Methotrexate folic acid

In view of the importance in biochemical processes of pteridines such as folic acid, methotrexate, L-biopterin, and leucettidine <1996CHEC-II(7)679>, synthetic routes to fused pteridines continue to occupy considerable attention. Imidazo-fused pteridines have now been prepared from 3-aminopyrazine-2-carboxamides via carbodiimide intermediates. If the amido-nitrogen in the starting compound is further substituted, as in the scheme, the... 

The main folate antagonist is methotrexate, an analogue of folic acid. Methotrexate competitively inhibits dihydrofolate reductase, the enzyme responsible for the synthesis of purine and pyramidine from folic acid. Trimetrexate, a methotrexate analogue, is useful in treating methotrexate-resistant tumours. It is also used to treat Pneumocystis carinii infections. Methotrexate is usually given orally, but may also be given intravenously or intrathecally. In addition to its use in cancer therapy, it is used in the treatment of psoriasis. Methotrexate can cause an obstructive nephropathy due to its precipitation in the renal calyx. 

Because of its close structural similarity to folic acid, methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase. (Recall that this enzyme converts folic acid to its biologically active form, THF.) Rapidly dividing cells require large amounts of folic acid. Methotrexate prevents the synthesis of THF, the one-carbon carrier required in nucleotide and amino acid synthesis. It is therefore toxic to rapidly dividing cells, especially those of certain tumors and normal cells that divide frequently such as hair and GI Tract cells. 

The antimetabolites are structurally similar to endogenous compounds and are antagonists of folic acid (methotrexate), purines (mercaptopurine, thioguanine), or pyrimidines (fluorouracil, cy-tarabine). Antimetabolites are CCS drugs acting primarily in the S phase of the cell cycle. Their sites of action on DNA synthetic pathways are shown in Figure 55-3. In addition to their cytotoxic effects on neoplastic cells, the anti metabolites also have immunosuppressant actions. Some of the uses of the antimetabolites in neoplastic disease are listed in Table 55-2. 

Several anticancer drugs contain the pyrimidine ring. An early drug, still in use today is methotrexate, which acts by inhibiting the formation of folic acid. Methotrexate is also used to treat rheumatoid arthritis. For... 

Figure 42 Multifunctional PAMAM dendrimer as drug-delivery agent composed of folic acid, methotrexate, FITC, and acetyl- and Tris-capped NH2...

Methotrexate — see Folic acid, 4-amino-4-deoxy-10-methyl-... 

Methotrexate belongs to the class of antimetabolites. As a derivative of folic acid it inhibits the enzyme dihydrofolate reductase resulting in a decreased production of thymidine and purine bases essential for RNA and DNA synthesis. This interruption of the cellular metabolism and mitosis leads to cell death. 

Methotrexate 7.S-20 mg once weekly Oral or IM 4-8 weeks N, D, hepatotoxicity, alopecia, new-onset cough or SOB, MYL CBC, creatinine, LFTs q 4-8 weeks Monitor for signs of infection Concomitant use of folic acid Avoid alcohol Use contraception if childbearing potential... 

Cardiovascular Keep doses of NSAIDs and glucocorticoids low, consider initiation of folic acid to reduce homocysteine level elevations induced by methotrexate, consider initiation of low-dose aspirin and/or HMG-CoA reductase inhibitors (statins), and encourage smokers to discontinue tobacco use and assist with the development of a tobacco-cessation plan.11,12... 

Methotrexate, an antimetabolite, is indicated for moderate to severe psoriasis. It is particularly beneficial for psoriatic arthritis. It is also indicated for patients refractory to topical or UV therapy. Methotrexate can be administered orally, subcutaneously, or intramuscularly. The starting dose is 7.5 to 15 mg per week, increased incrementally by 2.5 mg every 2 to 4 weeks until response maximal doses are approximately 25 mg/wk. Adverse effects include nausea, vomiting, mucosal ulceration, stomatitis, malaise, headache, macrocytic anemia, and hepatic and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by giving oral folic acid 1 to 5 mg/day. Methotrexate should be avoided in patients with active infections and in those with liver disease. It is contraindicated in pregnancy because it is teratogenic. 

An electron impact mass spectrum of calcium leuco-vorin has not been obtained because the compound is not sufficiently volatile. It would be difficult to isolate the free acid without first dehydrating the compound. Due to its ionic nature, calcium leucovorin will not dissolve in common silylating reagents. Field desorption, another mass spectral technique, generally lends itself more to compounds like leucovorin. Indeed, this technique has been applied successfully to methotrexate and other folic acid analogs.1 ... 

Methotrexate Folic acid analog cancer chemotherapy, arthritis Inhibits proliferation T-cell suppression granulocytopenia lymphocytopenia... 

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. 

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 ... 

Q85 Methotrexate is an antimetabolite of folic acid and has immunosuppressant properties. Methotrexate may be used in Crohn s disease. 

Folic acid is used as an adjunct to methotrexate therapy to limit methotrexate-induced side-effects such as mucositis and stomatitis. 

Methotrexate is an antimetabolite of folic acid and has immunosuppressant properties. It inhibits the enzyme dihydrofolate reductase that is required for the synthesis of purines and pyrimidines. It is used in malignant disease, Crohn s disease, rheumatic disease and psoriasis. Folic acid is given with methotrexate to reduce the occurrence of side-effects particularly the risk of mucositis. 

These are pyrimidine derivatives and are effective because of differences in susceptibility between the enzymes in humans and in the infective organism. Anticancer agents based on folic acid, e.g. methotrexate, inhibit dihydrofolate reductase, but they are less selective than the antimicrobial agents and rely on a stronger binding to the enzyme than the natural substrate has. They also block pyrimidine biosynthesis. Methotrexate treatment is potentially lethal to the patient, and is usually followed by rescue with folinic acid (A -formyl-tetrahydrofolic acid) to counteract the folate-antagonist action. The rationale is that folinic acid rescues normal cells more effectively than it does tumour cells. 

Inhibition of nucleobase synthesis (2). Tetrahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 272). The folate analogues aminopterin and methotrexate (ame-thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of iicense. 

Dihydrofolate reductase acts as an auxiliary enzyme for thymidylate synthase. It is involved in the regeneration of the coenzyme N, N -methylene-THF, initially reducing DHF to THF with NADPH as the reductant (see p. 418). The folic acid analogue methotrexate, a frequently used cytostatic agent, is an extremely effective competitive inhibitor of dihydrofolate reductase. It leads to the depletion of N, N -methylene-THF in the cells and thus to cessation of DNA synthesis. 

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. 

In stark contrast, the second historically significant anti-cancer drug, methotrexate, originated from nutritional research. The observation that the vitamin folic acid stimulated prohferation of acute lymphoblastic leukemia (ALL) cells in children prompted synthesis of folate analogues. In the late 1940s methotrexate became the first drug to induce remissions in children with ALL [11]. 

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

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