Folic acid antagonist

Acylation of 2-methylpyrido[2,3-d]pyrimidines with anhydrides gives 2-acylmethyl derivatives (67), whilst bromination to the 7-bromomethyl derivative has been reported for 7-methylpyrido[3,2-d]pyrimidines (56JCS4433) in a synthesis of potential folic acid antagonists. 

Folic acid antagonist inhibits dihydrofolate reductase (DHFR) blocks reduction of folate to tetrahydrofolate inhibits de novo purine synthesis results in arrest of DNA, RNA, and protein synthesis... 

The surface epithelial cells of the small intestine are renewed rapidly and regularly. It takes about two days for the cells of the duodenum to be renewed completely. As a result of its rapid renewal rate, the intestinal epithelium is susceptible to various factors that may influence proliferation. Exposure of the intestine to ionizing radiation and cytotoxic drugs (such as folic acid antagonists and colchicine) reduces the cell renewal rate. 

Recently, tritiated folic acid became available, making possible a nonmicrobiological method for studying the metabolism of folic acid. It obviates the toxic effects of folic acid antagonists on microbial assay organisms. This technique was used to follow the uptake, metabolism, and excretory products of folic acid (A4, J2, J3). 

Antimetabolites (inhibition of purine and pyrimidine nucleotide synthesis) Methotrexate Folic acid antagonist, inhibits tetrahydrofolate reductase and therefore dTMP synthesis 6-Mercaptopurine Interferes with purine synthesis 5-Fluorouracil Inhibits dTMP synthesis ... 

Antimetabolites are subdivided into three groups folic acid antagonists (methotrexate), purine antagonists (mercaptopurine, thioguanidine), and pyrimidine antagonists (fluo-rouracil, floxuridine, cytarabine). 

Pyrimethamine, a folic acid antagonist, exhibits antimicrobial action against the causative agent of malaria and possesses sporontocidal action. It is also effective with respect to the causative agent of toxoplasmosis. It is used for preventing malaria and treating toxoplasmosis. 

Pharmacology Leucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs that act as folic acid antagonists. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. 

Folic acid antagonist overdosage In the treatment of accidental overdosages of folic acid antagonists, administer leucovorin as promptly as possible. As the time interval between antifolate administration (eg, methotrexate) and leucovorin rescue increases, leucovorin s effectiveness in counteracting toxicity decreases. 

Leucovorin calcium Wellcovorin) Folic acid antagonists (eg, methotrexate)... 

Renal stones Triamterene has been found in renal stones with other usual calculus components. Use cautiously in patients with histories of stone formation. Hematologic effects Triamterene is a weak folic acid antagonist. Because cirrhotics with splenomegaly may have marked variations in hematological status, it may contribute to the appearance of megaloblastosis in cases where folic acid stores have been depleted. Perform periodic blood studies in these patients. 

Folic acid antagonists are of historical interest as a representative of this group, i.e. methotrexate, produced the first, although temporary, remissions in leukemia and the first cure of a solid tumor, choriocarcinoma. 

Mechanism of Action An antidote to folic acid antagonists that may limit methotrexate action on normal cells by competing with methotrexate for the same transport processes into the cells Therapeutic Effect Reverses toxic effects of folic acid antagonists. Reverses folic acid deficiency. 

Folic acid antagonist overdose PO 2-15 mg/day for 3 days or 5 mg every 3 days. Megaloblastic anemia secondary to folate deficiency IM 1 mg/day Colon cancer IV 200 mg/m followed by 370 mg/m fluorouracil daily for 5 days. Repeat course at 4-wk intervals for 2 courses then 4-5 wk intervals or 20 mg/m followed by 425 mg/m fluorouracil daily for 5 days. Repeat course at 4-wk intervals for 2 courses then 4-5 wk intervals. 

Folic Acid Antagonists. Folic acid antagonists block the biosynthesis of purine nucleotides. Methotrexate (7.76) is the prototypic fohc acid antagonist and functions by binding to the active catalytic site of dihydrofolate reductase, thereby interfering with the synthesis of the reduced form that accepts one-carbon units lack of this cofactor blocks the synthesis of purine nucleotides. As well as being used in the treatment of cancer, methotrexate has been used in the management of rheumatoid arthritis, psoriasis, and even asthma. 

It is used as leucovorin calcium (calcium folinate). It is 5-formyl derivative of tetrahydrofolic acid and it acts as an antidote to folic acid antagonists like methotrexate or pyrimethamine which inhibit the enzyme dihydrofolate reductase. 

It is indicated in overdose of methotrexate, folic acid antagonists and as adjuvant treatment of colorectal carcinoma. 

Fusion with the cells compensates for this deficiency. When fused and unfused cells are incubated in the presence of the folic acid antagonist aminopterin, the de novo synthesis of purines and pyrimidines for DNA is blocked. Cells deficient in HGPRT die, whereas hybrid cells are able to bypass aminopterin blockage by metabolism of hypoxanthine and thymidine added to the medium. In the generation of mouse hybridomas, an number of myelomas deficient in HGPRT are available, all originating from MOPC 21, a spontaneous myeloma from the BALB/c mouse strain. 

Some of the unusual features of folic acid noled by investigators include (I) folic acid antagonists used in cancer therapy with temporary remissions (2) lolic acid occurs in chromosomes (3) folic acid is distributed throughout cells (4) needed for mitotic step metaphase to anaphase (5) antibody formation decreased in lolic acid deficiency (6) choline-sparing effects (7) analgesic in humans—pain threshold is increased (8) antisulfonatnide effects (9) enterohepatic circulation of folate (10) synthesized by psittacosis virus (11) concentrated in spinal fluid. 

Antimetabolites include 5-fluorouracil [51-21-8] (153) and amethopterin [59-05-2] (154), a folic acid antagonist, which produce sterility in female flies when fed at 0.01—0.05% in the diet. 

Methotrexate (Amethopterin) is a folic acid antagonist that binds to dihydrofolate reductase, thus interfering with the synthesis of the active cofactor tetrahydrofolic acid, which is necessary for the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. 

The major antimalarial agents are the 4-aminoquinoline derivative (e.g., chloroquine), 8-aminoquinoline derivative (e.g., primaquine), folic acid antagonist (e.g., pyrimethamine), and... 

Methotrexate is a folic acid antagonist, binding reversibly to dihydrofolate reductase. This prevents purine/pyrimidine biosynthesis and DNA synthesis.3... 

Using nitrogen mustards (1943) and Folic acid antagonists (1948)... 

Therapeutic Function Antidote (folic acid antagonists), Antianemic... 

Amcthopterin) lJse antineoplastic (folic acid antagonist)... 

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