The folic acid antagonists

There are antagonists of the biosynthesis of dihydrofolic acid, and antagonists of its utilization. The history of the discovery of the antibacterial sulfonamides, typical antagonists of biosynthesis, was given in Sections 2.1 and 6.3.1. In 1940, Woods showed that the anti-bacterial action of sulfanilamide depended on its competition with j -aminobenzoic acid (P.7), which is a natural metabolite (Woods, 1940). Later this competition was shown to take place at the site on the enzyme dihydrofolate synthetase, which uses j -aminobenzoic acid to build up the molecule of dihydrofolic acid (2.74) (G.M. Brown, 1962). 

The selectivity of the antibacterial sulfonamides depends on the nonutilization of/ -aminobenzoic acid by mammals, which do not make their own dihydrofolic acid, but obtain it in food. Pathogenic bacteria, on the other hand, cannot absorb preformed dihydrofolic acid (Wood, Ferone and Hitchings, 1961), and hence are vulnerable to the sulfonamides which prevent them from synthesizing it. 

Sulfapyridine (Ewins and Phillips, 1939), the first heterocyclic-substituent-type sulfonamide, was soon superseded by sulfathiazole, which was in turn displaced by the three more selective sulfapyrimidines shown in Table 2.5 these, by 1942, were widely accepted as the most useful and innocuous of the sulfonamides for oral use in a wide variety of severe bacterial infections. 

At the present time, the largest use of sulfonamide antibacterials is as urinary antiseptics, e.g. those caused by E. coli and Proteus mirabilis. They are also used in treating nocardiosis (of lungs or foot), trachoma (eye), lymphogranuloma venereum, dermatitis herpatiformis, and valued for the prophylaxis of streptococcal infections in those prone to them, and in preventing recurrence of rheumatic fever. 

The antibacteri il sulfonamides fall mainly into two classes, (a) those that are eliminated fairly rapidly and (b) those that maintain a high blood-concentration for a long time. Of class (a), the most used are  

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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. 

For a displacement interaction to become clinically important, a second mechanism usually operates sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Similarly aspirin and probenecid (and possibly other nonsteroidal anti-inflammatory drugs) displace the folic acid antagonist methotrexate from its protein-binding site and reduce its rate of active secretion by the renal tubules the result is serious methotrexate toxicity. 

If the intent is to develop a complete a priori description, the pharmacokinetics must be included. Several relevant studies have been done for some of the commonly used cancer chemotherapeutic agents two are described here. The first is the folic acid antagonist, methotrexate (MTX) the second is cytosine arabinoside (ARA-C). Both are active against leukemia, which is of primary interest here. 

Pteridines are also used as pharmaceuticals. Triamterene 15 is a diuretic that promotes excretion of Na" and retains K+. The folic acid antagonist methotrexate 16 (amethopterin) is of considerable importance as an antineoplastic agent in cancer chemotherapy. 

Enzymes, their substrates and other metabolites. 289 Metabolite analogues definition, derivation, and mode of action. 295 History of metabolite antagonism prior to 1940. 302 The folic acid antagonists. 303... 

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. 

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). 

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. 

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 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. 

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... 

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