Antifolic acid compounds

The most important drug in this group is methotrexate. 

N-[4-[[(2,4-Diamino-6-pteridinyl) methyl] methylamino] benzoyl]-L-glutamic acid BP (1973) USP  

It is prepared by treating together 2,4,5,6-tetraaminopyrimidine 2,3-di-bromopropionaldehyde, disodium / -(methylamino)-benzoylglutamate, iodine and potassium iodide and subsequently followed by heating with lime water. 

It is the first ever antineoplastic agent that produced appreciable remissions in leukemia. It is extensively employed for the treatment of acute lymphoblastic leukemia. It is invariably used in combination cheotherapy for palliative management of limg eaneer, breast cancer and epidermoid cancers of the head. It is frequently recommended for the treatment and prophylaxis of meningeal leukemia based on its ability to penetrate the central nervous system. It is also of value in choricarcinoma and related trophoblastie tumours of women. 

For maintenance therapy ofacute lymphoblastic leukemia is 15-30 mg per body surface 

---

G. H. Hitchings and his co-workers have made a comprehensive studyof antifolic acid activity in 2,4-diaminopyrimidines. They have demonstrated that very many such compounds, both simple and fused, show such activity. In the course ofthis work some pyrido[3,2-d]-pyrimidines and a large number of pyrido[2,3-d]pyrimidinesi ... 

Substitution on the phenyl ring of antifolates was described as early as 1951 by Cosulich et al. [192] in the form of 3 -chloroAMT (V.l), 3 -broraoAMT (V.2), and 3 -chloroMTX (V.3), which were obtained by chlorination or bromination of the parent compounds in AcOH. Other 3 -chloro compounds reported by the Lederle group [192] were the A -nitroso, 9,10-dimethyl ( adenopterin ), 2-AW-dimethylamino and 4-piperidino analogues, as well as several with side-chain moieties other than glutamic acid. Compound (V.3)... 

The glutamic moiety of TNP-351, a pyrrolo[2,3-d]pyrimidine glutamic acid derivative, and related compounds have been transformed into their A-co-masked ornithine analogs which show remarkable antifolate activity <00CPB1270>. The reaction of the heterocyclic enamine 77 with tosyl azide leads to the tosylimino derivative of 1,2,4-triazolo[l, 5-a]pyrimidine 79. Extrusion of nitrogen from the primary adduct 78 is followed by a 1,2-shift of a methyl group to yield 79 <00JHC195>. 

Pharmacology Aminosalicylic acid is bacteriostatic against Mycobacterium tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. The mechanism of action has been postulated to be inhibition of folic acid synthesis (but without potentiation with antifolic compounds) or inhibition of synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis. 

The folic acid biosynthesis has been extensively explored to design effective antimalarials. A number of classes of compounds have been developed, which interfere with different steps of the folate synthesis in plasmodia [14]. These antimalarials, which are collectively known as antifolates, may be broadly divided in three groups. 

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. 

The isolation in the 1940s of the antianemic factor now known as folic acid and its subsequent synthesis resulted, after many false leads, in the first successful antivitamin antimetabolite aminopterin (Table 4-5). This compound produced sustained remissions in leukemia. The N10-methyl homolog, now designated as MTX (Table 4-5), superseded aminopterin the same year. It is still the only clinically significant antifolate carcinolytic drug. 

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. 

The effect of substituting other acidic groups for carboxyl at the y-position of folates and antifolates has been of interest in recent years because of the possibility that these compounds would inhibit not only DHFR but also FPGS [284-287]. 

---