Folic acid methotrexate reaction

Recently, Choy et al. also reported that LDHs are an efficient drug reservoir for folate derivatives [187]. Folic acid derivatives, folinic acid and methotrexate (MTX), have been successfully hybridized with Mg/Al LDHs by ion-exchange reactions. Cellular uptake tests with the MTX-LDH hybrids were carried out in the fibroblast (human tendon) and osteosarcoma (SaOS-2) cell lines by in vitro assay. They found that the LDH not only plays a role as a biocompatible delivery matrix for drugs but also facilitates a significant increase in the delivery efficiency. 

Trimetrexate (88) Is an antineoplastic agent related to the well-established folic acid antimeta-bolite methotrexate. It can be synthesized by selective diazotization of the most basic amino group of 2,4,6-triamino-5-methylquinazoline (85) followed by a Sandmeyer displacement with CuCN to give nitrile 86. Careful reduction asing Raney nickel produces the aminomethyl intermediate 87 or, if the reaction is carried out in the presence of 3,4,5-triniethoxyaniline, trimetrexate (88) [24]. One presumes that that outcome is a consequence of amine exchange at the partially reduced imine stage and further reduction. 

I I 3. The answer is c. (Hardman, pp 1243-1247.) Antimetabolites of folic acid such as methotrexate, which is an important cancer chemotherapeutic agent, exert their effect by inhibiting the catalytic activity of the enzyme dihydrofolate reductase. The enzyme functions to keep folic acid in a reduced state. The first step in the reaction is the reduction of folic acid to 7,8-dihydrofolic acid (FH2), which requires the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). The second step is the conversion of FH2 to 5,6,7,8-tetrahydrofolic acid (FH ). This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADH) or NADPH. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thymidylate. The affinity of methotrexate for dihydrofolate reductase is much greater than for the substrates of folic acid and FH2. The action of... 

Nausea and mucosal ulcers are the most common toxicities. Progressive dose-related hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (< 1%). Liver toxicity is not related to serum methotrexate concentrations, and liver biopsy follow-up is only recommended every 5 years. A rare hypersensitivity-like lung reaction with acute shortness of breath is documented, as are pseudolymphomatous reactions. The incidence of gastrointestinal and liver function test abnormalities can be reduced by the use of leucovorin 24 hours after each weekly dose or by the use of daily folic acid, although this may decrease the efficacy of the methotrexate. This drug is contraindicated in pregnancy. 

Another group of inhibitors prevents nucleotide biosynthesis indirectly by depleting the level of intracellular tetrahydrofolate derivatives. Sulfonamides are structural analogs of p-aminobenzoic acid (fig. 23.19), and they competitively inhibit the bacterial biosynthesis of folic acid at a step in which p-aminobenzoic acid is incorporated into folic acid. Sulfonamides are widely used in medicine because they inhibit growth of many bacteria. When cultures of susceptible bacteria are treated with sulfonamides, they accumulate 4-carboxamide-5-aminoimidazole in the medium, because of a lack of 10-formyltetrahydrofolate for the penultimate step in the pathway to IMP (see fig. 23.10). Methotrexate, and a number of related compounds inhibit the reduction of dihydrofolate to tetrahydrofolate, a reaction catalyzed by dihydrofolate reductase. These inhibitors are structural analogs of folic acid (see fig. 23.19) and bind at the catalytic site of dihydrofolate reductase, an enzyme catalyzing one of the steps in the cycle of reactions involved in thymidylate synthesis (see fig. 23.16). These inhibitors therefore prevent synthesis of thymidylate in replicating... 

Aminopterin and amethopterin (methotrexate) are 4-amino analogues of folic acid (Fig. 11.3) and interfere with the production of the active folate coenzyme by blocking the enzyme dihydrofolate reductase (reaction b in Fig. 13.1) (see also Fig. 11.6). 

Methotrexate [meth oh TREX ate] (MTX) is structurally related to folic acid and acts as an antagonist of that vitamin by inhibiting dihydrofolate reductase1, the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4) it therefore acts as an antagonist of that vitamin. Folate plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units. (Figure 38.7)2. 

A review of the literature shows that photochemical reactions generally follow first-order kinetics. However, pseudo first-order, zero-order, and even fractional-order kinetics have been reported. Drugs reported to follow first-order kinetics include nifedipine (8) doxepin (41), riboflavin (28), minoxidil (48), adriamycin (52), doxorubicin, daunorubicin and epirubicin (61), folic acid (66), menadione sodium bisulfite (67), tetracycline hydrochloride (71), decarbazine (73), furosemide (74), democlocycline (76) and hydrocortisone, and prednisolone (90). Apparent pseudo first-order rate has been reported for pyridoxine (84). Indomethacin (91), sodium nalidixate (65), methotrexate (92), and metronidazole (68) have been reported... 

Adverse reactions. Methotrexate is the best tolerated of the DMARDs and more than half of the patients who corrunence are still taking the drug more than 5 years later. Nausea and mouth ulcers are reduced or eliminated by the addition of folic acid. Transient elevation of the hepatic transaminases is... 

Drugs. Antiepilepsy drugs, particularly phenytoin, primidone and phenobarbital, occasionally cause a macrocytic anaemia that responds to folic acid. This may be due to enzyme induction by the antiepileptics increasing the need for folic acid to perform hydroxylation reactions (see Epilepsy) but other factors such as reduced absorption may be involved. Administration of folic acid causes a recurrence of seizures in some patients. Some anti-malarials, e.g. pyrimethamine, may interfere with conversion of folates to the active tetrahydrofolic acid, causing macrocytic anaemia. Methotrexate, another folate antagonist, may cause a megaloblastic anaemia especially when used long-term for leukaemia, rheumatoid arthritis or psoriasis. 

Dihydrofolate reductase (DR) is showm near the top of Figure 9.6, This enzyme catalyzes the reduction of Hjfolate to H folate. DR is part of the cycle of reactions in the synthesis of thymidylic acid. The enzyme also catalyzes the reduction of folic acid to dihydrofolic acid and then to EclrahydrofoJic acid, DR is the target of the anti cancer drug methotrexate (MTX), MTX exerts its toxic effects more nn rapidly... 

Methotrexate is a folic acid antagonists that indirectly suppresses the synthesis of purine and is particularly effective in rapidly proliferating cell populations such as cancer. It depresses the primary and secondary antibody response, the homograft reaction, the graft-versus-host response, and the development of hypersensitivity. Methotrexate is used in the treatment of certain cancers. It is very toxic in long-term use, especially to the liver. The toxic effect of methotrexate is reversed by use of... 

Many other examples of this concept exist. A recent example is methotrexate, a derivative of folic acid that has been used successfully in treating certain carcinomas as well as rheumatoid arthritis. Just as in the case above, methotrexate, because of its resemblance to folic acid, can enter into some of the same chemical reactions as folic acid, but it cannot ultimately serve the same inherent biological function. Here that role is involvement in reactions critical to cellular division. Although methotrexate is toxic to all dividing cells, those cells that divide most rapidly—cancer cells—are most vulnerable to its effect. 

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