphate by negative feedback, preventing its transformation to adenosine or guanine nucleotides, which are necessary for synthesizing DNA. Thus, mercaptopurine inhibits synthesis and interconversion of purine nucleotides, which leads to a halt in DNA synthesis in proliferating cells during the cell cycle.

Mercaptopurine is used for treatment of lymphobastomas, myeloblastoma leucosis, and to treat neuroleukemia. Synonyms of this drug are isimpur, classen, purinethol, and others.

Thioguanine: Thioguanine, 2-aminopurin-6-thiol (30.1.2.12), is made from 2,8-dichloro-6-hydroxypurine (30.1.2.7), in which the second chlorine atom at C2 is replaced with an amino group when reacted with ammonia, forming 2-amino-8-chloro-6-hydroxy-purine (30.1.2.7), which is then reduced by hydrogen iodide to 2-aminopurin-6-ol (30.1.2.11). Replacement of the hydroxyl group with a mercapto group at C6 is carried out by reacting it with phosphorous pentasulfide, which forms thioguanine (30.1.2.12) [14, 16-20].

In the body, thioguanine is converted into an active form, 6-thioguanin-5-phosphate. The main mechanism of its action consists of including its triphosphate form into DNA, replacing the guanine nucleotide, and inhibiting DNA synthesis.

Mercaptopurine is important as a drug of supportive therapy in treatment of both adults and children. Thioguanine may have specific clinical use, or may be used in combination with other drugs in severe myelogenous therapy. Synonyms of this drug are lanvis and others.

30.1.3 Pyrimidine derivatives

A large number of fluorinated analogs of pyrimidine are synthesized as potential anticancer drugs. Fluorouracil and fluoxuridine have been studied the most. It is possible that the most important mechanism of action of fluorinated pyrimidines is the inhibition of thymidylate synthetase synthesis, thus affecting the process of DNA production. This action is accompanied by formation of an active metabolite, 5-fluorodeoxyuridinomonophosphate from both fluorouracil and fluoxuridine. 5-fluorodeoxyuridinomonophosphate forms a complex with reduced folate N5,N10-methylentetrahydrofolate. This complex inhibits thymidylate sythetase and reduces methylation of 2-deoxyuridine acid for formation of thymidylic acid. The resulting thymidine deficit causes damage and death of cells.

It is also believed that the triphosphorylated form of fluorinated analogs of pyrimidine can be included in RNA, and can have an effect on protein synthesis.

Fluorouracil: Fluorouracil, 4-fluorouracil (30.1.3.3), is made by condensing the ethyl ester of fluoroacetic acid with ethylformate in the presence of potassium ethoxide, forming hydroxy-methylenfluoroacetic ester (30.3.1), which cyclizes by reacting it with S-methyl-isothiourea to 2-methylthio-4-hydroxy-5-fluoropyrimidine, which is subsequently hydrolyzed by hydrochloric acid to fluorouracil (30.1.3.3) [21,22]. An alternative method of synthesizing

5-fluorouracid is direct fluorination of uracil with fluorine or trifluoromethylhypofluoride [23-28].

F-CH2-COOC2H5 + HCOOC2H5

c2h5ok c2h5ooc. ^f

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