10-Methylfolic acid

Studies in this area were reported as early as 1949 by Lederle chemists [243], who used the Waller synthesis (2,4,5,6-tetraaminopyrimidine, 2,3-dibromo-propionaldehyde and an Af-(4-aminobenzoyl)-a-amino acid or ester) to prepare the alanine, valine, isoleucine, serine, threonine, phenylalanine and tryptophan analogues (VIII.1)-(VIII.7), respectively. Compounds (VIII.2) and (VIII.3) were also treated with CI2 in AcOH to obtain the 3 -chloro derivatives (VIII,8) and (VIII.9). Although the data reported were very scanty, consisting only of activity ratios relative to 10-methylfolic acid in the S.faecium microbioassay, replacement of the glutamate moiety by a-amino monoacids was clearly shown to be an unpromising route to potent antifolates. 

Synonyms. Amethopterin 4-Amino-lO-methylfolic Acid a-Methopterin. 

Amino-4-desoxyfolic acid, IX, 101 formate and, IX, 103 thymidine and, IX, 103 4-Amino-4antileukemic activity of, IX, 101 formate and, IX, 103 2-Amino-6,8-dihydroxypurine(8-hy-droxyguanine), IX, 138 6-Amino-2,8-dihydroxypurine(2,8-dihydroxyadenine), IX, 138 4-Aminofolic acid, IX, 133-135 antagonism to citrovorum factor, VIII, 46 IX, 12... 

Diamino-6,7-diphenylpteridine 4-Aminofolic acid (Aminopterin), N -methylfolic acid (Methopterin), 4-amino-N -methylfolic acid (A-metho-pterin)... 

For other antagonists, L(-f-)glutamic acid was replaced by d(—)glu-tamic acid thus, for example, Martin et al. (405) synthesized N-[4 (2-amino-4-hydroxy-7-methyl-6-pteridyl)methyl aminobenzoyl]-D(—)glu-tamic acid or D-methylfolic acid, whose inhibitory activity was moderate. 

Category Antimetabolite Antineoplastic Folate analogue Half-life Terminal up to 198 Hours Clinically important, potentially hazardous interactions with folic acid/folates, L-methylfolate... 

Methylation is the addition of a carbon atom to a molecule, usually causing a change in the function of the methylated molecule. For example, methylation of the neurotransmitter dopamine by catechol-O-methyltransferase renders it inactive. With only two exceptions, 5-adenosylmethionine (SAM), an activated form of the essential amino acid methionine, is the methyl donor for each of the more than 150 methylation reactions, which regulate a large number of cellular functions. One exception is methylation of homocysteine (HCY) to methionine by the cobalamin (vitamin Bi2)-dependent enzyme methionine synthase, which utilizes 5-methyltetrahydrofolate (methylfolate) as the methyl donor, serving to complete the methionine cycle of methylation, as illustrated in Fig. 1 (lower right). Notably, HCY formation from S-adenosylhomocysteine (SAH) is reversible and, as a result, any decrease in methionine synthase activity will be reflected as an increase in both HCY and SAH. This is significant because SAH interferes with SAM-dependent methylation reactions, and a decrease in methionine synthase activity will decrease all of these reactions. Clearly methionine synthase exerts a powerful influence over cell function via its control over methylation. 

Fernandes-Costa, F., and Metz, J., Binding of methylfolate and pteroylglutamic acid by the specific serum folate binder. J. Lab. Clin. Med. 93, 181-188 (1979). 

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