Antimetabolites are structural analogs of ordinary cellular metabolites such as folic acid, pyrimidines and pyrines, which after being introduced in the body, begin to imitate the structure of ordinary metabolites. They compete with metabolites to block important reactions leading to formation of DNA/RNA.
So, by competing with natural pyrines and pyrimidines in metabolic schemes, they interfere with the synthesis of nucleic acids, thus being included in place of ordinary metabolites. This leads to the formation of cellular products, which cannot function normally. Thus, cellular processes of division and multiplication are disrupted.
In addition, because they are structural analogs of natural substances, antimetabolites can act not only by being introduced into the metabolic process and form "false" nonfunctional metabolites, but also by inhibiting catalytic functions of certain enzymes or enzyme systems.
Antimetabolites are subdivided into three groups: folic acid antagonists (methotrexate), purine antagonists (mercaptopurine, thioguanidine), and pyrimidine antagonists (fluo-rouracil, floxuridine, cytarabine).
Folic acid antagonists, in particular methotrexate, act by competitively binding with the enzyme dehydrofolate reductase in place of folic acid. This is the general starting compound for enzyme-catalyzed reactions of transferring a methyl group. Folates are carriers of a single carbon group (methylating group) necessary during purine and pyrimidinethimidylate synthesis, and in particular for methylating deoxyuridine monophosphate to deoxythimidine monophosphate. Dihydrofolate reductase's affinity with antimetabolics is much higher than with usual substrates—folic acid and its reduced forms. Because of the pronounced affinity of dehydrofolatereductase to methotrexate, even large doses of folic acid introduced simultaneously turn out to be useless in preventing the effects of methotrexate.
cooh h cooh cooh folic acid h cooh dihydrofolic acid folic acid dihydrofolic acid cooh cooh methotrexate methotrexate
Methotrexate: Methotrexate, V-[p-[[2,4-diamino-6-piperidinyl)methyl]methylamino]-benzoyl]-L-(±)-glutamic acid (18.104.22.168), is made by reacting V-(4-methylaminoben-zoyl)glutaminic acid (22.214.171.124) with 2-amino-4-hydroxyl-6-bromomethylpteridine
(126.96.36.199). In order to do this, N-(4-methylaminobenzoyl)glutaminic acid (188.8.131.52) is synthesized from 4-nitrobenzoyl chloride, which is reacted with L-glutamic acid, forming N-(4-nitrobenzoyl)glutamic acid (184.108.40.206), the nitro group of which is reduced to an amino group using hydrogen over Raney nickel, which gives N-(4-aminobenzoyl)glutamic acid (220.127.116.11). This undergoes reductive methylation using formaldehyde and hydrogen, which forms N-(4-methylaminobenzoyl)glutamic acid (18.104.22.168).
The second part of the methotrexate molecule, 2-amino-4-hydroxy-6-bromomethylpteri-dine (22.214.171.124), is made from 2,4,6-triaminopyrimidine (126.96.36.199), which is easily synthesized by reacting malonic acid dinitrile with guanidine. This is nitrosylated by anhydrous nitrous acid to 2,4,6-triamino-5-nitrosopyrimidine (188.8.131.52), and then it is reduced by sodium borohydride to 2,4,5,6-tetraaminopyrimidine (184.108.40.206). Upon reacting this with 1,2-dibromopropionic aldehyde, the product of attaching bromine to acrolein, 2-amino-4-hydroxy-6- bromomethyl-pteridine (220.127.116.11) is formed. Alkylating the amine nitrogen atom of N-(4-methylaminbenzoyl)glutamic acid (18.104.22.168) with resulting bromide (22.214.171.124) gives methotrexate (126.96.36.199) [1-8].
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