Antifolate

Antifog agents Antifoggants Antifolate TS inhibitor Antifouling agents Antifreeze... 

Fohc acid is safe, even at levels of daily oral supplementation up to 5—10 mg (97). Gastrointestinal upset and an altered sleep pattern have been reported at 15 mg/day (98). A high intake of foHc acid can mask the clinical signs of pernicious anemia which results from vitamin deficiency and recurrence of epilepsy in epileptics treated with dmgs with antifolate activity (99). The acute toxicity (LD q) is approximately 500 and 600 mg per kg body weight for rats and mice, respectively (100). 

The dmgs known as antifolates act as effective blood schizonticides. Unfortunately, the parasites readily develop resistance to them. Most antifolates show poor oral tolerance, absorption, and host toxicity. They fall into two types depending on the mechanisms by which they operate. 

The second type of antifolates bind preferentially with, and thus selectively inhibit, the enzyme dihydrofolate reductase contained in the plasmodia. This interferes with the abiUty of the malaria parasites to convert dihydrofolate to tetrahydrofoUc acid. In the erythrocyte host, however, dihydrofolate... 

Fig. 8. Thymidylate synthase inhibitors designed to fit into the A/, AJ -methylenetetrahydrofolate binding site. The best inhibitors from each class are the classical antifolate TS inhibitor (31), the naphthostyril-based lead compound (32), and the tetrahydroquinoline-based lead compound (33), iC values (in nAI)...

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 ... 

The folate antagonists, pyrimethamine and sulfadiazine, inhibit the parasite s DHFR/TS synthase enzyme complex and the DHPS, respectively (Fig. 4) (see antimalarial drugs). To avoid deficiency of folic acid in patients treated with antifolate antagonists, folinic acid supplementation is recommended to reduce bone-marrow suppression. 

In malaria chemotherapy, resistant parasites have significantly reduced the efficiency of classic antifolate drugs. In the search for novel inhibitors of... 

Antifolate Drugs or Glutamine Analogs Block Purine Nucleotide Biosynthesis... 

Several reactions of IMP biosynthesis require folate derivatives and glutamine. Consequently, antifolate drugs and glutamine analogs inhibit purine biosynthesis. 

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. 

Roy, K., et al. Chromosomal localization of the murine RFC-1 gene encoding a folate transporter and its amplification in an antifolate resistant variant overproducing the transporter. Cancer Genet. Cytogenet. 1998, 305, 29-38. 

Methotrexate -antifolate antimetabolite cell cycle dependent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hepatotoxicity—more common in high-dose therapy -CNS toxicity—dizziness, malaise, blurred vision, encephalopathy -nephrotoxicity—including acute renal failure, particularly at high doses... 

Trimetrexate -antifolate antimetabolite -bone marrow suppression -mucocutaneous effects (mucositis, stomatitis) -nausea and vomiting -fever -maculopapular rash—usually self-limited -anorexia, malaise -above toxicities increased in patient with hypoalbuminemia (<3.5)... 

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>. 

T. Lee and P. A. Kollman, Theoretical studies suggest a new antifolate as a more potent... 

The enzyme mediating remethylation, 5-methyltetrahy-drofolate-betaine methyltransferase (Fig. 40-4 reaction 4), utilizes methylcobalamin as a cofactor. The kinetics of the reaction favor remethylation. Faulty remethylation can occur secondary to (1) dietary factors, e.g. vitamin B12 deficiency (2) a congenital absence of the apoenzyme (3) a congenital inability to convert folate or B12 to the methylated, metabolically active form (see below) or (4) the presence of a metabolic inhibitor, e.g. an antifolate agent that is used in an antineoplastic regimen. 

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