ANTIFOLATES 2-Amino

Among these drugs, the dihydrofolate reductase (DHFR) inhibitors are used clinically with a certain amount of success. They belong to two major classes the classical antifolates which feature a polar amino-acid side chain terminus and those containing nonpolar side chains, called lipophilic or nonclassical anti-folates. 

Common Name 4-Amino-4-deoxyfolic acid 4-Aminofolsaure 4-Amino-PGA Aminopterin 4-Aminopteroylglutamic acid 4-Aminopteroylglutaminsaure Antifolic acid Antifolsaure... 

What are called antifolate drugs pertain in general to blocking the biosynthesis of purines and pyrimidines, the heterocyclic bases used in the further synthesis of DNA and RNA, where folic acid is required as a coenzyme (or vitamin) for the enzyme dihydrofolate reductase. The previously mentioned compound called methotrexate or amethopterin (4-amino-A °-methyl folic acid), being a structural analog of folate or folic acid, locks up the enzyme dihydrofolate reductase, which in turn blocks the synthesis of a thymidine nucleotide necessary for cell division. 

As part of the major effort undertaken at the Chester Beatty Research Institute in the area of quinazoline antifolates, Jones [42] synthesized 5,8-dideazafolate (III.156), 5-methyl-5,8-dideazafolate (III.160), and 5-chloro-5,8-dideazafolate (III. 161) by a synthesis which basically followed the Davoll scheme, except for one important modification 2,4-diamino-quinazoline-6-carbonitriles were converted into 2-amino-4(3//)-oxoquinazohne-6-carboni-triles in boiling 2 M HCl rather than in alkali. Hydrolysis of the 4-amino group under these conditions was more than 99% complete, thus ensuring the purity of the final products. 

In order to gain information about the likely mechanism of membrane transport of the 2-amino-4(377)-oxoquinazoline antifolates, Calvert et al. [45] examined the effect of varying concentrations of (III. 156) (up to 100/xM) on the accumulation of 4/xM [ H]MTX, 4/xM [ H]folate, and 4/xM pH]-methyltetrahydrofolate over 40 min by L1210 cells. Curiously, there was no inhibition of the uptake of any of these compounds by (III. 156). The authors concluded that (III. 156) might not utilize either the folate or reduced folate transport pathway, but did not indicate what alternative transport route for this compound might exist. Transport of (III. 156) via the folate carrier would seem a likely route of entry into cells, but might be inefficient in comparison with transport of the natural substrate. This would explain the inability to block the uptake of 4 xM folate even with 100 (III.156). 

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. 

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