Aminopterin-methotrexate

Aminopterin, methotrexate, S-fluorouracil, 5-fluoro-orotic acid, tepa, metepa, and apholate all sterilized at the higher concentration, but only the antimetabolites sterilized at the lower concentration. Whenever a compound induces sterility, a second series of tests is run to determine the range of effective concentrations. Some antimetabolites sterilized at concentrations as low as 0.0025%, whereas the minimum for alkylating agents was 0.25%. In the third series of tests, the specific sex sterilized is determined. The chemosterilants are presented in the food at sterilizing concentrations to individual sexes of flies. These flies are then mated with normal flies of the opposite sex. All the chemicals mentioned above sterilized the females, but aminopterin and methotrexate failed to sterilize the male flies, and 5-fluorouracil produced male sterility in only a few tests. Tepa, 5-fluoro-orotic acid, metepa, and apholate, when included in the food, regularly sterilized both sexes. Because of the inability of aminopterin, methotrexate, and 5-fluorouracil to sterilize males, these compounds were not considered further. 

Del Campo M, Kosaki K, Bennett FC, Jones KL. Developmental delay in fetal aminopterin/methotrexate syndrome. Teratology 1999 60(1) 10-12. 

In view of the well-documented inhibition of dihydrofolate reductase by aminopterin (325), methotrexate (326) and related compounds it is generally accepted that this inhibitory effect constitutes the primary metabolic action of folate analogues and results in a block in the conversion of folate and dihydrofolate (DHF) to THF and its derivatives. As a consequence of this block, tissues become deficient in the THF derivatives, and this deficiency has many consequences similar to those resulting from nutritional folate deficiency. The crucial effect, however, is a depression of thymidylate synthesis with a consequent failure in DNA synthesis and arrest of cell division that has lethal results in rapidly proliferating tissues such as intestinal mucosa and bone marrow (B-69MI21604, B-69MI21605). 

In the treatment of human neoplastic diseases methotrexate has largely supplanted aminopterin in chemotherapy, due to the better therapeutic index of the former in experimental animals, although this superiority over (325) has not been conclusively demonstrated in man. 

Inhibition of nucleobase synthesis (2). Tetrahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 272). The folate analogues aminopterin and methotrexate (ame-thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of iicense. 

A novel approach to the production of antimalarial drugs has been described taking advantage of the in vivo transformation of pteridines by resident enzymes <2005AAC3652>. It was shown that simple precursors such as 2,4-diamino-6-hydroxymethylpterin can be converted into aminopterin or methotrexate, depending upon the precursor chosen, and that the dihydrofolate reductase inhibitors so formed were active against Plasmodium falciparum. 

Amethopterin (Methotrexate, 4-amino-4-deoxy-Ar -methyIpteroyl-L-glutamic acid) [59-05-2] M 454.4, m 185-204°(dec), [a]p°+19° (c 2, 0.1N aq NaOH). Commonest impurities are 10-methyl pteroylglutamic acid, 4-amino-10-methylpteroylglutamic acid, aminopterin and pteroylglutamic acid. Purified by chromatography on Dowex-1 acetate, followed by filtration through a mixture of cellulose and... 

Other useful targets for pharmaceutical agents are thymidylate synthase and dihydrofolate reductase, enzymes that provide the only cellular pathway for thymine synthesis (Fig. 22-49). One inhibitor that acts on thymidylate synthase, fluorouracil, is an important chemotherapeutic agent. Fluorouracil itself is not the enzyme inhibitor. In the cell, salvage pathways convert it to the deoxynucleoside monophosphate FdUMP, which binds to and inactivates the enzyme. Inhibition by FdUMP (Fig. 22-50) is a classic example of mechanism-based enzyme inactivation. Another prominent chemotherapeutic agent, methotrexate, is an inhibitor of dihydrofolate reductase. This folate analog acts as a competitive inhibitor the enzyme binds methotrexate with about 100 times higher affinity than dihydrofolate. Aminopterin is a related compound that acts similarly. 

Inhibitors. Aside from its role in providing reduced folate coenzymes for cells, this enzyme has attracted a great deal of attention because it appears to be a site of action of the important anticancer drugs methotrexate (amethopterin) and aminopterin.293 364 365 These compounds inhibit dihydrofolate reductase in concentrations as low as 10 8 to 10 9 M. Methotrexate is also widely used as an immunosuppresant drug and in the treatment of parasitic infections. 

Synthesis of Analogues of Folic Acid, Aminopterin and Methotrexate as Antitumour Agents... 

The numbering system employed below for methotrexate (2), folic acid (9), and aminopterin (10) will be employed throughout this review. For convenience... 

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